Enhanced drug delivery in transdermal systems

专利摘要:
The composition for transdermal administration resulting from the mixture may comprise a therapeutically effective amount of a drug, including a parent drug and a prodrug; And pharmaceutically acceptable carriers, wherein said parent drug and prodrug are individually present in an amount sufficient for pharmacological effect. In a preferred embodiment, the mixture is a steroid and a steroid derivative of interest; And a therapeutically effective amount of a pharmaceutically active agent, including a carrier for the pharmaceutically active agent. The steroid and the corresponding steroid derivative are present in the weight ratio of steroid: the steroid derivative of 10: 1 to 1:10. In a preferred embodiment the ratio is from 6: 1 to 1: 6. In a preferred embodiment, the steroid derivative is a steroid ester. In another preferred embodiment, the carrier is a polymer comprising a pressure sensitive adhesive. In another embodiment, the parent drug is an ACE inhibitor such as ramipril and the prodrug is an ACE inhibitor prodrug such as ramipril ethyl and / or methyl ester.
公开号:KR20040010747A
申请号:KR10-2003-7016576
申请日:2002-06-18
公开日:2004-01-31
发明作者:하우즈데이비드；엔규옌비에트
申请人:노벤 파머수티컬즈, 인코퍼레이티드；
IPC主号:

专利说明:

ENHANCED DRUG DELIVERY IN TRANSDERMAL SYSTEMS
[2] Use of transdermal drug delivery systems, for example, pressure sensitive adhesives containing drugs as a means for administering a therapeutically effective amount of a medicament, is known. Such known delivery systems include incorporation of the drug into a carrier or other form of carrier, such as a polymer and / or pressure sensitive adhesive formulation of the drug. The pressure sensitive adhesive must effectively adhere to the skin and move the drug from the carrier through the skin into the patient's blood stream.
[3] In particular, steroids such as estradiol and noethynedrone are particularly well known for their use in transdermal drug delivery systems as hormone replacement therapy. These steroids are from Miami Noven Pharmaceuticals, Inc. It may be administered alone, such as the estradiol transdermal drug delivery system sold under the trademarks Vivelle® and Vivelle-Dot® manufactured by. See US Pat. No. 6,221,383. As an alternative, the two or more steroids are Noven Pharmaceuticals, Inc. It may be administered together as estradiol / norethedrone acetate transdermal drug delivery system sold under the trade name CombiPatch (R). See US Pat. No. 6,221,383. See US Pat. No. 5,474,783.
[4] Transdermal drug delivery systems with one or more drugs are generally more difficult to formulate in terms of different interactions from each drug and other drugs present, such as carriers, excipients, and the like. In addition, government agencies that regulate pharmaceutical products, such as the US FDA, require additional testing of multiple drugs, alone and together, to assure efficacy. Thus, when drugs such as steroids are administered, they are generally administered only in their own form (eg noethyne drone or noethyne drone acetate). See, eg, US Pat. No. 6,149,935.
[5] The use of steroids as additives to act as crystallization inhibitors in transdermal drug delivery devices wherein the drug is a hormone is described in WO 99/15156. WO 99/15156 teaches that the device is present in an amount insufficient to provide a significant pharmaceutical or physiological effect. Other patents include US Pat. No. 5,633,242; 4,906,169; 5,711,962; 6,153,216; 5,898,032; 5,811,117; And 6,024,974.
[6] One problem with the delivery of drugs such as steroids from the transdermal drug delivery system is the rate of drug release from the transdermal system (commonly referred to as "flux" or "permeation rate"). In particular, there are a variety of applications where it is desirable to have a larger flux of drug (eg steroid) from the system. There are also a number of applications where it is desirable to have a reduced flux of drugs (eg steroids) from the system. In other words, one problem in transdermal drug delivery is in controlling the blood profile level of the drug by controlling the delivery of the drug from the composition to the bloodstream of the sample through the skin.
[7] One known method for selectively controlling the rate of penetration of drugs from transdermal compositions is described in US Pat. No. 5,474,783, assigned to the assignee of the present invention. In this patent, two or more polymers are used in the formulation for adjusting the solubility of the drug in the carrier system. Controlling the rate of penetration is generally well done, but it is always desirable to control the rate of penetration of the drug in the desired manner to ensure longer or shorter duration of drug delivery and to increase the therapeutic effect or delay the onset of symptoms. It is not easily possible.
[8] Another problem with drugs, in particular steroid delivery, is the tendency for drugs (eg steroids) to crystallize in carriers of the transdermal system. This results in less steroids being useful for transdermal administration. Although addition of solubilizers, such as agents such as PVP, aids in the inhibition of crystallization, there are applications where it is desirable to have a greater crystallization effect.
[9] U.S. Patent 6,368,616 discloses two-phase (water and oil) liquid compositions comprising at least: (A) NSAID; (B) alcohol (defined as melting point depressant, column 4, line 60); (C) water; And optionally (D) a second melting point depressant. The composition is described as having two phases with a solvent almost melted at 25 ° C. "Second melting point depressant" referred to in the '616 patent is defined as a solvent, reinforcing agent, adjuvant or drug such as anesthetic or NSAID.
[10] U.S. Patent 4,529,601 discloses a combination of two different local anesthetic drugs that melt together at room temperature. Preferable melting point is less than 40 degreeC, More preferably, it is less than 25 degreeC.
[1] The present invention relates to a transdermal drug delivery system. In particular, the present invention relates to transdermal drug delivery systems for delivering a therapeutically effective amount of a drug, including a parent drug and a prodrug. In particular, the present invention relates to transdermal drug delivery systems for the delivery of steroids and methods of making and using the same.
[111] BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a graph showing drug flux from a composition containing noethine drone acetate and estradiol, and a composition containing nohetine drone / norethine drone acetate and estradiol.
[112] Figure 2 is a combination of noethine drone acetate and noethine drone from a composition containing noethine drone acetate and estradiol, noethine drone / norethine drone acetate and no northine drone / norethine drone acetate, and It is a graph showing the flux of noethine drones from the composition containing ethyne drone and estradiol.
[113] FIG. 3 shows the drug flux of the combined testosterone / testosterone acetate from the composition containing testosterone / testosterone acetate, the testosterone acetate flux from the same composition, the testosterone flux from the same composition, Testoderm (R). Is a graph showing the flux of testosterone from the transdermal drug delivery system called).
[114] 4 is a graph showing drug and prodrug theoretical permeation from a single transdermal composition containing the parent drug and two prodrugs.
[115] 5 shows the cumulative permeation of norepinephrine for the parent drug / prodrugs of various combinations.
[116] 6 shows the cumulative permeation of norepine drone acetate for the parent drug / prodrugs of various combinations.
[117] 7 shows the compound cumulative permeation of norepine drone and norepin drone acetate for various combinations of parent drug / prodrugs.
[118] 8 shows the cumulative transmission of ramipril and its prodrugs.
[119] 9 shows cumulative permeation of ramipril prodrugs with and without reinforcing agents.
[11] Summary of the Invention
[12] It is an object of the present invention to overcome the disadvantages of the known art described above. It is another object of the present invention to provide a transdermal drug delivery system with increased control over the rate of penetration of the drug, signs of drug effect and / or duration of delivery and / or regulation of drug effect. Another object of the present invention is to provide a transdermal drug delivery system with improved flux of steroids compared to systems of the same size. Another object of the present invention is to provide a composition with reduced or no crystal formation in a transdermal drug delivery system.
[13] In achieving the foregoing and other objects, according to one aspect of the present invention there is provided a composition, preferably a skin composition, produced from a mixture comprising: a therapeutic of a drug comprising a parent drug and a prodrug Effective amount; And as a pharmaceutically acceptable carrier, the parent drug and the prodrug are individually present in an amount sufficient for pharmacological effect. In a preferred embodiment, the composition has a symptom of longer or shorter therapeutic effect than the same composition having pharmacologically equivalent amounts of the parent drug or prodrug alone. In another embodiment, the composition has a blood level profile that is different from an equivalent composition having a pharmacologically equivalent amount of the parent drug or prodrug alone. In another preferred embodiment, the composition has a faster or slower permeation rate than an equivalent composition having a pharmacologically equivalent amount of the parent drug or prodrug alone. In another preferred embodiment, the composition has a longer or shorter therapeutic shelf life than a composition having pharmacologically equivalent amounts of the parent drug alone. In another embodiment, the prodrug is more lipophilic than the parent drug and the prodrug with a greater rate of penetration through the skin. In another preferred embodiment, the melting point of the combined parent drug and prodrug is lower than the melting point of the parent drug or prodrug alone. According to another preferred embodiment, the carrier comprises a pressure sensitive adhesive comprising at least two polymers wherein the permeation of the drug is adapted by changing the type and / or proportion of the at least two polymers.
[14] According to a preferred aspect of the present invention there is provided a steroid derivative that provides a source of steroids and therapeutically active steroids; And a therapeutically effective amount of a pharmaceutically active agent comprising a carrier of the pharmaceutically active agent, preferably a skin composition, wherein the steroid and the steroid derivative are 10: 1 to 1:10. Steroid: Present in weight ratio of steroid derivatives. In a preferred embodiment, the steroid derivative is a steroid ester. In another preferred embodiment the carrier is a polymer comprising a pressure sensitive adhesive.
[15] According to another aspect of the invention, an ACE inhibitor and the corresponding ACE inhibitor prodrug; And a therapeutically effective amount of a drug comprising a pharmaceutically acceptable carrier. Preferably, the ACE inhibitor is ramipril and the prodrug is ramipril methyl and / or ethyl ester.
[16] According to another aspect of the present invention, there is provided a method of preparing the above-mentioned composition comprising forming a mixture of a parent drug and a prodrug (preferably a steroid and the corresponding steroid derivative) and a carrier. Preferably, the carrier is a polymer and the method further comprises forming the mixture into a polymer matrix and drying the polymer matrix to remove volatile solvent to form the composition.
[17] According to another aspect of the invention, the method comprising the steps of applying the aforementioned composition to the skin of an animal or human; And maintaining the composition in contact with the skin for a predetermined time sufficient to administer a therapeutically effective amount of the pharmaceutically active agent.
