WO2015056956A1 - Controlled release pharmaceutical composition based on propionic acid - Google Patents

Controlled release pharmaceutical composition based on propionic acid Download PDF

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WO2015056956A1
WO2015056956A1 PCT/KR2014/009634 KR2014009634W WO2015056956A1 WO 2015056956 A1 WO2015056956 A1 WO 2015056956A1 KR 2014009634 W KR2014009634 W KR 2014009634W WO 2015056956 A1 WO2015056956 A1 WO 2015056956A1
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release
water
pharmaceutical composition
pelubiprofen
hours
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PCT/KR2014/009634
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French (fr)
Korean (ko)
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강세연
채보람
성은진
이종현
송세현
손세일
이홍우
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대원제약주식회사
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Priority to CN201480057073.2A priority Critical patent/CN105705166B/en
Priority to RU2016118775A priority patent/RU2669920C2/en
Publication of WO2015056956A1 publication Critical patent/WO2015056956A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a pharmaceutical composition comprising a propionic acid-based nonsteroidal anti-inflammatory drug, and more particularly, to a controlled-release propionic acid-based pharmaceutical composition. More specifically, the present invention relates to a pharmaceutical composition comprising pelubipropene and a release-controlled polymer, which is a propionic acid-based drug, and relates to a pharmaceutical composition comprising a water-insoluble polymer as a release-controlled polymer.
  • Pelubiprofen, ( ⁇ )-(E) -2- [4- (2- (Oxo-cyclohexylidenemethyl) -phenyl] propionic acid is a nonsteroidal analgesic and anti-inflammatory agent (NSAIDs) represented by the following formula.
  • Pelubiprofen is a prodrug-type drug that is converted into a drug by hepatic metabolism. Compared with celecoxib, it is known to have an equivalent pain relief effect.
  • Korean Patent No. 922519 filed previously by the present applicant is present, which contains felubiprofen having an average particle diameter of 1 to 30 ⁇ m as an active ingredient.
  • a pharmaceutical formulation for oral administration for anti-inflammatory analgesics which has improved dissolution rate and stability, including excipients such as lactose and lactose, has been disclosed.
  • Korean Laid-Open Patent Publication No. 2008-39400 discloses a sustained-release pharmaceutical composition of a high water-soluble drug containing an active ingredient having a short half-life and a hydrophilic polymer.
  • Korean Patent Publication No. 167078 discloses a sustained release oral dosage form comprising ibuprofen and the like as an active ingredient, comprising a plurality of drug particles dispersed in a hydrophilic, water-swellable polymer.
  • sustained release formulations disclosed so far have merely focused on delaying the release of the drug from the formulation and have not been in mind with the reduction of gastrointestinal side effects of pelubiprofen.
  • the present invention is to provide a novel sustained release formulation capable of reducing gastrointestinal side effects while sustaining the release of felubiprofen.
  • a pharmaceutical composition comprising felubipropene and a release controlling polymer
  • a pharmaceutical composition wherein the release controlling polymer is a water-insoluble polymer.
  • the composition is provided with a pharmaceutical composition, which is eluted at less than 30% for 2 hours in the gastrointestinal tract (pH 1.2 eluate).
  • the composition is provided in the small intestine region (pH 6.8 eluent) is eluted at least 50% for 2 hours is provided.
  • the water-insoluble polymer is a cellulose derivative such as carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate, microcrystalline lead, white lead, carnauba lead, light lead, emulsified
  • a pharmaceutical composition which is selected from the group consisting of waxes such as lead, methacrylate copolymers, ethylcellulose, polyvinylacetate, collidone AL, and mixtures thereof.
  • the administration of pelubiprofen twice a day can exhibit an analgesic effect for 24 hours, to increase the therapeutic effect by providing the ease of administration to the patient by reducing the number of administration of the drug, and to reduce the gastrointestinal side effects May decrease.
  • 1 is a graph showing an elution pattern according to the ratio of collidone RS.
  • FIG. 2 is a graph showing pH 1.2 elution patterns of Example 1 and Comparative Examples 3 and 4.
  • FIG. 1 is a graph showing pH 1.2 elution patterns of Example 1 and Comparative Examples 3 and 4.
  • Figure 3 is a graph showing the pH 6.8 elution patterns of Example 1 and Comparative Examples 3, 4.
  • Figure 4 is a graph showing the results of the animal experiment of Example 1 and the conventional pelubiprofen formulation.
  • sustained release dosage forms that allow a reduced frequency of administration, such as twice daily, would be more desirable.
  • Pelubiprofen has a half-life within 6 hours, so multiple doses per day are necessary to effectively control pain. Therefore, sustained release of pelubiprofen is advantageous in terms of dose compliance, but in order to prevent gastrointestinal side effects, it is additionally required to suppress drug release in the gastrointestinal tract and to continue drug release in the small intestine region as much as possible. do.
