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    • 专利摘要:
    PURPOSE: A sustained release formulation containing polyethylene glycol as an absorption promoter, together with a base material for sustained release containing an acrylic polymer and a higher aliphatic alcohol is provided. Therefore, the formulation provides extended release time of active drugs. CONSTITUTION: A sustained release formulation of a poorly soluble drug contains 5 to 10% by weight of an acrylic polymer and 5 to 10% by weight a higher aliphatic alcohol as a base material for sustained release, 2 to 5% by weight of an acrylic polymer polyethylene glycol as an absorption promoter and 20 to 35% by weight of an absorbent of micro-crystalline cellulose and an erosion promoter of corn starch as an excipient. The acrylic polymer is Eudragit RL, RS, S, E30D and L30D, the higher aliphatic alcohol is cetostearyl alcohol. The polyethylene glycol has a molecular weight of 1,000 to 20,000.
    公开号:KR20030060730A
    申请号:KR1020020017467
    申请日:2002-03-29
    公开日:2003-07-16
    发明作者:김현준；오현주；강성구；서경재；장사정
    申请人:하나제약 주식회사；
    IPC主号:
    专利说明:

    Sustained release pharmaceutical composition of poorly soluble drug
    [1] The present invention relates to a sustained release formulation composition for slowly releasing therapeutically active poorly soluble drugs, and more particularly, to a sustained release base composed of a poorly soluble drug, an acrylic polymer and a higher aliphatic alcohol, and a polyethylene glycol stimulating agent. And it relates to a sustained release formulation composition to maintain the effective blood concentration of the drug for a long time by the dissolution control excipient is a certain content ratio.
    [2] There are many reports on sustained-release preparations, and various polymer materials are used for most of these preparations. For example, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, flulan, gelatin, collagen, casein, agar, gum arabic, dextrin, ethylcellulose, methylcellulose, chitin, chitosan, mannan, carboxy Methyl ethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycols, sodium alginate, polyvinyl alcohol, cellulose acetate, polyvinylpyrrolidone, silicone, polyvinyl acetal diethylamino acetate, albumin, etc. [Sustained and controlled Release Drug Delivery Systems (1978) MARCEL DEKKER, INC.].
    [3] Sustained-release drugs are usually administered orally. An important feature of sustained-release drugs is that the active drug must be released slowly over an extended period of time in the effective blood concentration range, and must not contain toxic or irritant components, and a high dose of drug. It should also be suitable.
    [4] Conventionally, sustained release has been achieved by controlling the dissolution and diffusion of medicines, and for this purpose, fatty materials, polymers, natural synthetic and semisynthetic gums and the like have been commonly used.
    [5] Sustained release preparations are effectively used in a group of drugs that act as antihypertensive agents and anti-inflammatory drugs that have a constant concentration in the blood. Examples of such drugs are felodipine (felodipine), nicardipine (nicardipine), nifedipine (nifedipine), diclofenac (diclofenac), ibuprofen (ibuprofen), indomethacin (indomethacin) and the like.
    [6] Among the effective drugs, methods related to sustained-release formulations for felodipine include the following.
    [7] Korean Patent No. 85,807 used a method in which felodipine mixed with a solubilizer was mixed with a hydrophilic gel system, that is, hydroxypropylmethylcellulose (HPMC), which is a hydrophilic swelling substrate.
    [8] In Korean Patent Laid-Open No. 99-028693, an insoluble active ingredient such as felodipine is dispersed in a hydrophilic poloxamer to make a solid dispersion, and the solid dispersion is used as a core for polymeric oral administration. Thereafter, for a long time, the release of the active ingredient is controlled.
    [9] Sustained release delivery systems should be ideally adapted to ensure that release pathways and profiles meet physiological and chronic therapeutic requirements. Techniques are known for formulations that control or sustain the release of water-soluble drugs, although certain moderately soluble drugs and very little insoluble poorly soluble drugs cannot be applied to sustained release formulations that are relatively suitable for water-soluble drugs. Indicates difficulty. It is not possible to predict whether a particular sustained release formulation will provide the desired release sustainability for a relatively insoluble drug, and it is not possible to produce a sustained release formulation that exhibits effective utilization in vivo when a drug that is insoluble in water is consumed. A significant amount of experimentation is required to obtain. Pelodipine, a poorly soluble drug that is almost insoluble in water, sometimes presents this problem when incorporated into a sustained release formulation, and this property is an important consideration when formulating felodipine.