[18] Further objects, features and advantages of the present invention will become apparent from the following detailed description of preferred embodiments.
[19] Detailed Description of the Preferred Embodiments
[20] The present invention provides, in particular, transdermal drug delivery compositions for administering a therapeutically effective amount of drug by delivery of a combination parent drug and prodrug.
[21] Preferred embodiments of the invention provide particularly transdermal drug delivery compositions for administering therapeutically effective amounts of steroids, in particular transdermal compositions, having a flux greater than known compositions.
[22] As used herein, “transdermal” delivery is delivered to the bloodstream by transdermal (or “through the skin” or “skin”) and transmucosal administration, such as by passing the drug through skin or mucosal tissue. I would like to.
[23] The term "flux" (also called "permeation rate"), as used herein, is defined as the absorption of a drug through the skin or mucous membranes and is described by Fick's first law of diffusion.
[24] J = -D (dCm / dx),
[25] Where J is the flux at g / cm ² / sec, D is the diffusion coefficient of the drug through the skin or mucosa at cm ² / sec, and dCm / dx is the concentration gradient of the drug across the skin or mucosa.
[26] As used herein, "drug" is defined as any therapeutically, prophylactically and / or pharmacologically or physiologically beneficial active ingredient, or mixture thereof, delivered to an organism to obtain a desirable, usually beneficial effect. More specifically, any drug that is capable of producing a local or systemic pharmacological response in a plant or animal, regardless of whether it is essentially therapeutic, diagnostic or prophylactic, is within the concept of the present invention. The drug may be pharmacologically active or may require additional in vivo changes. The term "drug" includes both "parent drug" and "prodrug" as follows. The drug should be used in an amount sufficient to prevent, treat, diagnose or treat a disease or other condition, as the situation requires.
[27] As used herein, "parent drug" is defined as the same as "drug" except that no in vivo transformation is performed that further provides pharmacological activity.
[28] As used herein, a "prodrug" is defined as a less pharmacologically active derivative of a parent molecule that requires spontaneous or enzymatic in vivo transformation in the organism to release a more active parent drug. Prodrugs are variants or derivatives of the parent drug having groups cleavable under metabolic conditions. Prodrugs become pharmacologically active parent drugs in vivo when undergoing solvolysis or enzymatic denaturation under physiological conditions. Prodrugs may be called single, double, triple, etc., depending on the number of in vivo transformation steps required to release the active parent drug in the organic vegetation, and indicate a number of functional groups present in the precursor type form. Prodrugs commonly known in the art include acid derivatives well known to those skilled in the art and include, for example, esters prepared by reaction of suitable alcohols with the parent acid, amides prepared by the reaction of the parent acid compound with the amine, Or a basic group reacted to form an acylatated base derivative. Bundgard, Design of prodrugs pp. 7-9, 21-24, Elsevier, Amsterdam 1985; Silverman, The Organic Chemistry of drug Design and drug Action, pp. 352-401, Academic Press, San Diego, Calif., 1992; and Burger's Medicinal Chemistry and drug Chemistry, Fifth Ed., Vol. 1, pp. See 172-178,949-982 (1995).
[29] As used herein, “pharmacologically equivalent amount” means the amount of parent drug or prodrug that has an equivalent therapeutic effect as the selected combination of parent drug and prodrug.
[30] As used herein, “blood profile level” is generally defined as the concentration of the blood level of the parent drug or prodrug over a selected period from the start of administration.
[31] As used herein, steroids are defined as a group of lipid compounds including sterols, bile acids, cardiac glycosides, saponins, corticosteroid steroids and hormones. The basic structure of a steroid is a known four ring fusion structure.
[32] According to one aspect of the present invention, the inventors have found that the rate of penetration of the blood profile level of a subject to which the drug is administered percutaneously can be more easily controlled by the use of a prodrug combined with the parent drug. By administering the parent drug and the prodrug combination, blood profile levels can be affected by the following two sides: (1) total solubility of the parent drug / prodrug in the carrier; And (2) selection of prodrugs for transporting through the skin and performing metabolism from the body of the sample to the parent drug.
[33] By controlling the total solubility of the parent drug / prodrug in the carrier, the overall saturation concentration of the parent drug / prodrug will be controlled so that the rate of release of the drug from the carrier will be increased and / or decreased. The overall solubility of the parent drug / prodrug in the carrier can be adjusted by adapting the concentrations of the parent drug and the prodrug to each other. This method depends on the different solubility of the parent drug and the prodrug in the composition due to the different polarity of the parent drug and the prodrug and other factors such as hydrogen bonding. Alteration of substituents on the molecule can have a significant effect on solubility. In addition, the use of cosolvents and other solvating agents can be used to adapt the solubility of the parent drug and the prodrugs in the composition.
[34] Another related method for controlling the overall solubility of the parent drug / prodrug concentrate is to select the polymer forming the carrier on the basis of solubility. Selection based on solubility of the polymer in order to optimize the permeation rate of the parent drug / prodrug without prodrugs or parent drug is described in the aforementioned '783 patent (which is incorporated by reference in its entirety). The same principle as to the solubility of the drug in the polymer mixture will also apply to carriers with the parent drug / prodrug combination.
[35] "Mixed" is the absence or little chemical reaction or crosslinking (other than simple H-bonds) between polymers in a polymeric adhesive carrier.
[36] Polymers comprising a multi-polymer adhesive carrier are inert to the drug and are preferably immiscible with each other. Forming a mixture of multiple polymers results in an adhesive carrier having a characteristic "net solubility parameter", the choice of which advantageously allows for selective control of the drug delivery rate by adapting the solubility of the drug in the multi-polymer adhesive carrier.
[37] Solubility parameters (also called "SP") are defined as the sum of all intermolecular attractive forces, which are experimentally related to the degree of mutual solubility of multiple chemical species. General discussion of solubility parameters is described in Vaughan, "Using Solubility Parameters in Cosmetics formulation," J. Soc. Cosmet. Chem., Vol. 36, pages 319-333 (1985). A number of methods have been developed for the determination of solubility parameters from theoretical calculations to full experimental calibration. The simplest method is Hildebrand's method, which calculates solubility parameters from molecular weight, boiling point and density data, which yields values that are commonly available in many materials and generally within the range of other calculation methods.
[38] SP = (△ Ev / V) ^1/2 ,
[39] At this time, V = molecular weight / density and ΔEv = evaporation energy.
[40] As an alternative, SP = (ΔHv / V-RT / V) ^1/2
[41] ΔHv = heat of evaporation, R = gas constant, and T is the absolute temperature ° K.
[42] Since materials such as high molecular weight polymers have too low evaporation pressure to detect, it is not possible to use ΔHv, so several methods have been developed that utilize the sum of the contribution of atoms and groups to ΔHv:
[43] ΔHv = i △ hi,
[44] Δhi is the contribution of each atom or group to the heat of molar evaporation. One conventional method is described in R. F. Fedors, Polymer Engineering and Science, Vol. 14, p. 147 (1974). In this method, ΔEv and V are
[45] ΔEv = i Δei and V = by simply estimating vi, where ΔEi and vi are the contributions of additional atoms and groups to evaporation energy and molar volume, respectively.
[46] Another method of calculating the solubility parameter of a substance is described in Small, J. Applied Chem. Vol. 3, p. 71 (1953).
[47] Solubility parameters of some illustrated adhesive polymers are disclosed in the '783 patent.
[48] The transdermal penetration rate of the parent drug / prodrug formulation is controlled by changing the polymer component of the polymer adhesive carrier to alter the difference in solubility parameters of the multipolymer adhesive carrier relative to the parent drug / prodrug formulation.
[49] Transdermal penetration rates can also be controlled by varying the relative proportions of the polymer comprising the polymer adhesive carrier.
[50] The polymeric adhesive carrier is preferably formulated to be a pressure sensitive adhesive at room temperature and have other desirable features of the adhesive used in transdermal drug delivery techniques; Such features include good adhesion to the skin, the ability to peel off or remove without substantial trauma to the skin, and retention of viscosity with age. In general, the multi-polymer adhesive carrier should have a glass transition temperature (Tg) measured between about −70 ° C. to 0 ° C. using a differential scanning calorimeter.
[51] The choice of particular polymer composition is largely governed by the parent drug / prodrug to be incorporated in the device as well as the desired rate of parent drug / prodrug delivery. One skilled in the art can readily determine the rate of delivery of the drug from the polymeric transdermal adhesive carrier to select the appropriate combination of polymer and drug for the particular application. Various techniques can be used to determine the rate of delivery of the drug from the polymer. By way of example, the delivery rate can be determined by measuring drug movement from one chamber to another through the body skin over time and calculating the drug delivery or flux rate from the data obtained. Specific polymers, preferred acrylic and silicone based polymers are described below.
[52] Other methods for controlling the plasma profile of a sample include, for example, the selection of prodrugs based on molar molecular weight or polarity. By increasing the molecular weight of the prodrug, the time to effective sign of prodrug penetration will be increased compared to the parent drug. One example of this effect is the use of noethine drone and noethine drone acetate. The rate of permeation of noethine drone rises rapidly after application, while the high molecular weight noethine drone acetate reaches its maximum after the rate of noethine drone starts to decrease. See, eg, FIG.