  • sustained release means used conventionally employs the idea of forming a gel layer when the formulation is in contact with body fluids to prolong the erosion of the formulation and slow the diffusion of the drug.
  • Typical sustained release components are usually selected from hydrogels such as cellulose polymers or water-soluble polymers such as polyethylene oxide or methacrylate polymers.
  • the present inventors earnestly studied the sustained-release pharmaceutical composition containing felubiprofen, surprisingly, when containing felubiprofen and a water-insoluble polymer as a release control polymer, the release of the drug in the gastrointestinal tract
  • the present invention has been completed by finding that the sustained release is limited in the small intestine region.
  • a pharmaceutical composition comprising felubipropene and a release controlling polymer
  • the release controlling polymer is a water-insoluble polymer
  • water-insoluble polymer examples include cellulose derivatives such as carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate, waxes such as microcrystalline lead, white lead, carnauba lead, light lead and emulsified lead, Methacrylate copolymer, ethylcellulose, polyvinylacetate, collidone AL and mixtures thereof.
  • the preferred water-insoluble polymer is collidone.
  • the dissolution rate for 2 hours in the gastrointestinal tract is less than 30%.
  • the release of felubiprofen in the gastrointestinal tract is extremely limited, and in the case of using a conventional sustained release material, a large amount of felubiprofen is released in the gastrointestinal tract, which is a characteristic of the present invention.
  • the suppression of drug release in the gastrointestinal tract by the combination of pelubiprofen and a water-insoluble polymer is surprising, because for other active ingredients belonging to NSAIDs, for example, ketoprofen or roxof Lofen and the like do not reduce drug release in the gastrointestinal tract even when combined with a water-insoluble polymer.
  • the dissolution rate for 2 hours in the small intestine region is 50% or more. This means that felubiprofen is continuously released in the small intestine area, thus, it is possible to achieve a release pattern that exhibits the efficacy of the drug while reducing the frequency of administration.
  • drug release in the gastrointestinal and small intestine regions is based on pH 1.2 eluate and pH 6.8 eluate.
  • the content of the water-insoluble polymer may be included in 5% by weight to 50% by weight of the total weight of the composition
  • the content of felubiprofen may be included in 10% by weight to 50% by weight of the total weight of the composition.
  • the pharmaceutical composition of the present invention after mixing pelubiprofen with excipients and binders, combined with a suitable solvent and then dried to prepare tableting granules or filling granules, and then the water-insoluble polymers and lubricants It can be prepared by the addition of a pharmaceutically acceptable excipient. Alternatively, other assembly methods commonly known in the art may be used.
  • lactose, calcium hydrogen phosphate, starch, polyol may be used, and mannitol, isomalt, xylitol may be used as the polyol;
  • binder hydroxypropyl cellulose, polysaccharide may be used, and as the polysaccharide, xanthan gum and carrageenan may be used;
  • disintegrant carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, starch can be used;
  • lubricant magnesium stearate and talc can be used.
  • the content of the additives can be appropriately used by those skilled in the art according to the specific prescription, 10 to 50% by weight of the excipient, 1 to 25% by weight of the binder, 1 to 25% by weight of the disintegrant, 1 to 10% by weight of the lubricant May be included as a%.
  • the form of the pharmaceutical preparation for oral administration according to the present invention may be most preferably a tablet in view of the convenience of the patient.
  • suitable formulations such as powders, capsules, granules, syrups and the like can also be used and can be prepared in various oral dosage forms by conventional methods.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of ethyl cellulose and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose 4.6g, Eudragit RS 25.0g were mixed and combined with ethanol, and dried at 60 ° C until the loss of drying is 2.0% or less, and 20 mesh sieve It was established using. 4.6 g of magnesium stearate was added to the sieved material, mixed and tableted.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hypromellose phthalate and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of acrylic acid and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of carbomer and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve.
  • the formulation was combined with a suspension in which 25.0 g of polyvinyl acetate was dispersed, dried at 60 ° C until drying loss of 2.0% or less, stipulated using a 20 mesh sieve, and 4.6 g of magnesium stearate was added and mixed. After tableting.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 10.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 40.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 65.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hypromellose and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
  • Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 °C until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hydroxypropyl cellulose and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
  • ketoprofen 90 g of ketoprofen, 90 g of lactose monohydrate, and 4.6 g of hydroxypropyl cellulose were mixed and then combined with water, dried at 60 ° C. until the weight loss of 2.0% or less was established, and was established using a 20 mesh sieve. 25.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
  • the dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 liquid) and at a temperature of 37 ⁇ 0.5 ° C. 1 and 2 hours after the start of the experiment, the eluate was collected, filtered through a 0.45 ⁇ m filter, and analyzed by UV. The results are shown in Table 1. (Unit%)
  • the dissolution rate (%) in the pH 6.8 eluate was tested to evaluate the difference in drug release in the small intestine when the pelubiprofen was sustained by using a water-insoluble polymer and a water-soluble polymer.