    [10] The present invention includes a sustained release base composed of an acrylic polymer and a higher aliphatic alcohol so that the poorly soluble drug exhibits a physiologically easy dissolution rate, and when the polyethylene glycol is included as a wicking accelerator, the sustained release drug is easily eluted. The present invention has been completed by knowing that a formulation can be prepared.
    [11] Accordingly, an object of the present invention is to provide a sustained release formulation composition in which poorly soluble drugs are continuously eluted for a long time.
    [12] The present invention relates to a sustained release formulation composition comprising a poorly soluble drug, a sustained release base and a wicking accelerator and an excipient, wherein the composition contains 5 to 10 wt% of an acrylic polymer and 5 to 10 wt% of a higher aliphatic alcohol as a sustained release base. It is characterized by containing 2 to 5% by weight of polyethylene glycol as an accelerator.
    [13] Referring to the present invention in more detail as follows.
    [14] The present invention induces physiologically easy continuous dissolution of poorly soluble drugs by using a combination of polyethylene glycol as a predetermined content ratio as a sustained release base for sustained release of poorly soluble drugs and a swelling accelerator. have.
    [15] Sustained release formulation compositions of the present invention comprise conventional excipients, including slow release bases and wicking agents and dissolution controlling excipients that allow a poorly soluble effective drug and a poorly soluble drug to be released in a specified amount within a specified time.
    [16] The poorly soluble drug contained as an effective drug in the sustained-release preparation of the present invention is used as an antihypertensive agent and an anti-inflammatory drug, for example, felodipine, nicardipine, nifedipine, diclofenac Ibuprofen, indomethacin, and the like may also be used. The amount of the effective drug corresponds to the corresponding active amount of the drug, which is different depending on the characteristics of the effective drug, and therefore, the present invention does not place any particular limitation on the amount of the effective drug.
    [17] In the present invention, as a sustained release base, an acrylic polymer and a higher aliphatic alcohol are used together to exhibit a certain level of hydrophobic binding force, so that the manufactured drug is sustained without being easily decomposed by an emulsion or the like. That is, when they are used alone, effective sustained release effect cannot be obtained or exhibits too strong binding force, so that physiologically easy sustained release effect cannot be obtained.
    [18] As the acrylic polymer included as the sustained release base, any acrylic polymer which is acceptable for pharmaceutical use can be used for the purpose of the present invention. The acrylic polymer used in the present invention may be a cationic, anionic or nonionic polymer, and may be an acrylate or methacrylate formed of methacrylic acid or methacrylic acid ester. Acceptable acrylic polymers for the purposes of the present invention are preferably marketed under the trade name 'Eudragit', and the types thereof are Eudragit RL, RS, S, E30D and L30D, more preferably Eudragit RL. It is
    [19] The acrylic polymers described above exhibit optimal release rates when contained in the total composition in the range of 5 to 10% by weight.
    [20] The higher aliphatic alcohols included as the sustained release base are pharmaceutically acceptable, and cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol, myristyl alcohol, mixtures thereof and the like can be used. The higher aliphatic alcohol is preferably contained in the range of 5 to 10% by weight in the total composition.
    [21] In the composition of the present invention, polyethylene glycol is contained in the sustained-release agent of poorly soluble drug for the purpose of promoting wicking. The polyethylene glycol melts upon contact with water and draws an emulsion into the tablet to act as a disintegrant. Helps provide optimum dissolution rates for sustained release mechanisms. It is preferable that the polyethyleneglycol used by this invention uses the thing of the range of 1,000-20,000, More preferably, it is 6000. The polyethylene glycols described above provide optimum dissolution rates when contained in the total composition in the range of 2 to 5% by weight.