[53] In this regard, as the molecular weight of the prodrug increases, the rate of penetration of the prodrug will be slower than the parent drug. In conclusion, increasing the concentration of high molecular weight prodrugs can compensate for the decrease in permeation rate of the parent drug, where continuous drug delivery over time is desired.
[54] Of course, it can be seen that there is some degree of correlation between the two large concepts described above. For example, molecular weight can affect both the amount of prodrug that can dissolve in the carrier as well as the movement through the skin.
[55] Another parent drug / prodrug formulation method for controlling blood profile levels is by the selection of prodrugs based on different polarities. As described in co-pending application No. 10 / 014,785, more lipophilic prodrugs promote the introduction of prodrugs into the stratum corneum of the complete skin of the sample, where the prodrugs are pharmacologically active and more polar parent drug. Is considered to be fully hydrolyzed. Hydrolysis from the blocked functional groups of the prodrug to the functional groups in the parent drug in turn accelerates the diffusion of the drug through the skin into the sample's blood. That is, initially lipophilic prodrugs are attracted to the lipophilic stratum corneum at a faster rate than the parent drug. During travel through the skin, prodrugs are reverse hydrolyzed into at least some parent drug. When hydrolysis occurs, the more polar parent drug is released from the lipophilic skin into the relatively polar blood stream. Thus, by selecting prodrugs on the basis of polarity, the rate of penetration across the skin is controllably increased relative to the parent drug. Thus, by using prodrugs in addition to the parent drug, the composition will provide faster penetration rates and indications.
[56] In addition, the signs and duration can also be controlled by the use of prodrugs due to the fact that systemic metabolism of the parent drug may be reduced due to the use of the prodrugs. In general, see Bundgaard. That is, the selection of appropriate prodrugs allows for longer effective treatment periods when the rate of in vivo conversion to the active parent drug itself is involved. While simultaneous administration of prolonged active prodrugs occurs, the initial dose may be introduced as the active parent drug itself. Prodrugs that are active for a long time will be metabolized for a period of days to weeks, for example, to maintain therapeutic levels of the active parent. Commercially available long-acting esters include haloperidol decanoate (Haldol®) and testosterone enanthate (Delatestryl®). Parenteral administration of these molecules will delay the therapeutic level of the parent drug for 2-4 weeks. Similar long-term active effects would be expected in transdermal drug delivery.
[57] The inventors have discovered that the inventive formulation of the parent drug and the prodrug can affect the melting point and thus affect the crystallization of the parent drug / prodrug combination in the carrier. The possibility of high drug loading on transdermal platforms without crystallization is indicated by a number of factors. Among them are drug functionality (acidic, basic), lack of drug polarity or polarity, selection of solvents, matrix polymers and other excipients. Typically, solvents, polymers, and excipients are used in many combinations to optimize transdermal drug delivery of certain drugs.
[58] The melting point of a pure drug is constant in STP and must be a constant lot to be pharmaceutically acceptable as a raw material. The inventors have found a pharmaceutically acceptable method of reducing the purity of a given drug (and thus lowering its melting point) while still using a parent drug / prodrug combination while still having a pharmacologically equivalent effect. The two compounds interact to produce a mixture that exhibits a lower initial melting point than each individual compound. This low melting point parent / prodrug formulation substantially enhances the rate of penetration when properly introduced into the transdermal platform. This enhancement is mainly due to the increased non-crystallized drug loading possible with the mixture. Observation shows that (a) increased drug flux using the parent / prodrug mixture fluxes individually than each (Figure 7) (b) increased permeation of the parent is achieved by increased loading of the prodrug ( 5 and 6).
[59] The use of prodrugs to enhance drug permeation is preferred for incorporation of small molecule enhancers such as ethanol, flohydric alcohol or terpenes, as these prodrugs also contribute to achieving delivery of therapeutically effective doses. Moreover, the use of prodrugs rather than small molecule reinforcements may reduce or eliminate the inconvenience, stability and processability problems associated with such reinforcements when making transdermal systems.
[60] The melting point drops of various combinations of noethine drone and noethine drone acetate and estradiol and estradiol prodrugs are shown in Tables I and II. The indicated amounts of parent drug and prodrug were mixed by sieving the crystalline powder drug through a 250 micron screen. Samples of each mixture were placed in capillaries and melting point measurements were performed using a Haake melting point instrument according to USP Reference Standards. Optimal drop in melting point range is observed when the amount of prodrug exceeds the amount of parent drug, but shows a lowered melting point when compared to samples of individual compounds at all ratios.
[61] Noethine drone Noethyne drone acetate Initial melting point ℃ Final melting point ℃ 40 mg 40 mg 146 183 20 mg 40 mg 147 174 20 mg 60 mg 146 171 20 mg 80 mg 146 155 10 mg 90 mg 147 154 40 mg 20 mg 147 191 80 mg 20 mg 148 197 90 mg 10 mg 152 202 50 mg 0 mg 206 209 0 mg 50 mg 163 166
[62] Similar experiments were performed using estradiol and some of its corresponding prodrugs in a 1: 1 ratio. The results show a drop in melting point range, as shown in Table II. The use of low melting estradiol prodrugs seems to lower the estradiol melting point.
[63] compound Melting Point Range ℃ Estradiol 177 Estradiol 17-enanthate 94-95 Estradiol 17-acetate 220-222 Estradiol: estradiol 17-enanthate 88-129 Estradiol: estradiol 17-acetate 162-200
[64] The melting point drop is achieved by combining the parent drug and the prodrug, and this phenomenon seems to explain the crystal inhibition in the transdermal formulation platform. Testing of melting point interactions of two or more formulated drugs themselves provides an improved method of predicting and achieving drug decision inhibition. Also, since the number of solubility parameter determinants is much larger and often somewhat difficult to define, melting point interaction is a simpler method than observing solubility parameter crystallization. Thus, the melting point measurement will provide another tool for determining the desired drug formulation and then testing the performance of skin penetration on the appropriate matrix platform.
[65] The most useful prodrugs are the ones that have the lowest melting point of the parent drug / prodrug combination. A parent / prodrug combination that exhibits a high melting point (individually rather than the lowest melting point) would be particularly useful for controlling the rate of penetration that would otherwise be too high or too fast, or depletion of the drug before the end of a period of time.
[66] This will be particularly important for the formation of the next generation of transdermal drug delivery systems (especially in hormone replacement therapy) that are needed to deliver therapeutically effective amounts of drugs over a period of up to one week or several weeks. In order to achieve prolonged delivery, increased drug concentration is usually required but then the problem of crystallization is increased. Determination of the melting point of the parent drug / prodrug combination will provide a method and means of optimizing and controlling the rate of penetration.
[67] The result of the melting point effect on crystallized drug combinations (eg, parent drug and prodrugs) suggests that a preferred embodiment of the present invention will use prodrugs having a lower melting point than the parent drug.
[68] Particularly useful drug combinations include steroids and their corresponding prodrugs, such as the steroids described herein. Estradiol enanthate and estradiol propionate have been found to be preferred in combination with estradiol to estradiol acetate. Testosterone enanthate in combination with testosterone is preferred over testosterone propionate. Other useful drugs include ramipril and its prodrugs, specifically ACE inhibitors such as ramipril methyl ester and ramipril ethyl ester. In a typical invention, the weight ratio of parent drug to prodrug is 10: 1 to 1:10. The more preferable ratio is 6: 1 to 1: 6, and more preferably 1: 3 to 3: 1.
[69] In a particularly preferred aspect of the invention, the parent drug is ramipril and the prodrug is ramipril methyl ester and / or ramipril ethyl ester. Consistent with the present invention, Applicants have found that using ramipril as one of its prodrugs, in this case methyl or ethyl esters, provides an altered flux (in this case, increased flux) compared to the parent drug or prodrug alone. It was. The use of methyl esters together with the parent drug ramipril is preferred because it provides greater flux than ethyl esters. The preferred weight ratio of ramipril to ramipril methyl ester is generally from 2: 1 to 1: 9. The preferred weight ratio of ramipril to ramipril ethyl ester is generally from 1: 1 to 1: 5, more preferably from 1.1: 1 to 1.1: 5.
[70] In a particularly preferred aspect of the invention, the parent drug is a steroid and the prodrug is a corresponding steroid derivative. Steroids having free hydroxyl groups at positions on the steroid ring, such as the 17-, 3- or 11-positions of the fused ring, are useful in this aspect of the invention. Especially preferred are hormones such as estrogen, progestin and androgen. The steroid prodrug (called a steroid derivative in this embodiment) is defined as the corresponding structure for the steroid where the free hydroxy at the 3, 11 or 17 position reacts with the alcohol reaction site. Especially preferred are steroid derivatives reacted at position 17. Regardless of whether the steroid or its steroid derivative is incorporated into the carrier composition as a dominant drug, each provides a source of steroid in the blood stream so that the intended physiological effect occurs through metabolic conversion of the derivative in the case of that steroid derivative. To achieve.