  • Experiments were performed with the tablets prepared in Examples 1 to 6 and the tablets prepared in Comparative Examples 1 and 2 as follows.
  • the dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ⁇ (pH 6.8 liquid), the temperature of 37 ⁇ 0.5 °C. 1 and 2 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 ⁇ m filter and analyzed by UV, and the results are shown in Table 2. (Unit%)
  • the dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ⁇ (pH 6.8 liquid), the temperature of 37 ⁇ 0.5 °C. After 1 hour, 2 hours and 4 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 ⁇ m filter and analyzed by UV, and the results are shown in Table 3 and FIG. 1 (unit%).
  • Example 8 71.5 96.4 98.1
  • Example 1 39.7 88.7 95.5
  • Example 9 35.2 70.7 94.5
  • Example 10 27.5 54.1 80.3
  • the dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 and pH 6.8), at a temperature of 37 ⁇ 0.5 ° C., and a rotational speed of the paddle at 100 rpm. After 1 hour, 2 hours and 4 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 ⁇ m filter, and analyzed by UV. The results are shown in Table 4 and FIGS. 2 and 3 (unit%).
  • the dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 liquid) and at a temperature of 37 ⁇ 0.5 ° C. 0.5 hours, 1 hour, and 2 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 ⁇ m filter, and analyzed by UV. The results are shown in Table 5 (unit mg).

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Abstract

Provided is a pharmaceutical composition comprising pelubiprofen and a controlled release polymer, wherein the pharmaceutical composition is characterized in that the controlled release polymer is a non aqueous polymer.

Description

제어방출되는 프로피온산 계열의 약제학적 조성물Controlled-release Propionic Acid-Based Pharmaceutical Compositions
본 발명은, 프로피온산 계열의 비스테로이드성 소염진통제를 포함하는 약제학적 조성물에 관한 것으로서, 구체적으로는 제어방출되는 프로피온산 계열의 약제학적 조성물에 관한 것이다. 보다 상세하게는, 프로피온산 계열의 약물인 펠루비프로펜과 방출제어고분자를 포함하는 약제학적 조성물에 관한 것으로서, 방출제어고분자로서 비수용성 고분자를 포함하는 것을 특징으로 하는 약제학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition comprising a propionic acid-based nonsteroidal anti-inflammatory drug, and more particularly, to a controlled-release propionic acid-based pharmaceutical composition. More specifically, the present invention relates to a pharmaceutical composition comprising pelubipropene and a release-controlled polymer, which is a propionic acid-based drug, and relates to a pharmaceutical composition comprising a water-insoluble polymer as a release-controlled polymer.
펠루비프로펜, (±)-(E)-2-[4-(2-(Oxo-cyclohexylidenemethyl)-phenyl] propionic acid는 비스테로이드 계열의 진통 및 소염제(NSAIDs)로서 하기 화학식으로 표시된다.Pelubiprofen, (±)-(E) -2- [4- (2- (Oxo-cyclohexylidenemethyl) -phenyl] propionic acid is a nonsteroidal analgesic and anti-inflammatory agent (NSAIDs) represented by the following formula.
[규칙 제91조에 의한 정정 03.12.2014]　
Figure WO-DOC-3
[Revision under Rule 91 03.12.2014]
Figure WO-DOC-3
이 물질은 골 관절염, 류마티스성 관절염, 근골격성 통증, 수술 후 후유증, 요통, 치통 등과 같은 다양한 종류의 질병 치료에 약리활성을 보이며, 일본국 등록특허 제1167548호 및 일본국 등록특허 제1637767호(일본출원번호 1984-142567호)에 공지된 화합물이다. 펠루비프로펜은 간대사에 의해 약효를 가지는 물질로 전환되는 프로드럭 타입의 약물로서, 사이클로옥시게나아제의 일종인 COX-2를 억제함으로서 프로스타글란딘의 생성을 억제하는 약리기전을 가지고 있고, 디클로페낙이나 셀레콕시브와 비교하여 동등이상의 통증경감 효과가 있는 것으로 알려져 있다.This substance has pharmacological activity in the treatment of various types of diseases such as osteoarthritis, rheumatoid arthritis, musculoskeletal pain, postoperative sequelae, back pain, toothache, and the like. Japanese Application No. 1984-142567). Pelubiprofen is a prodrug-type drug that is converted into a drug by hepatic metabolism. Compared with celecoxib, it is known to have an equivalent pain relief effect.
