• 专利附录
  • 专利说明
  • 权利要求
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  • 同族专利
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  • 优先权
    • 专利摘要:
    The present invention disclosed herein relates to a method of increasing the concentration of achievable pharmaceutically active ingredient related to the fill composition viscosity for a dosage unit. The method is particularly useful for the preparation of soft gelatin capsules containing ibuprofen, naproxen, indomethacin and acetaminophen as pharmaceutically active ingredients. As a result of the present method, in order to achieve the same therapeutically effective dosage, a smaller amount of the composition component is needed in addition to the pharmaceutically active ingredient, whereby a significant increase in the concentration of the pharmaceutically active ingredient results in a total filling of the formulation. The volume and dosage unit size are reduced or the concentration of the pharmaceutically active ingredient is increased.
    公开号:KR20030041982A
    申请号:KR10-2003-7002971
    申请日:2001-08-28
    公开日:2003-05-27
    发明作者:틴달스테픈찰스；웹스터크리스토퍼클리브；퍼디난도조세핀크리스틴；루이스잭클린캐롤
    申请人:알.피.쉐러 테크놀러지즈 인코포레이티드；
    IPC主号:
    专利说明:

    Process for preparing pharmaceutical composition for soft gelatin formulation {PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS FOR USE WITH SOFT GELATIN FORMULATIONS}
    [3] Filled one piece soft gels have been widely known and used for a variety of applications for many years. Because softgels have different properties from typical telescoping two-piece hardshell capsules, softgels can retain liquid fillers. Typically, softgels contain orally consumable materials such as vitamins and pharmaceutical compositions that are liquid excipients or carriers.
    [4] In general, not all liquids are suitable as excipients or carriers for the inclusion of softgels. For example, water, propylene glycol, glycerin, low molecular weight alcohols, ketones, acids, amines, and esters cannot be used as soft carriers by themselves, because they interact with the gel, and if present, they are present in relatively small amounts. Can only exist.
    [5] Another limitation associated with softgels is the ability to administer a single dose of the pharmaceutically active ingredient to the solution in an acceptable fill volume. Often, it is difficult to separate the pharmaceutically active ingredient into a volume of solution that is small enough to produce a softgel that delivers the desired dosage, is economically efficient, and is comfortable for patient ingestion. It is known to develop a solvent system for a pharmaceutical active ingredient that does not interact sensitively with the active ingredient or the softgel casing itself.
    [6] The chemical nature of certain types of drugs required the development of specific solvent systems for soft gel formulations. Yu et al., Australian Patent Application No. 81573/87, includes an acidic pharmaceutical formulation and a solvent system consisting of 10 wt% to 80 wt% polyethylene glycol, 1 wt% to 20 wt% water, and hydroxide ionic species. Pharmaceutical formulations suitable for filling soft gels are disclosed. The solvent system dissolves pharmaceutical preparations such as ibuprofen in sufficient concentration for soft gelatin capsules.
    [7] It does not require an increase in total fill volume (and thus an increase in the overall size of the formulation), and / or does not increase the cleavage of the gelatin casing, and increases the concentration of the active ingredient which is a soft gelatin formulation and / or dosage unit. It is known to be difficult to achieve. In addition, maintaining a workable viscosity during this process is a problem. Therefore, there is a need to improve the pharmaceutical industry's method of manufacturing pharmaceutical formulations in a way that is more economical to manufacture and more comfortable for patients.
    [8] Summary of the invention
    [9] The present invention provides a method for increasing the concentration of a pharmaceutically active ingredient in a soft gelatin dosage unit, thereby reducing the total fill volume for the dosage unit or formulation, or in another form, increasing the concentration of the active ingredient. Can be used to In addition, using the method of the present invention, it is possible to reduce or avoid all undesirable interactions of the filling component with the gelatin casing.
    [10] The method according to the invention increases the concentration of pharmaceutically active ingredient achievable with respect to the filling viscosity for use in soft gelatin dosage units, and gradually increases the pharmaceutically active ingredient and hydroxide ion source in polyethylene glycol. It consists of adding.