[71] Steroid esters are the corresponding structures of steroids in which free hydroxy groups are esterified on the ring. Examples of steroids and their esters include estradiol and estradiol benzoate, estradiol 17-beta cypionate, estradiol 17-propionate, estradiol hemisuccinate (utocol), estradiol enanthate, estra Diol undecylate, estradiol acetate, and estradiol propionate. Other examples include testosterone and its corresponding testosterone esters such as 17 meta-sipionate, testosterone enanthate, testosterone nicotinate, testosterone phenylacetate, testosterone proprionate and the like. Also included are non-esters having groups on the 17 position, such as testosterone 17-chloral hemiacetal, or ethers having groups on the 3-position, such as estradiol 3-methyl ether.
[72] Other steroids that may be used are, for example, allylestrenol, anageston, desogestrel, dimethosterone, dydrogesterone, etisterone, ethinodiol, gestodene, haloprogesterone, 17-hydroxy- 16-methylene-progesterone, 17.alpha-hydroxyprogesterone, linestrenol, hydroxyprogesterone, melengestrol, noethynedrone, noethinodrel, norgestosterone, norgestinate, norgestrel, Progestins, such as norgestrienone, norbinisterone, pentagestrone, and trigesterone.
[73] Anabolic steroids include androisoxazole, androstenediodol, bolandiol, bolosterone, clostebol, ethylrestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methanedriol, methenolone And methyltrienolone, nandrolone, norvoletone, oxymesterone, stenbolone and trenbolone. Androgen steroids include boldenone, fluoxymesterone, mestanolone, mesterolone, methanedrostenolone, 17-methyltestosterone, 17.alpha-methyltestosterone 3-cyclopentyl enol ether, noethanendrolone, normethaneron And oxandrolone, oxymesterone, oxymetholone, prasterone, stanrolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal and thiomesterone.
[74] Estrogens can include conjugated estrogen hormones, equilenin, equilin, estradiol, estradiol benzoate, estradiol 17. beta-cypionate, estradiol, estrone, ethynyl estradiol and mixtures thereof.
[75] Additional steroids include 21-acetoxyprefenenone, alclomethasone, algstone, amicinolone, beclomethasone, betamethasone, budesonide, chloroprednisone, clobetasol, blobetason, clocortolone, clofred Knoll, Corticosterone, Cortisone, Cortibazole, Deplazacort, Desonide, Desoxymethasone, Dexamethasone, Diflorason, Diflucortolone, Diflufredonate, Enoxolone, Fluazacort, Flu Chlorolide, Flumethasone, Flunisolidide, Fluorcinolone acetonide, Fluorcinolone, Fluorocortin butyl, Fluorocortolone, Fluorometholone, Fluperolone, Flufrednidene, Fluprednisolone, Fluandrenolide , Formocortal, hacinononide, halomethasone, halopredone, hydrocortamate, hydrocortisone, marzipridone, medridone, mefrednisone, methiol prednisolone, mome May be a glucocorticoid, such as hand-furoate, the parameters in hand, Fred carboxylic your bait, prednisolone, prednisone, Kirkwall, Fred, Fred alkylpiperidinyliden, thixotropic de Cortez and triamcinolone.
[76] Mineral corticoids such as aldosterone, deoxycorticosterone and fludrocortisone.
[77] In known devices, the steroid derivatives of interest are administered in the light of crystallization problems arising from the use of non-derived steroids. The inventors have found that synergistic effects in flux as well as a decrease in crystallization are observed when steroids are administered with the steroid derivatives in question. That is, the flux from the combination of steroids and steroid derivatives is greater than the same amount of flux of the steroid or steroid derivative alone. For example, in a system containing estradiol and noethine drone acetate, the addition of noethine drone and the reduction of the amount of noethine drone acetate so that the blending amount is the same as the original amount of noethine drone acetate are noethine drone / norethine Enables increased delivery of drone acetate.
[78] Another unexpected advantage of the present invention is that the total amount of steroid / linked steroid derivative delivered in the system is significantly greater than the amount of drug from the steroid or a composition containing only that steroid derivative. For example, the Applicant has found that, in compositions containing both noethine drone and noethine drone acetate, the total amount of steroid delivered from the system is 65% larger than the system containing only comparable amounts of noethine drone acetate. It was.
[79] In order to achieve this synergistic effect, the weight ratio of steroid / the steroid derivative is important. Preference is given to a ratio of the range of steroids from 10: 1 to 1:10 to the corresponding steroid derivative. A more preferred ratio is in the range of 6: 1 to 1: 6 steroids: the corresponding steroid derivatives. The rate of providing greater synergy depends on the pharmaceutically active agent in the system. For example, in administration of the steroids and steroid derivatives alone, larger amounts of steroids produce the greatest synergy compared to the steroid derivatives. In this embodiment, the preferred ratio is 1: 1 to 3: 1, more preferably 3: 2 to 5: 2, even more preferably about 2: 1. However, when additional steroids are present (eg estradiol), the opposite ratio provides the greatest synergy. In this embodiment, the preferred ratio is steroid: the corresponding steroid derivative is 1: 1 to 1: 3, more preferably 2: 3 to 2: 5, and even more preferably 1: 2. Any ratio that provides a synergistic flux is within the scope of the present invention.
[80] Moreover, the combination of steroid derivatives also has been found to inhibit the crystallization of drug species in transdermal carrier compositions, where any derivative has been found to work better than another. As shown in Table III, the addition of estradiol methyl ether to estradiol acetate in transdermal carrier compositions significantly improved crystal inhibition, while the combination of estradiol acetate and estradiol propionate showed no improvement at the tested concentrations. Do not. The Example observed the crystal formation under a microscope using a viewing field of 38.5 mm ² after 2 weeks at 25 ° C., 65% -70% relative humidity.
[81] % ingredient Example A Example B Example C Example D Example E Estradiol acetate 3 - - 3 3 Estradiol propionate - 3 - 3 - Estradiol methyl ether - - 3 - 3 Acrylic Adhesive (GMS 788) 5 5 5 5 5 Oleyl alcohol 6 6 6 6 6 Dipropylene glycol 9 9 9 9 9 Silicone Adhesive (BIO-PSA-7-4603) 75 75 75 72 72 Polyvinylpyrrolidone (KOLLIDON-30) 2 2 2 2 2 Crystal formation ≥100 Long branched chain crystal none Branched crystals ≤2
[82] Determination of steroid derivatives that work better than others when combined with steroids or other steroid derivatives can be determined through routine experimentation using the present specification as a guide.
[83] The following detailed description is generally set forth in the context of parent drug / prodrugs. The same applies to the preferred embodiments of the steroid / steroid derivatives described above.
[84] The amount of parent drug / prodrug present in the composition can vary widely and depends on a number of factors such as the carrier, the length of administration, the desired therapeutic effect, and the like. The minimum amount of parent drug / prodrug in the system is selected based on the amount of parent drug / prodrug that passes through the skin for the time for the composition to be provided for treatment. Typically, the amount of parent drug / prodrug in the composition may vary from 0.1 to 50% by weight, preferably low steroids / the corresponding steroid derivatives are allowed by the present invention in the range of about 0.3 to 20% by weight. Other possible ranges may include 0.1 to 10 weight percent or 0.1 to 6 weight percent.
[85] The drug is present in the carrier. As used herein, “carrier” or “vehicle” is referred to as a carrier material suitable for transdermal drug administration, and any material known in the art, such as any liquid, gel, solvent, liquid diluent, solubilizer, Polymers, and the like, which are nontoxic and do not react significantly with the skin or other ingredients of the composition in a detrimental manner. The carrier is present in an amount sufficient to achieve its function of carrying the parent drug / prodrug. Preferably the carrier is present in an amount in the range of 2 to 99% by weight, more preferably in an amount of 30 to 90% by weight, even more preferably in an amount of 40 to 80% by weight. The carrier preferably has little water and more preferably contains no water.
[86] Particularly preferred carriers are flexible, limiting compositions. The phrase “flexible confinement system” refers to surfaces and contacts that are capable of maintaining contact in solid form to facilitate topical application without physiological adverse reactions and without significant degradation by aqueous contact during administration to the patient. It is intended to mean a solid form that is compatible with the surface. Particularly preferred flexible confinement systems are polymer carriers, such as pressure sensitive adhesive matrix types, in which the parent drug / prodrug is dispersed directly in the pressure sensitive adhesive or reservoir type carrier.
[87] Examples of suitable adhesives as the matrix type flexible confinement delivery system include those described in US Pat. Nos. 5,474,783 and 5,656,386, both of which are incorporated by reference to Noven Pharmaceuticals, Inc., Florida, Miami, and incorporated herein by reference. Cited. Other flexible confinement systems known in the art include films, plasters, dressings, and bandages, as well as multilayer delivery systems in which the parent drug / prodrug is solubilized or contained in one or more separation layers, and the drug / prodrug is applied to the skin or mucosa. And a reservoir type delivery system solubilized or contained within a reservoir or depot separate from an adhesive attached directly to the adhesive.
[88] As mentioned above, particularly preferred carriers are pressure sensitive adhesive flexible defined carriers. They can include any viscoelastic material that adheres immediately to most substrates with very light pressure and remains viscous forever. A polymer is a pressure sensitive adhesive that falls within the meaning of the term as used herein as long as it serves as a pressure sensitive adhesive as a mixture with a tackifier, plasticizer or other additive or has the properties of a pressure sensitive adhesive itself. Pressure sensitive adhesives also include mixtures of polymers such as polyisobutylene (PIB) of different molecular weights and mixtures of different polymers, wherein each resulting mixture is pressure sensitive. Other useful rubber-based pressure sensitive adhesives are hydrocarbon polymers such as natural and synthetic polyisoprene, polybutylene and polyisobutylene, styrene / butadiene polymers styrene isoprene-styrene block copolymers, hydrocarbon polymers such as butyl rubber, halogen-containing polymers Such as polyacrylonitrile, polytetrafluoroethylene, polyvinylchloride, polyvinylidene chloride, and polychlorodiene and other copolymers thereof.