펠루비프로펜을 포함하는 약제학적 제제로서는, 본 출원인이 이전에 출원한 한국 등록특허 제922519호가 존재하는데, 여기에는 1~30㎛의 평균 입자직경을 갖는 펠루비프로펜을 유효성분으로 함유하고, 유당등의 부형제를 포함하는 용출률 및 안정성이 개선된 소염진통제용 경구 투여용 약제학적 제제가 개시되어 있다. As a pharmaceutical preparation comprising felubiprofen, Korean Patent No. 922519 filed previously by the present applicant is present, which contains felubiprofen having an average particle diameter of 1 to 30 μm as an active ingredient. A pharmaceutical formulation for oral administration for anti-inflammatory analgesics, which has improved dissolution rate and stability, including excipients such as lactose and lactose, has been disclosed.
위 제제는 1일 3회 투여를 전제로 한 것인데, 왜냐하면, 펠루비프로펜은 반감기가 짧은 약물이므로, 통증을 효과적으로 조절하기 위해서는 1일 수회 복용해야 할 필요가 있기 때문이었다.The above formulations are based on three doses per day, because pelubiprofen is a drug with a short half-life, so it needs to be taken several times a day to effectively control pain.
그러나, 펠루비프로펜과 같은 NSAIDs의 경우, 1일 수회 복용시 복약순응도가 낮고, 약물이 위장관에 노출되는 빈도가 증가하여 위장관 부작용의 발생률이 높아진다. However, in case of NSAIDs such as pelubiprofen, the medication compliance is low when taken several times a day, and the frequency of drug exposure to the gastrointestinal tract increases, which increases the incidence of gastrointestinal side effects.
따라서, 펠루비프로펜을 유효성분으로 포함하는 약제학적 제형으로서 복용횟수를 감소시킬 수 있다면, 복용편이성이 향상됨과 동시에 위장관 부작용이 감소될 것으로 예상되어 서방화 제제의 개발을 위한 연구가 많이 진행되었다.Therefore, if the number of doses can be reduced as a pharmaceutical formulation containing pelubiprofen as an active ingredient, it is expected that the ease of taking and the side effects of the gastrointestinal tract will be reduced. .
한국공개특허공보 제2008-39400호에는, 짧은 반감기를 갖는 유효성분과 친수성 중합체를 함유하는 고수용성 약물의 서방성 약학 조성물이 개시되어 있다.Korean Laid-Open Patent Publication No. 2008-39400 discloses a sustained-release pharmaceutical composition of a high water-soluble drug containing an active ingredient having a short half-life and a hydrophilic polymer.
한국등록특허공보 제167078호에는 친수성, 수팽윤성 중합체내에 분산된 복수개의 약제입자를 포함하는, 이부프로펜등을 유효성분으로 하는 서방성 경구 제형이 개시되어 있다.Korean Patent Publication No. 167078 discloses a sustained release oral dosage form comprising ibuprofen and the like as an active ingredient, comprising a plurality of drug particles dispersed in a hydrophilic, water-swellable polymer.
그러나, 지금까지 개시된 서방성 제형은, 단순히 제형으로부터 약물의 방출을 지연시키는 것에만 초점을 맞추었을 뿐, 펠루비프로펜의 위장관 부작용 감소를 염두에 둔 것은 아니었다. However, the sustained release formulations disclosed so far have merely focused on delaying the release of the drug from the formulation and have not been in mind with the reduction of gastrointestinal side effects of pelubiprofen.
본 발명은, 펠루비프로펜의 방출을 서방화시키면서도, 위장관 부작용을 줄일 수 있는 신규한 서방화 제제를 제공하는 것을 해결과제로 한다.The present invention is to provide a novel sustained release formulation capable of reducing gastrointestinal side effects while sustaining the release of felubiprofen.
보다 구체적으로는, 펠루비프로펜을 포함하는 제형을 단순히 서방화시키는 경우, 위장에서 용출되는 펠루비프로펜에 의한 위장관 부작용의 발생을 방지하기 위해서, 위장영역에서는 용출률이 극히 적고, 소장영역에서의 용출률을 극대화시킨 신규한 서방화 제제를 제공하는 것을 해결과제로 한다. More specifically, in the case of simply sustained-release of the formulation containing felubiprofen, in order to prevent the occurrence of gastrointestinal side effects caused by felrubiprofen eluted from the stomach, dissolution rate is extremely low in the gastrointestinal tract, The problem is to provide a novel sustained release formulation with a maximum dissolution rate.
본 과제를 해결하기 위해서 하기와 같은 수단이 제공된다. In order to solve this problem, the following means are provided.
펠루비프로펜과 방출제어고분자를 포함하는 약제학적 조성물에 있어서, 상기 방출제어용 고분자가 비수용성 고분자인 것을 특징으로 하는 약제학적 조성물이 제공된다. In a pharmaceutical composition comprising felubipropene and a release controlling polymer, a pharmaceutical composition is provided, wherein the release controlling polymer is a water-insoluble polymer.
상기 약제학적 조성물에 있어서, 상기 조성물은 위장영역(pH 1.2 용출액)에서 2시간 동안 30% 미만으로 용출되는 것을 특징으로 하는 약제학적 조성물이 제공된다.In the pharmaceutical composition, the composition is provided with a pharmaceutical composition, which is eluted at less than 30% for 2 hours in the gastrointestinal tract (pH 1.2 eluate).