    [11] Therefore, a) a substantial amount of polyethylene glycol used in the fill composition is combined with the first part of the pharmaceutically active ingredient to form an initial suspension; b) mixing the suspension; c) adding a first portion of a hydroxide ion source to said suspension; d) mixing the components until they are sufficiently dissolved to produce a workable viscosity; e) adding a second part of the pharmaceutically active ingredient to the solution to form another suspension; f) mixing the suspension; g) adding a second portion of the doxide ion source to the suspension; h) mixing the components until dissolved in the solution, wherein the first and second portions of the pharmaceutically active ingredient and the first and second portions of the hydroxide ion source are respectively the resulting fill composition A method of increasing the concentration of a pharmaceutically active ingredient relative to the viscosity of a fill composition for a dosage unit, less than the total amount of each ingredient used in the present invention, is disclosed wherein the resulting fill composition is a solvent system particularly suitable for the preparation of soft gelatin capsules. More active ingredients to be administered without containing a pharmaceutically active ingredient and without increasing the total fill volume and dosage unit size. In other forms, the resulting fill composition may increase the concentration of active ingredient to be used relative to the dosage unit size.
    [12] Pharmaceutically active ingredients suitable for use in the present invention include, but are not limited to, acidic compounds such as ibuprofen, naproxen, indomethacin and acetaminophen. Preferred pharmaceutically active ingredient is ibuprofen.
    [13] The solvent system prepared according to the invention consists of polyethylene glycol (PEG) and a hydroxide ion source. Polyethylene glycols that may be used in the present invention include those having a molecular weight range of about 200 Daltons to about 100,000 Daltons, preferably having a range of about 400 Daltons to about 700 Daltons. Suitable hydroxide ion sources for use in the present invention include sodium hydroxide (NaOH) and potassium hydroxide (KOH), more preferably potassium hydroxide.
    [14] According to the method of the invention, the first part of the pharmaceutically active ingredient is combined with polyethylene glycol and mixed together to form the first suspension. Then, a first portion of the hydroxide ion source is added and the components are mixed to a sufficient degree to produce a workable viscosity. A second part of the pharmaceutically active ingredient is added and mixed to form a second suspension, and a second part of the hydroxide ion source is added to the suspension to form a solution. The first and second portions of each of the pharmaceutically active ingredient and the hydroxide ion source consist of the total amount of each ingredient used to prepare the liquid fill composition.
    [15] In another embodiment, the method further comprises the additional step of adding a pharmaceutically active ingredient and adding a hydroxide ion source. Thus, at least three parts of each pharmaceutically active ingredient and hydroxide ion source can be used in the methods of the present invention.
    [16] The present invention also provides soft gelatin capsules containing the filling composition prepared according to the method of the present invention.
    [17] In addition, the present invention
    [18] a) an acidic pharmaceutically active ingredient having a concentration of at least 50% by weight, preferably about 55% by weight of the total fill composition
    [19] b) polyethylene glycol; And
    [20] c) providing a fill composition for gelatin capsules that constitutes a hydroxide ion source having a concentration of about 5.5% by weight or less of the total fill composition.
    [21] The preparation of liquid filling compositions according to the process of the invention increases the concentration of achievable pharmaceutically active ingredients in the solvent system for a given viscosity. One feature of the present invention is that in addition to the pharmaceutically active ingredient, lesser amounts of ingredients can be used for the filling composition. For example, less amount of polyethylene glycol is needed for the same amount of active ingredient. Therefore, a lower total fill volume can be used compared to the prior art to achieve the same dosage of the pharmaceutically active ingredient. The present invention enables a more economical manufacturing method and improves patient comfort by reducing the capsule size or the number of dosage units required for treatment.
    [22] Another advantage of the present invention is that the method requires a smaller total amount of hydroxide ion source, significantly reducing the likelihood of soft gelatin mass degradation by the hydroxide ions. Thus increasing the storage capacity and shelf life of the product.
    [1] This application claims priority to US application Ser. No. 09 / 649,947, filed August 29, 2000.
    [2] The present invention disclosed herein relates to oral pharmaceutical formulations. In particular, the present invention relates to an improved process for preparing pharmaceutical compositions for soft gel formulations. The method of the invention results in a smaller dosage form of the active ingredient.