    [22] In addition, the composition of the present invention contains an excipient, which is a pharmaceutically acceptable conventionally used. Such excipients comprise most of the composition of the present invention and typically comprise 65 to 90% by weight of the total composition. In particular, the present invention uses a dissolution-controlled excipient among the excipients, characterized in that the dissolution-controlled excipient is to induce easy release by white water, water-soluble substances such as lactose, microcrystalline cellulose, and erosion Corn starch or the like may be contained, and by adding an appropriate amount thereof, a sustained release formulation showing easy dissolution rate with respect to poorly soluble drugs can be prepared.
    [23] The sustained release formulation composition of the present invention described above may be prepared in a solid dosage form according to a conventional process. In addition to the above-mentioned ingredients, any of the pharmaceutically acceptable excipients are mixed, combined, and granulated together and then compressed to produce sustained-release tablets that are easy for poorly soluble drugs. Binders that may be essential for the formulation of suitable dosage forms include polyvinylpyrrolidone, gelatin, gelatinized starch, and the like, and diluents include lactose, sodium chloride, dextrin, and the like. There is no restriction in particular.
    [24] For example, in order to formulate into matrix tablets, the sustained release formulation composition is assembled with the main component and the dissolution controlling excipient through one or more wet granulation to form uniform granules and then dried. The granules are then sieved to a certain size using a suitable screen-in device and compressed into a matrix tablet. In formulating the above-described matrix tablets, excipients may be used 20 to 35% by weight wicking agent such as microcrystalline cellulose (the role of absorbing milk in the matrix) and 5 to 15% by weight of erosion accelerator such as corn starch. have. The wicking agent and the erosion accelerator serve to promote dissolution of the solid matrix and release of the pharmaceutically active substance dispersed therein.
    [25] In general, magnesium stearate, colloidal silicon dioxide, lubricants such as talc, lubricants, etc. added to the granulated anhydride are not easy to use in the present invention. In the present invention, when the lubricant and the lubricant are added as described above, the dissolution rate is not easily increased due to the hydrophobicity of the tablet, and the disintegrant added before granulation exhibits the disintegration power only when contacted with water. If the above erosion does not occur, the dissolution rate is not easy. In the present invention in place of such a lubricant, by containing polyethylene glycol, it absorbs the oil into the tablet while being wet with water when in contact with the lubricant and serves to promote the disintegration of the tablet.
    [26] When formulated into tablets using the sustained release formulation composition according to the present invention, in order to prevent the early inflow or non-inflow of the aqueous medium into the tablet to be compressed to have a suitable hardness, the hardness of the tablet is about 4-7 kg It is preferable.
    [27] As described above, in the present invention, the poorly soluble drug contains a sustained release base, a wicking accelerator, and an elution control excipient of a specific composition so that the poorly soluble drug can be released for a long time within the effective blood concentration range, and also the composition The ingredients are pharmaceutically acceptable substances and therefore do not give any toxicity or irritation. In particular, the use of specific wicking agents and erosion accelerators as excipients can achieve optimal release of the drug.
    [28] Such a present invention will be described in more detail based on the following examples, but the present invention is not limited thereto.
    [29] Example 1
    [30] 0.5 g of felodipine, 7.8 g of lactose, 6.4 g of microcrystalline cellulose and 1.7 g of corn starch were mixed well with an appropriate mixing device. 1.6 g of Eudragit (Rohm Pharma. GmbH. Weiterstat) was dissolved in 8 ml of ethanol used as granulation fluid. The granulating fluid was incorporated into the mixed powder until the wet granular material was obtained while coalescing the powder. Then, this was dried and screened in through No. 20 sieve. 1.5 g of cetostearyl alcohol was mixed with 1 ml of ethanol, warmed to 60 ° C. and incorporated into the hot granule material using an appropriate mixing device. After cooling to room temperature, the granules were screened again through No. 20 sieve. 0.7 g of polyethylene glycol 6000 were mixed onto the granules. Pelodipine tablets were prepared by compressing the tablets on an appropriate tablet machine to a hardness of 4-7 kg using a round double convex die of 8.60 mm diameter.