상기 약제학적 조성물에 있어서, 상기 조성물은 소장영역(pH 6.8 용출액)에 있어서 2시간 동안 50% 이상 용출되는 것을 특징으로 하는 약제학적 조성물이 제공된다. In the pharmaceutical composition, the composition is provided in the small intestine region (pH 6.8 eluent) is eluted at least 50% for 2 hours is provided.
상기 약제학적 조성물에 있어서, 상기 비수용성 고분자는 카보머, 카르복시메칠셀룰로오스 칼슘, 셀룰로오스아세테이트프탈레이트, 메칠셀룰로오스, 히드록시프로필메칠셀룰로오스프탈레이트와 같은 셀룰로오스유도체, 미결정납, 백납, 카르나우바납, 경납, 유화납과 같은 왁스류, 메타아크릴레이트 코폴리머, 에칠셀룰로오스, 폴리비닐아세테이트, 콜리돈에스알 및 이들의 혼합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 약제학적 조성물이 개시된다.In the pharmaceutical composition, the water-insoluble polymer is a cellulose derivative such as carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate, microcrystalline lead, white lead, carnauba lead, light lead, emulsified Disclosed is a pharmaceutical composition, which is selected from the group consisting of waxes such as lead, methacrylate copolymers, ethylcellulose, polyvinylacetate, collidone AL, and mixtures thereof.
본 발명에 의하면, 펠루비프로펜을 1일 2회 복용함으로서 24시간 동안 진통효과를 나타낼 수 있으며, 약물의 투여횟수의 감소를 통해 환자에게 복용 편이성을 제공하여 치료효과를 증대시키고, 위장관 부작용을 감소할 수 있다.According to the present invention, the administration of pelubiprofen twice a day can exhibit an analgesic effect for 24 hours, to increase the therapeutic effect by providing the ease of administration to the patient by reducing the number of administration of the drug, and to reduce the gastrointestinal side effects May decrease.
도 1은 콜리돈에스알 비율에 따른 용출패턴을 나타내는 그래프이다. 1 is a graph showing an elution pattern according to the ratio of collidone RS.
도 2는 실시예 1과 비교예 3, 4의 pH 1.2 용출패턴을 나타내는 그래프이다.2 is a graph showing pH 1.2 elution patterns of Example 1 and Comparative Examples 3 and 4. FIG.
도 3은 실시예 1과 비교예 3, 4의 pH 6.8 용출패턴을 나타내는 그래프이다.Figure 3 is a graph showing the pH 6.8 elution patterns of Example 1 and Comparative Examples 3, 4.
도 4는 실시예 1과 종래의 펠루비프로펜 제형의 동물실험 결과를 나타내는 그래프이다.Figure 4 is a graph showing the results of the animal experiment of Example 1 and the conventional pelubiprofen formulation.
짧은 반감기 및 위장관 부작용 발현의 우려가 있는 약물의 서방성 경구투여 형태를 제공하는 것은 어려운 일이다. 짧은 반감기를 가지고 있다면, 약물은 짧은 시간 동안에만 혈액에 잔류할 수 있어 활성이 단시간에만 지속된다. 그러한 약물의 경우, 혈액내 일정한 약물 농도를 효과적인 농도 이상으로 유지하기 위해서 복수의 일일 투여 처방전(1일 3회, 4회 또는 5회 이상)이 필요할 수 있다.It is difficult to provide sustained release oral forms of drugs that are subject to short half-lives and the appearance of gastrointestinal side effects. If you have a short half-life, the drug can remain in the blood for only a short time and the activity lasts only for a short time. For such drugs, multiple daily dosage prescriptions (three, four or five times daily) may be needed to maintain a constant drug concentration in the blood above the effective concentration.
복수의 일일 투여량은 불편하므로 환자의 복약순응도가 대단히 낮다. 따라서, 1일 2회와 같은 감소된 투여빈도를 허용하는 서방성 투여형태가 더욱 바람직할 것이다. Multiple daily doses are inconvenient and the patient's medication compliance is very low. Therefore, sustained release dosage forms that allow a reduced frequency of administration, such as twice daily, would be more desirable.
또한, 위장관 부작용을 발현시킬 수 있는 약물의 경우, 위장영역에서는 약물의 용출을 감소시키고 소장영역에서 연장된 시간 동안 방출을 촉진시키는 것이 유리함은 당연하다. 특히, NSAIDs의 경우, 약물을 위장영역에서 지속적으로 방출시키는 것은 부작용 발생의 위험성을 증가시킨다는 점에서 지양되어야 한다.In addition, in the case of drugs capable of expressing gastrointestinal side effects, it is natural to reduce the dissolution of the drug in the gastrointestinal tract and to promote the release for an extended time in the small intestine. In particular, for NSAIDs, continuous release of the drug in the gastrointestinal tract should be avoided in that it increases the risk of developing adverse events.