    [23] As used herein, the term "soft gelatin dosage unit" is meant to encompass any dosage unit and / or formulation using gelatin or gelatin-like casings. Various casing materials have been recommended for soft capsules including gum, carrageenans, hydroxypropylate starch, cellulose and the like. As used herein, the term "soft gelatin dosage unit" means a dosage form consisting of mammalian gelatin, fish gelatin, rubber, guar, carrageenan, modified starch, and the like.
    [24] The terms "fill" and "fill composition" refer to those portions of the dosage unit (eg, fill, capsule, etc.) that are enclosed or contained in the outermost. When the term is used in connection with a soft gelatin dosage unit, it refers to a composition enclosed within gelatin containment.
    [25] As used herein, "workable viscosity" refers to increasing the effort required or lacking substantial resistance and / or useless resistance to the physical fluctuations required to mix the in-process components of the present invention.
    [26] The general process steps of the present invention allow the active ingredient and the hydroxide ion source to be gradually added to the polyethylene glycol in order to balance the components in the solvent system with respect to the active ingredient in the process, thereby providing a high concentration of packing viscosity. To achieve a pharmaceutically active ingredient. In the first step of the process, the first part of the pharmaceutically active ingredient is combined with all or significantly more polyethylene glycol to be used in the fill composition and mixed in the initial suspension. Thereafter, a first portion of the hydroxide ion source is added to the suspension and the components are mixed until dissolved enough to produce a workable viscosity. To this mixture, a second part of the pharmaceutically active ingredient is added and mixed. Then, a second portion of the hydroxide ion source is added and the components are dissolved until the resulting liquid fill composition is obtained.
    [27] In an interchangeable manner as described, each total pharmaceutically active ingredient and hydroxide ion source are gradually increased to add, thereby causing a higher concentration of active ingredient per total volume of filling, without causing excessively high viscosity. In this way, a solvent system for the active ingredient is produced which balances the interaction between the active ingredient and the viscosity of the charge. On the other hand, the preparation of pharmaceutically active ingredients at such high concentrations in this system results in suspensions that are too viscous to mix on a commercial and / or substantial scale using conventional equipment. As a result, the addition of the hydroxide component cannot be accommodated. Those skilled in the art have recognized that homogeneous mixtures are important in the pharmaceutical arts and that proper mixing or stirring is required to achieve homogeneous mixtures suitable for encapsulation in gelatin capsules and the like.
    [28] Maintaining a workable viscosity throughout the process can change the number of addition steps for each component, as well as the relative amounts of pharmaceutically active ingredient and hydroxide ion source added each time in the process. The active ingredient may be added in an amount suitable for the total active ingredient in the range of about 10% to about 90% of the total amount of the active ingredient (100%) to be added. In addition, the hydroxide ion sources may each be added in an amount of about 10% to 90% of the total hydroxide ion source to be added. During the process, the amount of each component added is not the same. Thus, as long as the workable viscosity is maintained throughout the process, various combinations of the number and amount of component repetitions are possible in accordance with the present invention. The amount of each part of the added components will vary depending on the active ingredients, the interrelationships between the components and the chemical properties of the reaction variables used in the process.
    [29] As a "two-step addition" process, for example, one half of the active ingredient may be added in each addition, followed by one half of the hydroxide ion source. Alternatively, one half of the active ingredient can be added, followed by one third of the hydroxide ion source, followed by the other half of the active ingredient and two thirds of the hydroxide ions. Can be. In addition, three or more addition steps may be used for each component in the process.
    [30] Pharmaceutically active ingredients useful in the present invention include acidic compounds such as ibuprofen, naproxen, indomethacin and acetaminophen. Preferred pharmaceutically active ingredient is ibuprofen.
    [31] Since decomposition of the gelatin casing is likely to occur above about 5.5% hydroxide content, the hydroxide ion source used in the present invention is generally present in an amount up to about 5.5% of the total fill composition volume. Suitable hydroxide ion sources include, but are not limited to, potassium hydroxide and sodium hydroxide. Preferred hydroxide ion source is potassium hydroxide. Most preferred for use in the present invention is an aqueous 50% potassium hydroxide solution. Potassium hydroxide is preferred as a hydroxide ion source because potassium hydroxide is more soluble in acidic pharmaceutical components than sodium hydroxide and is less prone to precipitation at various temperatures at low temperatures.