    [31] Comparative Examples 1 to 4
    [32] By the method of Example 1, the controlled-release felodipine tablets containing 5 mg of pelodipine (felodipine) as an effective drug was prepared by the prescription of Table 1, respectively.
    [33] NamePrescription Volume (g) Example 1Comparative Example 1Comparative Example 2Comparative Example 3Comparative Example 4 Effective drugFelodipine0.50.50.50.50.5 Slow release mechanismEudragit1.61.11.63- Cetostearyl alcohol1.52.21.5-3 Suction acceleratorPolyethylene Glycol 60000.7-1.40.70.7 ExcipientLactose7.815.87.17.97.9 Microcrystalline cellulose6.4-6.46.46.4 Corn starch1.7-1.71.71.7 Talc-0.4--- Magnesium Stearate-0.2---
    [34] Test Example: Dissolution Test
    [35] For each of the pelodipine tablets prepared in Example 1 and Comparative Examples 1 to 4, the dissolution test was carried out using the Korean Method of Elution Test Method 2 of the Korean Pharmacopoeia. A small amount of samples was collected at 1, 4, and 7 time periods, and the solution was analyzed. The results are shown in Table 2 below.
    [36] Elution timeDissolution Rate (%) Example 1Comparative Example 1Comparative Example 2Comparative Example 3Comparative Example 4 1 hours9.355.2411.5584.709.35 4 hours59.9714.1279.15-54.6 7 hours99.3820.50--91.85
    [37] According to the dissolution test results, the sustained release formulation (Example 1) according to the present invention gradually releases 80% or more of the active drug over 7 hours. On the contrary, the formulation of Comparative Example 1, which substitutes talc and magnesium stearate in place of polyethylene glycol, provides more hydrophobicity to a sustained release base composed of hydrophobic binding force, and thus, dissolution of poorly soluble drugs is not easy. The formulation of Comparative Example 2 containing 2 times more polyethylene glycol compared to the composition of Example 1 was confirmed that the dissolution rate at 4 hours exceeds the effective range and the formulation was destroyed before 7 hours. It was confirmed that the formulation of Comparative Example 3 containing Eudragit alone as a sustained release base exceeded the effective range within 1 hour and the formulation was destroyed before 4 hours. The formulation of Comparative Example 4 containing cetostearyl alcohol alone as a sustained release base had a lower dissolution rate than that of Example 1. As a result of the dissolution test, the tablet of Comparative Example 4 was unable to maintain the formulation for 7 hours and was left for 1 hour. In the bay, the tablets were broken and eluated while falling off into debris.
    [38] Summarizing the above dissolution rate test results, if the content of polyethylene glycol is increased beyond the limited range (2 to 5%) of the present invention, the tablet is quickly destroyed by the excessive inflow of the fluid, thereby showing an inexpensive dissolution rate. In addition, the present invention has the characteristics that the ideal elution is possible by simultaneously containing Eudragit and cetostearyl alcohol as a sustained release base, on the contrary, when Eudragit is contained alone, Eudragit itself is water-insoluble However, swelling in water, biological or artificial gastrointestinal fluids and buffers facilitates the permeation of water into the tablets and works with water-soluble polyethylene glycols, causing the tablets to break before the reference time, whereas cetostearyl alcohol alone If the tablet is poorly dissolved due to excessive curing, or even if the ratio is adjusted, the tablet does not elute the active ingredients little by little, but falls into non-uniform fragments, so that a constant dissolution rate cannot be expected. Standard range of 45-70% with dissolution rate showing 40.73-73.23% No reproducible elution results are obtained.
    [39] In addition, in the manufacturing method of Example 1, but was separated and granulated respectively, Eudragit and cetostearyl alcohol used as a sustained-release agent, in the following Example 2 was granulated by mixing Eudragit and cetostearyl alcohol, The dissolution rate change of each sustained-release preparation prepared in Example 1 and Example 2 was confirmed and shown in Table 3 below.