[89] Other useful pressure sensitive adhesives (“PSAs”) may include acrylic pressure sensitive adhesives and silicone pressure sensitive adhesives described in US Pat. Nos. 5,474,783 and 5,656,386. Suitable commercial acrylic polymers include commercially available polymers and are trade names Duro-Tak by National Starch and Chemical Corporation, Bridgewater, NJ such as Duro-Tak 87-2194, Duro-Tak 87-2196, Duro-Tak 87-1197 And polyacrylate adhesives available under the trades 87-4194, 87-2510, 87-2097 and 87-2852. Other suitable acrylic adhesives include the trade name Gelva-Multipolymer Solution (GMS) (Monsanto; St. Louis, Mo. ), Such as GMS 737, 788, 1151, 3087 and 7882.
[90] Suitable silicone pressure sensitive adhesives are described in Sobieski, et al., "Silicone Pressure Sensitive adhesives," Handbook of Pressure-Sensitive Adhesive Technology, 2nd ed., Pp. 508-517 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989), and are incorporated herein. Other useful silicone-based pressure sensitive adhesives include the following US patents: US Pat. No. 4,591,622; 4,584,355; 4,585,836; And 4,655,767. Suitable silicone pressure sensitive adhesives are commercially available and are trademarks of Dow Corning Corporation, Medical Products, Midland, Mich. BIO-PSA 7-4503, BIO-PSA 7-4603, BIO-PSA 7-4301, 7-4202, 7-4102 , 74106 and silicone adhesives sold under BIO-PSA 7-4303.
[91] The amount of polymer carrier may range from 2 to 99% by weight, preferably from 30 to 90% by weight, even more preferably from 40 to 80% by weight.
[92] Pressure sensitive adhesives may be mixed to control the solubility of the drug in the carrier system as described in the '783 patent. In a particularly preferred embodiment of the invention, the multi-polymer adhesive system comprises a pressure sensitive adhesive mixture of acrylic polymer, silicone polymer and soluble PVP (described below). The acrylic polymer and the silicone polymer are individually preferably in a weight ratio of about 2:98 to about 96: 4, more preferably about 2:98 to about 90:10, even more preferably about 2:98 to about 86 : 14. The amount of acrylic (also broadly referred to as polyacrylate) polymers and silicone-based polymers (also broadly referred to as polysiloxanes) is used in tripolymer adhesive systems to affect the rate of delivery of the parent drug / prodrug from the system through the skin. It is adapted to modify the saturation concentration of the drug / prodrug. Other useful ranges include about 5-85 weight percent acrylate polymer, 10-90 weight percent polyisobutylene and 5-95 weight percent silicone-based polymer.
[93] Transdermal drug delivery systems can also include agents known to accelerate delivery of the parent drug / prodrug through the skin. These formulations are referred to as skin penetration enhancers, accelerators, adjuvant and sorption promoters, collectively referred to herein as "enhancers," and are described in US Pat. No. 6,221,383. These include polyhydric alcohols such as dipropylene glycol, propylene glycol, and polyethylene glycol, which enhance the solubility of the parent drug / prodrug; Oils such as olive oil, squalene and lanolin; Fatty ethers such as cetyl ether and oleyl ether; Fatty acid esters such as isopropyl myristate which enhances the diffusibility of the parent drug / prodrug; Urea and urea derivatives, such as alatonin, which affect the ability of keratin to retain moisture; Polarities such as dimethyldecylphosphoxide, methyloctylsulfoxide, dimethylaurylamide, dodecylpyrrolidone, isosorbitol, dimethylacetonide, dimethylsulfoxide, decylmethylsulfoxide and dimethylformamide that affect keratin permeability menstruum; Salicylic acid, which softens keratin; Amino acids that are penetration aids; Benzyl nicotinate, a hair follicle opener; High molecular weight aliphatic surfactants, such as lauryl sulfate salts, which alter the surface condition of the skin, and administered drugs. Other formulations include oleic and linoleic acid, ascorbic acid, panthenol, butylated hydroxytoluene, tocopherol, tocopheryl acetate, tocopheryl linoleate, propyl oleate, and isopropyl palmitate. Especially preferred are combinations of glycerin, dipropylene glycol, butylene glycol, propylene glycol and polyhydric alcohols such as one or more oleyl alcohols and oleic acid.
[94] In some embodiments, the present invention may include a plasticizer, or a viscous agent is incorporated into the formulation to improve the adhesive properties of the pressure sensitive adhesive composition. Such plasticizers or tackifiers include (a) aliphatic hydrocarbons; (2) mixed aliphatic and aromatic hydrocarbons; (3) aromatic hydrocarbons; (4) substituted aromatic hydrocarbons; (5) hydrogenated esters; (6) polyterpenes; And (7) hydrogenated wood rosin.
[95] The adhesive used is preferably miscible with the mixture of polymers. In a preferred embodiment, the tackifier is a silicone fluid (eg, 360 Medical Fluid, Dow Corning Corporation, Midland, Mich.) Or mineral oil. Silicone fluids are useful for mixtures comprising polysiloxane as the main component. In another embodiment, mineral oil is a preferred tackifier, for example when synthetic rubber is a major component.
[96] For parent / prodrug molecules that are not readily available in the polymer system, cosolvents of the parent / prodrug and polymer may be added. Cosolvents such as lecithin, retinal derivatives, tocopherols, dipropylene glycol, triacetin, propylene glycol, saturated and unsaturated fatty acids, mineral oils, silicone fluids, alcohols, butyl benzyl phthalate, etc. The solubility of the prodrugs is useful in the practice of the present invention.
[97] In addition to the use of parent / prodrug combinations to inhibit crystallization, other crystallization inhibitors can be used. Preference is given to soluble PVP in which one known formulation is described in detail in polyvinylpyrrolidone (PVP), US Pat. No. 6,221,383. The term "polyvinylpyrrolidone" or "PVP" means a polymer that is a homopolymer or copolymer comprising N-vinylpyrrolidone as monomer unit. Typical PVP polymers are homopolymeric PVP and copolymer vinyl acetate vinylpyrrolidone. Homopolymeric PVP is known in the pharmaceutical industry by various names including povidone, polyvidone, polyvidonum, soluble polyvidonum, and poly (1-vinyl-2-pyrrolidone). Copolymer vinyl acetate vinylpyrrolidone is known in the pharmaceutical industry as Copolyvidoe, Copolyvidone and Copolyvidone. The term “soluble” when used in the context of PVP means that the polymer is soluble in water, generally rarely crosslinked and has a molecular weight of about 2,000,000 or less. The molecular weight of PVP usable in the present invention is preferably about 2,000 to 1,100,000, more preferably 5,000 to 100,000 and most preferably 7,000 to 54,000.
[98] The amount and type of PVP required in the foregoing preferred embodiments depends on the type and type of adhesive as well as the amount and type of parent drug / prodrug present in the adhesive, but can be readily determined through routine experimentation. Typically, PVP is present in an amount of about 1% to about 20% by weight, preferably in an amount of about 3% to about 15% by weight. However, the amount of PVP depends on the desired properties of the particular parent drug / prodrug and mixture used and can be higher than 20%, for example up to 40%. Commercially available useful PVPs are under the trade names BASF AG, Ludwigshafen, Germany as "Kollidon," such as "Kollidon 10," "Kollidon 17PF," "Kollidon 25," "Kollidon 90," "Kollidon 30," and "VA 64". Commercially available. Another useful PVP is also sold under the trade name Kollidon CL-M of BASF AG.
[99] Various extenders, fillers and other additives known to be used with the transdermal drug delivery system may be further provided in the compositions of the present invention. For example, hydrophilic components are particularly useful when the composition tends to absorb water when lecithin is used as a cosolvent. The type of hydrophilic component that has been used successfully is clay. The addition of clay has been found to improve adhesion in transdermal formulations without reducing the rate of parent drug / prodrug delivery. Suitable clays include aluminum silicate clay, kaolinite, montmorillonite, attapulgite, bentonite, halosite and the like.
[100] The device or individual dosage unit of the invention can be produced in any manner known to those skilled in the art. After the skin composition is formed, it may be brought into contact with the support layer in any manner known to those skilled in the art. Such techniques include calendar coating, hot melt coating, solution coating, and the like. Of course, support materials are known in the art and may include plastic films such as polyethylene, vinyl acetate resins, ethylene / vinyl acetate copolymers, polyvinyl chloride, polyurethane, metal foils, nonwovens, fabrics, and commercial laminates. . The support material generally has a thickness in the range of 2 to 1000 micrometers, and the skin composition is generally placed on the support material in a thickness in the range of 12 to 250 micrometer thickness.
[101] Suitable release liners are also well known in the art and include Bio-Relaease® liners. And a commercially available product of Dow Corning Corp., designated Syl-off® 7610 liner. In a preferred embodiment where the polysiloxane is part of a multipolymer adhesive carrier, the release liner should be miscible with the silicone adhesive. An example of a suitable commercial liner is 3M's 1022 Scotch Pak®. The structure of the transdermal delivery system of the present invention can be of any shape and size required or desired. By way of example, a single dosage unit may have a surface area in the range of 1 to 200 cm ² . Preferred sizes are from 5 to 60 cm ² .
[102] In aspects of the preferred method of the invention wherein the carrier is a flexible defined polymer, at least one polymer is optionally mixed with PVP to produce a pressure sensitive adhesive composition or a transdermal drug delivery system adhesive system (with incorporated parent: prodrug), It regulates the delivery of the parent drug: prodrug through the epidermis. In a preferred embodiment of the present invention, transdermal drug delivery systems comprise soluble PVP, polyacrylates, polysiloxanes, parent drug / prodrugs, optional reinforcing agent (s), cosolvent (s), and tackifiers, if necessary, suitable volatile solvents ( After mixing in the s), the mixture is produced by casting and removing the solvent (s) by evaporation to form a film. Suitable volatile solvents include alcohols such as isopropanol and ethanol; Aromatics such as xylene and toluene; Aliphatic such as hexane, cyclohexane, and heptane; Alkanate esters such as ethyl acetate and butyl acetate, including but not limited to.
[103] Exemplary general methods of preparation of embodiments are as follows:
[104] 1. The appropriate amount of solvent (s), any reinforcing agent (s), any PVP and organic solvent (s) (eg toluene) are combined and mixed together completely in a container.
[105] 2. Shake is then performed until the parent drug / prodrug is added to the mixture and the parent drug / prodrug is mixed uniformly therein.
[106] 3. The appropriate amount of polymer is then added to the parent drug / prodrug mixture and mixed thoroughly.
[107] 4. The formulation is then delivered to a coating operation which is coated onto the protective release liner at a controlled specific thickness.
[108] 5. The dry product on the release liner is then combined with the support material and wound into a roll for storage.
[109] 6. The appropriate size and shape “system” is die-cut from the roll material and placed in a bag.
[110] The order of steps, the amount of ingredients, and the amount and time of shaking or mixing can be important process variables that will depend on the particular polymer, parent / prodrug, cosolvent and reinforcing agent used in the formulation. These factors may be adapted by one skilled in the art, but it should be borne in mind for the purpose to provide a uniform product. It is contemplated that many other methods may be performed and may yield desirable results, including some modification of the order of the steps. In addition to having various shapes, the dosage unit product can be of various sizes. Surface areas ranging from 1 to 200 square centimeters are contemplated and presently preferred sizes are 5, 10, 15, 20, 30, 40 and 60 square centimeters.
[120] The following specific examples are included as examples of transdermal delivery systems and compositions that fall within the inventive concept. These examples are not intended to limit the scope of the invention in any way. Weight percentages in the examples are based on the dry weight of the system unless otherwise noted. In the drawings, "NET" means noethine drone and "NETA" means noethine drone acetate.
[121] The following commercially available adhesives were used in the examples. "Duro-Tak 87-2287" is a trade name of NATIONAL STARCH AND CHEMICAL CORPORATION, Bridgewater, N. J. of polyacrylate adhesives in organic solutions.
[122] "Bio-PSA 7-4603" is a trade name of DOW CORNING CORPORATION, MEDICAL PRODUCTS, Midland, Mich. Of polysiloxane adhesive in organic solution.
[123] "Gelva-Multipolymer Solution (GMS) 737 and 788" are trade names of Monsanto Company, Saint Louis, Mo., of polyacrylate adhesives in organic solvents.
[124] "KOLLIDON 30 and VA 64" are trade names of BASF Aktiengesellschaft, Ludwigschaften, Germany of polyvinylpyrrolidone polymer and vinyl acetate / vinylpyrrolidone copolymer.
[125] Example 1 and Comparative Example 1
[126] Transdermal delivery compositions are made of the following ingredients:
[127] Noethine drone1.2% Estradiol0.9 Noethine drone acetate2.5 PVP / VA Copolymer (VA64)15.0 Acrylic PSA (GMS737)5.0 Oleic acid3.0 Dipropylene glycol9.0 Silicone PSA (7-4603)63.4
[128] Steroid flux through body skin in vivo from the formulation of Example 1 is shown in FIG. 1 by triangles (Δ and ▲). Flux is also shown for commercial CombiPatch ™ products containing only estradiol and noethetrone acetate as shown as circles ((or ●) as Comparative Example (“CE”). As can be seen in FIG. 1, the flux of the combined noethine drone / norethrone drone acetate of Example 1 was significantly greater than the plus of noethine drone acetate only from CombiPatch ™, but the flux of estradiol was affected. There was no. The flux of estradiol was about the same.
[129] Example 2 and Comparative Example (CE) 2
[130] Transdermal steroids / corresponding steroid derivative delivery compositions were prepared with the following ingredients.
[131] FormulationCE 2-1CE2-2Ex. 2 Noethine drone1.2%0 %1.2% Estradiol0.90.90.9 Noethine drone acetate02.52.5 PVP / VA Copolymer (VA64)15.015.015.0 Acrylic PSA (GMS788)5.05.05.0 Oleic acid3.03.03.0 Dipropylene glycol9.09.09.0 Silicone PSA (7-4603)65.964.663.4
[132] The combined noethynedron / norethedrone acetate flux through the body skin in vivo from the formulation of Example 2 is shown in FIG. 2 in circles (•). Begyo example containing only noethine drone and noethine drone acetate shown in squares (■) and triangles (▲), respectively. As can be seen in FIG. 1, the flux of the combined noethine drone / norethine drone acetate was significantly greater than the flux of only noethine drone or noethine drone acetate in the same carrier composition.
[133] Example 3 and Comparative Example 3
[134] Transdermal steroids / corresponding steroid derivative delivery compositions were prepared with the following ingredients.
[135] Testosterone6.0% Testosterone acetate3.0 PVP Kollidon 3012.0 Acrylic PSA (GMS788)5.0 Oleic acid3.0 Dipropylene glycol9.0 Silicone PSA (7-4603)63.4
[136] The combined testosterone / testosterone acetate flux through the body skin in vivo from the formulation of Example 3 is shown in FIG. 3 in squares (■). Separate fluxes of testosterone and testosterone acetate from the formulation of Example 3, shown in circles (() and dark triangles (▲), respectively, are also shown. The flux of the testosterone composition sold under the trademark of Testoderm® (available from Alza, Inc.) is shown as a hollow triangle (Δ). As can be seen in Figure 3, the flux of the combined testosterone / testosterone acetate of Example 3 was significantly higher than the Testoderm® composition. In addition, the individual fluxes of Testosterone and Testosterone Acetate in Example 3 were larger than the fluxes of Testoderm®, indicating that each drug itself is being delivered in an amount sufficient to provide a physiological effect.
[137] Example 4 and Comparative Example 4
[138] Transdermal steroids / corresponding steroid derivative delivery compositions were prepared with the following ingredients.
[139] Example 4-1Example 4-2Example 4-3Example 4-4 Estradiol4 %4 %4%4 % Estradiol acetate-2.5-- Estradiol enanthate--2.5- Estradiol propionate---2.5 Kollidon 303333 Oleyl alcohol6666 Dipropylene glycol9997 Duro-Tak 87-22877777 Silicone PSA 7-46037168.568.568.5
[140] Examples 4-1 and 4-2 had crystals after 3 days. Examples 4-3 and 4-4 had no crystals on day 13. These results show that acetate esters of estradiol are not effective in inhibiting crystals, whereas propionate and enanthanate are effective in inhibiting crystals.
[141] Example 5-9
[142] Transdermal parent drug / prodrug delivery compositions were prepared with the following ingredients:
[143] Ingredients (w / w%)Example 5Example 6Example 7Example 8Example 9 Polysiloxane PSA ^(BIO-PSA 7-4603)5249464346 Polyvinylpyrrolidone (Kollidon 30)2525252525 Oleic acid55555 Dipropylene glycol1515151515 Noethine drone33330 Noethine drone acetate03699
[144] Examples 5 and 9 are comparative examples. The permeation rate of noethynedrone / norethyne drone acetate is shown in Figures 5-7. 5 shows the mean cumulative transmission of noethin drones of Examples 5-8. 6 is the average cumulative permeation for noethin drone acetate of Examples 6-9. Figure 7 shows the mean cumulative permeation of the combined noethine drone and noethine drone acetate of Examples 5-9. All figures show increased permeation of the parent drug / prodrug combination compared to prodrug (in this case noethynedrone acetate) or prodrug.
[145] The formulations of Examples 6-8 were also tested for crystal formation. Each mixture was cast onto a 15 ml wet gap applicator on a polyester release liner (ScotchPak® 1022; 3M, Minneapolis, Michigan). The cast down was allowed to air dry for 5 minutes at room temperature and humidity under a hood, followed by an additional 5 minutes in a convection air oven at 92 ° C. to dry any volatile solvent. Upon completion, the release liner coated with the dried drug mixture composition was laminated to the polyester side of the polyester / ethylene vinyl acetate support material (ScotchPak 3 9732; 3M, Minneapolis, Michigan). Individual units of 10 cm ² were die cut and placed under the microscope for visible irradiation at 25 × magnification. The mixture showed no crystal formation after 60 days.
[146] Melting point drop appears to be achieved by the combination of parent drug and prodrugs and this phenomenon seems to explain the crystal inhibition in the transdermal platform.
[147] Example 10
[148] The effects of prodrugs on flux were also studied using the ace inhibitor drug, ramipril. The flux rates of the two corresponding prodrugs-ramipril methyl ester and ramipril ethyl ester-were compared before blending with the parent drug. As shown in FIG. 9, in the absence of a permeation enhancer, the methyl ester prodrugs may contain 20% of the drug, 20% of the polyacrylate adhesive (DURO-TAK® 87-90880, and 60% of the polysiloxane adhesive). 73% higher flux than ethyl ester prodrug in a carrier formulation containing (BIO-PSA® 7-4102). 3% oleyl alcohol and 5% dipropylene glycol were added to the formulation (polysiloxane The adhesive was reduced to 52%) and the flux was almost doubled.In any case, using an ester prodrug instead of the parent drug could achieve a flux increase of more than 10 times (ramipril flux (▲) -15% in Figure 8). Only ramipril of was dissolved without crystal formation-vs. ramipril ethyl ester flux (Δ) without reinforcing agent in Figure 9.) The use of non-functional or hydroxy functional adhesives is also preferred.
[149] However, when both ramipril and the corresponding prodrugs are formulated in a formulation containing a reinforcing agent, higher flux can be obtained. As shown in Figure 8, the ramipril / prodrug blend significantly increased flux by about two times with the methyl ester prodrug blend. In all formulations incorporating a ramipril-methyl ester prodrug formulation, it was found that the flux was improved over that of any drug added with prodrug alone. When the ratio of ramipril to methyl ester prodrug was about 1: 2.33, an optimal flux was found at a drug concentration of 20% and there was no significant improvement above the 1: 3 ratio.
[150] With ramipril / ethyl ester prodrug formulation, the optimum flux at 20% drug concentration was achieved at a ratio of about 1: 3 ramipril / prodrug, with a flux increase of about 20% over ramipril ethyl ester alone. However, at about a 1: 1 ratio, it was found that the flux was reduced by about 19% compared to the flux of ramipril ethyl ester alone. Nevertheless, the ramipril / ethyl ester prodrug formulation achieved a significant flux increase over ramipril alone. Thus, it was found that the ramipril / prodrug combination provided increased flux than any of the drug itself alone, but the ramipril methyl ester prodrug showed higher flux than the ethyl ester derivative.
[151] While a number of preferred embodiments of the invention have been disclosed, it should be understood that various changes, adaptations, and improvements may be made without departing from the spirit of the invention and the appended claims.