    [32] Typically the initial suspension used in this process contains the total amount of polyethylene glycol to be used for the fill composition. Polyethylene glycols (PEG) that may be used in accordance with the present invention include those having a molecular weight of about 200 Daltons to about 100,000 Daltons, preferably about 400 Daltons to about 700 Daltons.
    [33] In another embodiment, polyethylene glycol derivatives may be used in accordance with the present invention. Suitable polyethylene glycol derivatives include, but are not limited to, polyethylene glycol ethers of alcohols and co-polymers of polyethylene glycol. A specific example of polyethylene glycol of alcohols is tetraglycol, which is a polyethylene glycol ether of tetrahydrofurfuryl alcohol.
    [34] In another form of embodiment, other solvent systems may be used in accordance with the present invention. For example, suitable solvent systems include those described in Makino et al. US Pat. No. 5,912,011 and Molton et al. US Pat. No. 5,376,688, the entire texts of which are incorporated herein by reference.
    [35] If such ingredients are present only in amounts sufficient to maintain the desired viscosity, additional ingredients may be used that increase the solubility of the pharmaceutically active ingredient of polyethylene glycol. Specific examples of the additional components include, but are not limited to, glycerin, propylene glycol and polyvinylpyrrolidone and combinations thereof. The amount and combination of additional ingredients used will vary depending on the chemical properties of the other ingredients used in the process.
    [36] General additives, including preservatives, stabilizers, wetting agents, colorants and the like can be used in connection with the process of the present invention.
    [37] Substantially optimizing the chemical interaction between the pharmaceutically active ingredient and the polyethylene glycol / potassium hydroxide solvent system as used in accordance with the process of the present invention provides a high concentration of active ingredient for a given viscosity of the PEG / KOH solvent system. Enable the ability to build. Throughout the process of the present invention, at each step, the viscosity of the composition is adjusted through the chemical properties of each component with respect to the particular given increase ratio.
    [38] Example 1
    [39] Comparison of Methods to Prepare Filling Compositions Containing Ibuprofen
    [40] Two pharmaceutical compositions suitable for soft gelatin capsules were prepared according to two different methods. One method was carried out according to the conventional method (step 1), and the second method was carried out according to the present invention (step 2). Both methods produced compositions containing Ibuprofen (Equations 1 and 2, respectively) as suitable pharmaceutically active ingredients for soft gel capsules.
    [41] Process 1 was carried out as follows:
    [42] First, 20.4 kg PEG 600 was added to a heated mixing vessel and stirred until it reached a temperature below 35 ° C. 19.6 kg of ibuprofen was added to PEG 600 in the mixing vessel. The blend was mixed to form a slurry. Then, 5.0 kg (50 wt% KOH / 50 wt% water) of KOH solution was slowly added to the slurry while maintaining the solution at a temperature below 50 ° C. to give a clear solution. A total of 45 kg batch size was prepared.
    [43] Process 2 was carried out according to the invention as follows:
    [44] First, 15.0 kg PEG 600 was added to a heated mixing vessel and stirred until it reached a temperature below 35 ° C. Half of the total ibuprofen (12.5 kg) was added to PEG 600 in the mixing vessel and the blend was mixed to form a slurry. One third (1.7 kg) of the total amount of KOH solution (50 wt% KOH / 50 wt% water) was added to the vessel while maintaining a temperature below 50 ° C. The other half (12.5 kg) of ibuprofen was added to the mixture and mixed to form a slurry. The remaining two thirds of the KOH solution (3.3 kg) was added while maintaining the temperature below 50 ° C. to give a clear solution. The total batch size produced was 45 kg.
    [45] In a separate experiment, when the total amount of ibuprofen (25 kg) (as found in the reduced fill composition of Process 2) was added to PEG 600, it was found that the resulting suspension was inoperable, producing a mixture that was too thick and high in viscosity. Was observed.