펠루비프로펜은 6시간 이내의 반감기를 가지므로 통증을 효율적으로 조절하기 위해서는 1일 복수의 투여가 필요하다. 따라서, 펠루비프로펜을 서방화시키는 것은 복용순응도의 면에서 유리하지만, 위장관 부작용 발생을 방지하기 위해서는, 가능한 한 위장영역에서의 약물방출을 억제하고, 소장영역에서의 약물방출을 지속시키는 것이 추가적으로 요구된다.Pelubiprofen has a half-life within 6 hours, so multiple doses per day are necessary to effectively control pain. Therefore, sustained release of pelubiprofen is advantageous in terms of dose compliance, but in order to prevent gastrointestinal side effects, it is additionally required to suppress drug release in the gastrointestinal tract and to continue drug release in the small intestine region as much as possible. do.
종래에 사용되는 통상적인 서방화수단은 제형이 체액과 접촉하였을 때, 겔층을 형성하여 제형의 침식을 연장시키고 약물의 확산을 더디게 만드는 기술사상을 이용한다. Conventional sustained release means used conventionally employs the idea of forming a gel layer when the formulation is in contact with body fluids to prolong the erosion of the formulation and slow the diffusion of the drug.
일반적인 서방성 성분은 통상 셀룰로오스 중합체와 같은 히드로겔 또는 폴리에틸렌옥사이드 또는 메타크릴레이트 중합체과 같은 수용성 중합체로부터 통상 선택된다. Typical sustained release components are usually selected from hydrogels such as cellulose polymers or water-soluble polymers such as polyethylene oxide or methacrylate polymers.
그러나, 펠루비프로펜의 경우, 통상적인 수용성 중합체로부터 선택되는 서방성 물질을 사용하는 경우, 위장영역에서 약물의 용출이 활발해지므로 이와 같은 통상의 수용성 중합체를 이용하는 것은 바람직하지 않다. However, in the case of pelubiprofen, when using a sustained release material selected from a conventional water-soluble polymer, it is not preferable to use such a conventional water-soluble polymer because elution of the drug in the gastrointestinal tract becomes active.
이에, 본 발명자들이 펠루비프로펜을 포함하는 서방형 약제학적 조성물에 대해서 예의 연구한 결과, 놀랍게도, 펠루비프로펜과 방출제어고분자로서 비수용성 고분자를 포함하는 경우, 위장영역에서는 약물의 방출이 제한되며, 소장영역에서 지속적인 서방출을 달성할 수 있다는 지견을 얻어 본 발명을 완성하였다.Thus, the present inventors earnestly studied the sustained-release pharmaceutical composition containing felubiprofen, surprisingly, when containing felubiprofen and a water-insoluble polymer as a release control polymer, the release of the drug in the gastrointestinal tract The present invention has been completed by finding that the sustained release is limited in the small intestine region.
구체적으로 본 발명에서는, 펠루비프로펜과 방출제어고분자를 포함하는 약제학적 조성물에 있어서, 상기 방출제어용 고분자가 비수용성 고분자인 것을 특징으로 하는 약제학적 조성물이 제공된다. In detail, in the present invention, a pharmaceutical composition comprising felubipropene and a release controlling polymer is provided, wherein the release controlling polymer is a water-insoluble polymer.
상기 비수용성 고분자로서는, 카보머, 카르복시메칠셀룰로오스 칼슘, 셀룰로오스아세테이트프탈레이트, 메칠셀룰로오스, 히드록시프로필메칠셀룰로오스프탈레이트와 같은 셀룰로오스유도체, 미결정납, 백납, 카르나우바납, 경납, 유화납과 같은 왁스류, 메타아크릴레이트 코폴리머, 에칠셀룰로오스, 폴리비닐아세테이트, 콜리돈에스알 및 이들의 혼합물로 이루어진 군으로부터 선택될 수 있다. 특히, 바람직한 비수용성 고분자는 콜리돈에스알이다.Examples of the water-insoluble polymer include cellulose derivatives such as carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate, waxes such as microcrystalline lead, white lead, carnauba lead, light lead and emulsified lead, Methacrylate copolymer, ethylcellulose, polyvinylacetate, collidone AL and mixtures thereof. In particular, the preferred water-insoluble polymer is collidone.