权利要求:
Claims (52)
[1" claim-type="Currently amended] Therapeutically effective amounts of drugs, including parent drugs and prodrugs; And a composition for transdermal delivery of a drug produced from a mixture comprising a pharmaceutically acceptable carrier, wherein said parent drug and prodrug are individually present in an amount sufficient for pharmacological effect.
[2" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the composition has an onset of a longer or shorter therapeutic effect than an equivalent composition containing only pharmacologically equivalent amounts of the parent drug or prodrug.
[3" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the composition has a different blood level profile from an equivalent composition containing only a pharmacologically equivalent amount of the parent drug or prodrug.
[4" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the composition has a faster or slower rate of penetration than an equivalent composition containing only pharmacologically equivalent amounts of the parent drug or prodrug.
[5" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the composition has a longer or shorter therapeutic effect period than an equivalent composition containing only pharmacologically equivalent amounts of the parent drug.
[6" claim-type="Currently amended] The composition of claim 1, wherein the prodrug is more lipophilic than the parent drug and the prodrug has a greater penetration rate through the skin.
[7" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the parent drug is a steroid and the prodrug is a steroid in which free hydroxy at the 3, 11 or 17 position is reacted with the alcohol moiety.
[8" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the parent drug is a steroid, and the prodrug is a steroid in which free hydroxy at position 17 is reacted with an alcohol moiety.
[9" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the blended parent drug and the prodrug have a melting point lower than that of the parent drug or the prodrug alone.
[10" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 9, wherein the parent drug is a steroid and the prodrug is a steroid in which free hydroxy at the 3, 11 or 17 position is reacted with the alcohol moiety.
[11" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 9, wherein the parent drug is noethine drone and the prodrug is noethine drone acetate.
[12" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 11, wherein the weight ratio of noethine drone acetate: noethine drone is ≥ 1.
[13" claim-type="Currently amended] 10. The composition of claim 9, wherein the parent drug is estradiol and the prodrug is estradiol 17-enanthate.
[14" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 1, wherein the carrier comprises a pressure sensitive adhesive comprising at least two polymers and the permeation of the drug is adapted by changing the type and / or ratio of the at least two polymers.
[15" claim-type="Currently amended] A method of adapting a blood level profile or permeation of a drug from a transdermal drug delivery composition, comprising the following steps:
(a) selecting a parent drug and a prodrug;
(b) combining the parent drug and the prodrug in a carrier comprising at least one pressure sensitive adhesive;
(c) measuring the permeation and / or blood level profile of the drug;
(d) (i) selection of prodrugs; (ii) relative concentrations of parent drug and prodrugs; And (iii) adapting at least one of the total concentrations of the parent drug and the prodrug.
[16" claim-type="Currently amended] 16. The method of claim 15, wherein the at least one pressure sensitive adhesive comprises two pressure sensitive adhesives, and wherein the adapting of (d) further comprises (iv) adapting the type and / or ratio of the two pressure sensitive adhesives. How to Adapt Blood Level Profile or Permeation of Drugs from Transdermal Drug Delivery Compositions
[17" claim-type="Currently amended] A therapeutically effective amount of a drug comprising the steroid derivative as a source of steroid and a therapeutically active steroid; And a composition for transdermal delivery of a drug produced from a mixture comprising a pharmaceutically acceptable carrier, wherein the steroid and the steroid derivative are present in a weight / weight ratio of steroid to the steroid derivative of 10: 1 to 1:10. Composition for transdermal delivery of phosphorus drug.
[18" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 17, wherein the ratio is 6: 1 to 1: 6.
[19" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 17, wherein the steroid derivative is a steroid ester.
[20" claim-type="Currently amended] 18. The composition for transdermal delivery of a drug according to claim 17, wherein the carrier is a flexible, limited composition comprising one or more polymers.
[21" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 20, wherein the flexible confining composition comprises at least one acrylic polymer and a silicone polymer.
[22" claim-type="Currently amended] The carrier composition according to claim 20 or 21, wherein the flexible limiting composition is a pressure sensitive adhesive.
[23" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 17, wherein the composition further comprises an enhancer.
[24" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 23, wherein the enhancer comprises dipropylene glycol and at least one oleyl alcohol or oleic acid.
[25" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 20, wherein the steroid and the steroid derivative are present in an amount of up to 20% by weight, based on the total composition.
[26" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 20, wherein the steroid and the steroid derivative are present in an amount of up to 10% by weight, based on the total composition.
[27" claim-type="Currently amended] 20. The composition for transdermal delivery of a drug according to claim 19, wherein the steroid comprises at least one progestin.
[28" claim-type="Currently amended] 28. The process of claim 27 wherein the progestin is allylestrenol, anageston, desogestrel, dimethosterone, dydrogesterone, etisterone, ethinodiol, gestodene, haloprogesterone, 17-hydroxy- 16-methylene-progesterone, 17.alpha-hydroxyprogesterone, linestrenol, hydroxyprogesterone, melengestrol, noethynedrone, noethinodrel, norgestosterone, norgestinate, norgestrel, A composition for transdermal delivery of a drug comprising norgestrienone, norbinosterone, pentagestrone, and trigesterone.
[29" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 27, wherein the progestin is noethine drone and the steroid ester is noethine drone acetate.
[30" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 17, wherein the ratio is 1: 1 to 3: 1.
[31" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 17, wherein the ratio is 3: 2 to 5: 2.
[32" claim-type="Currently amended] 18. The composition for transdermal delivery of a drug according to claim 17, wherein the ratio is about 2: 1.
[33" claim-type="Currently amended] 20. The composition for transdermal delivery of a drug according to claim 19, wherein the steroid comprises at least one anabolic steroid and androgen steroid.
[34" claim-type="Currently amended] 34. The method of claim 33, wherein the anabolic steroid is androisoxazole, androstenediol, bolanddiol, bolosterone, closthebol, ethylrestrenol, formyldienolone, 4-hydroxy-19-nortestosterone, methane A composition for transdermal delivery of a drug comprising driol, methenolone, methyltrienolone, nandrolone, norbolone, oxymesterone, stenbolone and trenbolone.
[35" claim-type="Currently amended] The method of claim 33, wherein the androgen steroid is boldenone, fluoxymesterone, mestanolone, mesterolone, methanedrostenolone, 17-methyltestosterone, 17.alpha-methyltestosterone 3-cyclopentylenol ether, norethane Transdermal of drugs that include drones, normethane drones, oxandrolone, oxymesterone, oxymetholone, prasterone, stanrolone, stanozolol, testosterone, testosterone 17-chloral hemiacetal and thiomethone Composition for delivery.
[36" claim-type="Currently amended] The composition of claim 19, wherein the composition further comprises an additional steroid.
[37" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 36, wherein the additional steroid is estrogen.
[38" claim-type="Currently amended] 38. The process of claim 37 wherein the estrogens are conjugated estrogen hormones, equilenin, equilin, estradiol, estradiol benzoate, estradiol 17. beta-cypionate, estriol, estrone, ethynyl estradiol and mixtures thereof Composition for transdermal delivery of a drug that is selected from the group consisting of.
[39" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 37, wherein the steroid is noethine drone, the steroid ester is noethine drone acetate and the estrogen is estradiol.
[40" claim-type="Currently amended] 40. The composition of claim 39, wherein the carrier is a pressure sensitive adhesive comprising at least one acrylic polymer and a silicone polymer and the composition further comprises a reinforcing agent and a crystal inhibitor.
[41" claim-type="Currently amended] 41. The composition for transdermal delivery of a drug according to claim 40, wherein the reinforcing agent comprises dipropylene glycol and oleyl alcohol and the crystallization inhibitor comprises PVP.
[42" claim-type="Currently amended] Therapeutically effective amount of at least one steroid; And administering the drug in a pharmaceutically acceptable carrier, the combination comprising a steroid derivative that provides a source of a therapeutically active steroid, wherein the steroid and the steroid derivative are steroids. Is a steroid: the weight / weight ratio of the corresponding steroid derivative of 10: 1 to 1:10.
[43" claim-type="Currently amended] A method of inhibiting crystal formation of steroids in a transdermal drug delivery system comprising the step of combining two or more steroid glycoly derivatives in a pressure sensitive adhesive carrier composition.
[44" claim-type="Currently amended] 20. A method for preparing the transdermal composition according to claim 19, comprising forming a mixture of steroids, steroid esters and carriers.
[45" claim-type="Currently amended] Therapeutically effective amounts of drugs including noethine drone and noethine drone acetate; And a composition for transdermal delivery of a drug produced in a mixture comprising a pharmaceutically acceptable carrier, wherein noethynedrone and noethetrone acetate steroid are present in a weight / weight ratio of 1: 6 to 6: 1. Composition for transdermal delivery of a drug.
[46" claim-type="Currently amended] Therapeutically effective amounts of drugs including noethine drone and noethine drone acetate and estradiol; And a composition for transdermal delivery of a drug produced in a mixture comprising a pharmaceutically acceptable carrier, wherein the noethine drone and the noethine drone acetate are present in a weight / weight ratio of 1: 1 to 1: 3. Composition for transdermal delivery.
[47" claim-type="Currently amended] A therapeutically effective amount of a drug comprising the steroid and the corresponding steroid derivative providing a source of therapeutically active steroid; And a composition for transdermal delivery of a drug formed by a process comprising the step of mixing a pharmaceutically acceptable carrier, wherein the steroid and the steroid derivative are from 10: 1 to 1:10 of steroid: weight of the steroid derivative / A composition for transdermal delivery of a drug which is present in a weight ratio.
[48" claim-type="Currently amended] A therapeutically effective amount of a drug comprising the ACE inhibitor and the corresponding ACE inhibitor prodrug; And a composition for transdermal delivery of a drug produced from a mixture comprising a pharmaceutically acceptable carrier.
[49" claim-type="Currently amended] 49. The composition of claim 48, wherein the ACE inhibitor is ramipril and the ACE inhibitor comprises at least one ramipril ethyl ester and ramipril methyl ester.
[50" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 49, wherein the weight ratio of ramipril to ramipril ethyl ester is 1: 1 to 1: 5.
[51" claim-type="Currently amended] The composition for transdermal delivery of a drug according to claim 49, wherein the weight ratio of ramipril to ramipril methyl ester is from 2: 1 to 1: 9.
[52" claim-type="Currently amended] 49. The composition of claim 48, wherein the ACE inhibitor and the ACE inhibitor prodrug are individually present in an amount sufficient for pharmacological effect.

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
2001-06-18|Priority to US29838101P

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2001-06-18|Priority to US60/298,381

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2001-09-07|Priority to US94810701A

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2001-09-07|Priority to US09/948,107

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2002-06-18|Application filed by 노벤 파머수티컬즈, 인코퍼레이티드

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2002-06-18|Priority to PCT/US2002/016579

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2004-01-31|Publication of KR20040010747A

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2008-06-10|First worldwide family litigation filed

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2010-10-20|Application granted

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2010-10-20|Publication of KR100988542B1

优先权:

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申请号 | 申请日 | 专利标题

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US29838101P| true| 2001-06-18|2001-06-18|

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US60/298,381|2001-06-18|

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US94810701A| true| 2001-09-07|2001-09-07|

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US09/948,107|2001-09-07|

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PCT/US2002/016579|WO2002102390A1|2001-06-18|2002-06-18|Enhanced drug delivery in transdermal systems|