    [46] The amount of each component used in steps 1 and 2 and the concentration of the active ingredient (ibuprofen) obtained are summarized as follows:
    [47] Comparison of Prepared Ibuprofen Filling Compositions ingredientProcess 1Process 2 Ibuprofen19.6 kg25.0 kg PEG 60020.4 kg15.0 kg KOH5.0kg5.0kg sum45.0 kg45.0 kg Ibuprofen concentration43.5%55.6%
    [48] As can be seen from the results data in Table 1, when the fill composition was prepared according to the present invention, a significantly higher concentration of ibuprofen was obtained, which was an increase of 12.1% compared to the same total fill volume of 45.0 kg. In addition, the process according to the invention yields a ibuprofen to a total fill weight ratio of 0.556 or 5: 9. In contrast, the prior art method yielded ibuprofen at 0.435 fill weight ratio.
    [49] When using the method of the present invention to prepare soft gelatin dosage units, the solubility of pharmaceutically active ingredients such as ibuprofen is significantly increased, thus allowing less filling volume for the nominal dose to be used. Thus, it is necessary to produce smaller capsule sizes or fewer capsules, provide more efficient manufacturing, and improve patient comfort and compliance.
    [50] The entire disclosure of all patents, patent applications, and publications is incorporated herein by reference as if each were incorporated by reference. The present invention has been described in terms of various specifications and preferred embodiments and techniques. However, reasonable changes and modifications from the previous disclosure are possible without departing from the spirit or scope of the invention as defined by the claims.
    权利要求:
    Claims (30)
    [1" claim-type="Currently amended] a) combining the first portion of the pharmaceutically active ingredient with the substantial total amount of polyethylene glycol to be used in the fill composition to form an initial suspension;
    b) mixing the suspension;
    c) adding a first portion of a hydroxide ion source to said suspension;
    d) mixing the components until dissolved in the solution;
    e) adding a second part of the pharmaceutically active ingredient to the solution to form another suspension;
    f) mixing the suspension;
    g) adding a second portion of a hydroxide ion source to the suspension;
    h) mixing the components until dissolved in the solution, wherein the first and second parts of the pharmaceutically active ingredient and the first and second parts of the hydroxide ion source are each resulting A method for increasing the concentration of a pharmaceutically active ingredient relative to the viscosity of a fill composition for a dosage unit that is less than the total amount of each ingredient used for.
    [2" claim-type="Currently amended] The method of claim 1 wherein the dosage unit comprises soft gelatin capsules.
    [3" claim-type="Currently amended] The method of claim 1 wherein the pharmaceutically active ingredient is an acidic pharmaceutical compound.
    [4" claim-type="Currently amended] The method of claim 1, wherein the pharmaceutically active ingredient is selected from the group consisting of ibuprofen, naproxen, indomethacin and acetaminophen.
    [5" claim-type="Currently amended] The method of claim 4, wherein the pharmaceutically active ingredient is ibuprofen.
    [6" claim-type="Currently amended] The method of claim 1 wherein the pharmaceutically active ingredient is present in the resulting composition in a weight ratio of pharmaceutically active ingredient to total fill composition of at least 1: 2.
    [7" claim-type="Currently amended] The method of claim 6, wherein the pharmaceutically active ingredient is present in the resulting composition with a weight ratio of pharmaceutically active ingredient to total fill composition of at least 5: 9.
    [8" claim-type="Currently amended] The method of claim 1 wherein the polyethylene glycol has an average molecular weight of about 400 to about 700 daltons.
    [9" claim-type="Currently amended] The method of claim 1 wherein the polyethylene glycol is present in the resulting composition with a ratio of polyethylene glycol to total fill volume of about 1: 3.
    [10" claim-type="Currently amended] The method of claim 1 wherein said hydroxide ion source is selected from the group consisting of sodium hydroxide and potassium hydroxide and mixtures thereof.
    [11" claim-type="Currently amended] 10. The method of claim 9, wherein the hydroxide ion source is potassium hydroxide.
    [12" claim-type="Currently amended] 12. The method of claim 11, wherein potassium hydroxide is present in the resulting composition in less than about 5.5 weight percent of the total fill composition.