위와 같은 비수용성 고분자를 방출제어고분자로 사용하는 경우, 위장영역에서의 2시간 동안의 용출률은 30% 미만이다. 이는 위장영역에서의 펠루비프로펜 방출이 극히 제한됨을 의미하는데, 통상적인 서방화 물질을 이용하는 경우, 위장영역에서 다량의 펠루비프로펜이 방출된다는 점에서, 이는 본 발명의 특징적인 기술사상을 구성한다. 특히, 펠루비프로펜과 비수용성 고분자의 조합에 의해서 위장영역에서의 약물방출이 억제된다는 것은, 매우 놀라운 것인데, 왜냐하면, NSAIDs에 속하는 다른 유효성분의 경우, 예를 들어, 케토프로펜 또는 록소프로펜등은 비수용성 고분자와 조합하여도 위장영역에서의 약물방출이 저하되지 않기 때문이다. 즉, 비수용성 고분자와의 조합에 의해서 위장영역에서의 약물방출이 저하되어 위장관 부작용의 발현을 저하하는 것은, 펠루비프로펜과 비수용성 고분자의 조합에 의하여 달성되는 고유한 특성이라고 추측된다.When the above water-insoluble polymer is used as the release control polymer, the dissolution rate for 2 hours in the gastrointestinal tract is less than 30%. This means that the release of felubiprofen in the gastrointestinal tract is extremely limited, and in the case of using a conventional sustained release material, a large amount of felubiprofen is released in the gastrointestinal tract, which is a characteristic of the present invention. Configure. In particular, the suppression of drug release in the gastrointestinal tract by the combination of pelubiprofen and a water-insoluble polymer is surprising, because for other active ingredients belonging to NSAIDs, for example, ketoprofen or roxof Lofen and the like do not reduce drug release in the gastrointestinal tract even when combined with a water-insoluble polymer. In other words, it is assumed that the drug release in the gastrointestinal tract is lowered by the combination with the water-insoluble polymer and the expression of adverse gastrointestinal side effects is a unique characteristic achieved by the combination of the pelubiprofen and the water-insoluble polymer.
또한, 본 발명에 있어서, 비수용성 고분자를 방출제어고분자로 이용하는 경우, 소장영역에서의 2시간 동안의 용출률은 50% 이상이다. 이는 펠루비프로펜이 소장영역에서 지속적으로 방출한다는 것을 의미하며, 따라서, 투여횟수를 줄이면서 약물의 효능을 발휘하는 방출패턴을 달성할 수 있음을 나타낸다.In the present invention, when the water-insoluble polymer is used as the release controlling polymer, the dissolution rate for 2 hours in the small intestine region is 50% or more. This means that felubiprofen is continuously released in the small intestine area, thus, it is possible to achieve a release pattern that exhibits the efficacy of the drug while reducing the frequency of administration.
본 발명에 있어서, 위장영역 및 소장영역에 있어서의 약물방출은 pH 1.2 용출액 및 pH 6.8 용출액을 기준으로 한 것이다. In the present invention, drug release in the gastrointestinal and small intestine regions is based on pH 1.2 eluate and pH 6.8 eluate.
한편, 비수용성 고분자의 함유량은 조성물 총 중량당 5중량% 내지 50중량%로 포함될 수 있으며, 펠루비프로펜의 함유량은 조성물 총 중량당 10중량% 내지 50중량%로 포함될 수 있다. On the other hand, the content of the water-insoluble polymer may be included in 5% by weight to 50% by weight of the total weight of the composition, the content of felubiprofen may be included in 10% by weight to 50% by weight of the total weight of the composition.
본 발명의 약제학적 조성물은 펠루비프로펜과 부형제 및 결합제를 혼합한 후, 적절한 용매를 사용하여 연합한 후 건조하여 정립하여 타정용 과립 또는 충전용 과립을 제조한 후, 비수용성 고분자 및 활택제등의 약제학적으로 허용되는 부형제를 첨가하여 제조할 수 있다. 또는, 본 기술분야에 통상적으로 알려진 다른 조립방식을 이용할 수도 있다.The pharmaceutical composition of the present invention, after mixing pelubiprofen with excipients and binders, combined with a suitable solvent and then dried to prepare tableting granules or filling granules, and then the water-insoluble polymers and lubricants It can be prepared by the addition of a pharmaceutically acceptable excipient. Alternatively, other assembly methods commonly known in the art may be used.
상기 부형제로는 유당, 인산수소칼슘, 전분, 폴리올을 사용할 수 있으며, 폴리올로서 만니톨, 아이소말트, 자일리톨을 사용할 수 있으며; 결합제로는 히드록시프로필셀룰로오스, 폴리사카라이드를 사용할 수 있고, 폴리사카라이드로서는 잔탄검, 카라기난을 사용할 수 있고; 붕해제로는 카르복시메칠셀룰로오스 칼슘, 저치환도히드록시프로필셀룰로오스, 전분을 사용할 수 있으며; 활택제로는 스테아린산마그네슘, 탈크를 사용할 수 있다. As the excipient, lactose, calcium hydrogen phosphate, starch, polyol may be used, and mannitol, isomalt, xylitol may be used as the polyol; As the binder, hydroxypropyl cellulose, polysaccharide may be used, and as the polysaccharide, xanthan gum and carrageenan may be used; As the disintegrant, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, starch can be used; As the lubricant, magnesium stearate and talc can be used.