    [40] Example 2
    [41] 0.5 g of felodipine, 7.8 g of lactose, 6.4 g of microcrystalline cellulose, and 1.7 g of corn starch were mixed well with an appropriate mixer. 1.6 g of Eudragit (Rohm Pharma. GmbH. Weiterstat) was dissolved in 9 ml of ethanol used as granulation fluid. After dissolving Eudragit in ethanol completely, 1.5 g of cetostearyl alcohol was added again, followed by warm melting at 60 ° C., sufficient mixing, and granulation until a wet granular material was obtained from the above mixed powder using an appropriate coalition apparatus. Fluid was impregnated. After cooling to room temperature, the granules were again screened through No. 20 sieve. Then, this was dried and screened in through No. 20 sieve. 0.7 g of polyethylene glycol 6000 were mixed onto the granules. Pelodipine tablets were prepared by compressing the tablets on an appropriate tablet machine to a hardness of 4-7 kg using a round double convex die of 8.60 mm diameter.
    [42] Elution timeDissolution Rate (%) Example 1Example 2 1 hours9.357.2 4 hours59.9760.32 7 hours99.38101.10
    [43] According to the dissolution test results, each of the sustained-release preparations prepared by the method of Examples 1 and 2 gradually released more than 80% of the active drug over 7 hours. Therefore, it was confirmed that the method of separating and granulating Eudragit and cetostearyl alcohol, respectively, and the method of granulating Eudragit and cetostearyl alcohol, showed easy dissolution rates.
    [44] As described above, the present invention is characterized by a sustained release formulation composition of a poorly soluble drug containing a sustained release base composed of a higher aliphatic alcohol and an acrylic polymer, a wicking accelerator of polyethylene glycol and an appropriate release control excipient in a certain composition. The present invention provides an extended release time of the active drug by improving the properties of existing sustained release preparations, and provides a novel sustained release mechanism for pharmaceutical compositions useful for poorly soluble active drugs.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] A sustained release formulation composition comprising a poorly soluble drug and a sustained release base and an wicking accelerator and an excipient,
    The composition of the sustained-release drug composition of poorly soluble drugs, characterized in that 5 to 10% by weight of the acrylic polymer, 5 to 10% by weight of the higher aliphatic alcohol and 2 to 5% by weight of polyethylene glycol as the wicking accelerator is contained in the composition.
    [2" claim-type="Currently amended] The sustained release formulation composition of claim 1, wherein the acrylic polymer is Eudragit RL, RS, S, E30D and L30D.
    [3" claim-type="Currently amended] The sustained release formulation composition of claim 1, wherein the higher aliphatic alcohol is cetostearyl alcohol.
    [4" claim-type="Currently amended] The sustained-release preparation composition of poorly soluble drug according to claim 1, wherein the acrylic polymer and the higher aliphatic alcohol contained as the sustained release base are separately granulated or mixed and granulated.
    [5" claim-type="Currently amended] The sustained-release preparation composition of poorly soluble drug according to claim 1, wherein the polyethylene glycol is 1,000 to 20,000.
    [6" claim-type="Currently amended] The composition according to any one of claims 1 to 5, wherein the composition contains 20 to 35% by weight of wicking agent of microcrystalline cellulose and 5 to 15% by weight of erosion accelerator of corn starch as a dissolution control excipient. A sustained release formulation composition of poorly soluble drug, characterized in that.
    [7" claim-type="Currently amended] According to claim 1, wherein the poorly soluble drug is felodipine (felodipine), nicardipine (nicardipine), nifedipine (nifedipine), diclofenac (diclofenac), ibuprofen, indomethacin (indomethacin) and mixtures thereof A sustained release formulation composition of poorly soluble drug, characterized in that.
    [8" claim-type="Currently amended] Sustained-release tablet characterized in that the formulation of the composition of claim 1 in a tablet form.
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    同族专利:
    公开号 | 公开日
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-01-09|Priority to KR1020020001241
    2002-01-09|Priority to KR20020001241
    2002-03-29|Application filed by 하나제약 주식회사
    2003-07-16|Publication of KR20030060730A
    优先权:
    申请号 | 申请日 | 专利标题
    KR1020020001241|2002-01-09|
    KR20020001241|2002-01-09|
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