    [13" claim-type="Currently amended] The method of claim 1, wherein the pharmaceutically active ingredient is gradually added to at least 3 parts in the course of the process, each part being less than the total amount of the pharmaceutically active ingredient used in the resulting fill composition.
    [14" claim-type="Currently amended] The method of claim 1, wherein one of the first and second parts of the pharmaceutically active ingredient is less than about 90% by weight of the total pharmaceutically active ingredient.
    [15" claim-type="Currently amended] The method of claim 13 wherein each of the first and second portions of the pharmaceutically active ingredient is about 50% by weight of the total pharmaceutically active ingredient added.
    [16" claim-type="Currently amended] The method of claim 1, wherein the hydroxide ion source is gradually added to at least 3 parts in the course of the process, each part being less than the total amount of hydroxide ion source used in the resulting composition.
    [17" claim-type="Currently amended] The method of claim 1, wherein one of the first and second portions of the hydroxide ion source is less than about 90% by weight of the total amount of hydroxide ion source added.
    [18" claim-type="Currently amended] 17. The method of claim 16, wherein one of the first and second portions of the hydroxide ion source is about two thirds of the total weight of the hydroxide ion source added.
    [19" claim-type="Currently amended] A soft gelatin capsule containing the filling composition produced by the method of claim 1.
    [20" claim-type="Currently amended] 20. The soft gelatin capsule of claim 19 wherein the pharmaceutically active ingredient is an acidic pharmaceutical compound.
    [21" claim-type="Currently amended] The soft gelatin capsule of claim 20 wherein the pharmaceutically active ingredient is selected from the group consisting of ibuprofen, naproxen, indomethacin and acetaminophen.
    [22" claim-type="Currently amended] 22. The soft gelatin capsule of claim 21 wherein the pharmaceutically active ingredient is ibuprofen.
    [23" claim-type="Currently amended] Soft gelatin capsules having a liquid pharmaceutical composition containing ibuprofen present in an amount of at least 50% by weight of the total fill composition.
    [24" claim-type="Currently amended] The soft gelatin capsule of claim 23 wherein the liquid pharmaceutical composition contains ibuprofen present in an amount of about 56% by weight of the total fill composition.
    [25" claim-type="Currently amended] The soft gelatin capsule of claim 24 further comprising a hydroxide ion source present in an amount up to about 5.5% by weight of the total fill composition.
    [26" claim-type="Currently amended] 26. The soft gelatin capsule of claim 25 containing up to about 720 mg of the total fill composition.
    [27" claim-type="Currently amended] a) an acidic pharmaceutically active ingredient in a concentration of at least 50% by weight of the total fill composition;
    b) polyethylene glycol; and
    c) Filling composition for gelatin capsules containing a hydroxide ion source at a concentration of up to about 5.5% by weight total filling composition.
    [28" claim-type="Currently amended] The fill composition of claim 27, wherein the acidic pharmaceutically active ingredient has a concentration of about 56% by weight of the total fill composition.
    [29" claim-type="Currently amended] 28. The filling composition of claim 27, wherein the acidic pharmaceutically active ingredient is ibuprofen.
    [30" claim-type="Currently amended] 28. The fill composition of claim 27, wherein the hydroxide ion source is potassium hydroxide.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2000-08-29|Priority to US09/649,947
    2000-08-29|Priority to US09/649,947
    2001-08-28|Application filed by 알.피.쉐러 테크놀러지즈 인코포레이티드
    2001-08-28|Priority to PCT/US2001/026711
    2003-05-27|Publication of KR20030041982A
    2006-10-16|Application granted
    2006-10-16|Publication of KR100634571B1
    2009-03-02|First worldwide family litigation filed
    优先权:
    申请号 | 申请日 | 专利标题
    US09/649,947|2000-08-29|
    US09/649,947|US6387400B1|2000-08-29|2000-08-29|Process for preparing pharmaceutical compositions for use with soft gelatin formulations|
    PCT/US2001/026711|WO2002017855A2|2000-08-29|2001-08-28|Process for preparing pharmaceutical compositions for use with soft gelatin formulations|
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