상기 첨가제들의 함량은 구체적인 처방에 따라서 통상의 당업자들이 적절히 사용할 수 있는데, 조성물 총 중량당 부형제 10~50중량%, 결합제 1~25중량%, 붕해제 1~25중량%, 활택제 1~10중량%로 포함될 수 있다. The content of the additives can be appropriately used by those skilled in the art according to the specific prescription, 10 to 50% by weight of the excipient, 1 to 25% by weight of the binder, 1 to 25% by weight of the disintegrant, 1 to 10% by weight of the lubricant May be included as a%.
본 발명에 따른 경구투여용 약제학적 제제의 형태는 환자의 편의성의 관점에서는 가장 바람직하게는 정제일 수 있다. 그러나 산제, 캅셀제, 과립제, 시럽제등 기타 적합한 제제도 사용가능하며 통상의 방법에 의해 여러 가지 경구투여의 제형으로 제조가능하다. The form of the pharmaceutical preparation for oral administration according to the present invention may be most preferably a tablet in view of the convenience of the patient. However, other suitable formulations such as powders, capsules, granules, syrups and the like can also be used and can be prepared in various oral dosage forms by conventional methods.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 이에 의해 본 발명의 기술사상이 한정되는 것으로 해석되어서는 안된다.Hereinafter, preferred examples are provided to aid in understanding the present invention. However, the following examples are merely provided to more easily understand the present invention, and the technical spirit of the present invention should not be construed as being limited thereto.
실시예Example
실시예 1. 콜리돈에스알을 이용한 서방정제의 제조Example 1 Preparation of Sustained-Release Tablet Using Collidone SR
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
실시예 2. 에칠셀룰로오스를을 이용한 서방정제의 제조Example 2 Preparation of Sustained-Release Tablet Using Ethyl Cellulose
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 에칠셀룰로오스 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of ethyl cellulose and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
실시예 3. 유드라짓알에스를 이용한 서방정제의 제조Example 3 Preparation of Sustained-Release Tablet Using Eudragit RS
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g, 유드라짓알에스 25.0g을 혼합 후 에탄올로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose 4.6g, Eudragit RS 25.0g were mixed and combined with ethanol, and dried at 60 ° C until the loss of drying is 2.0% or less, and 20 mesh sieve It was established using. 4.6 g of magnesium stearate was added to the sieved material, mixed and tableted.
실시예 4. 히프로멜로오스프탈레이트를 이용한 서방정제의 제조Example 4 Preparation of Sustained-Release Tablet Using Hypromellose Phthalate
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 히프로멜로오스프탈레이트 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hypromellose phthalate and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
실시예 5. 아크릴이즈를 이용한 서방정제의 제조Example 5 Preparation of Sustained-Release Tablet Using Acrylic Ease
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 아크릴이즈 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of acrylic acid and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
실시예 6. 카보머를 이용한 서방정제의 제조Example 6 Preparation of Sustained-Release Tablet Using Carbomer
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 카보머 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of carbomer and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
실시예 7. 폴리비닐아세테이트를 이용한 서방정제의 제조Example 7 Preparation of Sustained-Release Tablet Using Polyvinylacetate
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 이 정립물을 폴리비닐아세테이트 25.0g 를 분산시킨 현탁액으로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하고, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. The formulation was combined with a suspension in which 25.0 g of polyvinyl acetate was dispersed, dried at 60 ° C until drying loss of 2.0% or less, stipulated using a 20 mesh sieve, and 4.6 g of magnesium stearate was added and mixed. After tableting.
실시예 8. 콜리돈에스알 비율에 따른 서방정제의 제조Example 8 Preparation of Sustained-Release Tablet According to Collidone AL Ratio
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 10.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 10.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
실시예 9. 콜리돈에스알 비율에 따른 서방정제의 제조Example 9 Preparation of Sustained-Release Tablet According to Collidone AL Ratio
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 40.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 40.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
실시예 10. 콜리돈에스알 비율에 따른 서방정제의 제조Example 10 Preparation of Sustained-Release Tablets According to the Collidone AL Ratio
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 65.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 65.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
비교예 1. 히프로멜로오스를 이용한 서방정제의 제조Comparative Example 1. Preparation of sustained-release tablet using hypromellose
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 히프로멜로오스 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hypromellose and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
비교예 2. 히드록시프로필셀룰로오스를 이용한 서방정제의 제조Comparative Example 2. Preparation of a sustained-release tablet using hydroxypropyl cellulose
펠루비프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 히드록시프로필셀룰로오스 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.Pelubiprofen 90g, lactose monohydrate 90g, hydroxypropyl cellulose was mixed and then combined with water, dried at 60 ℃ until the weight loss of 2.0% or less was established using a 20 mesh sieve. 25.0 g of hydroxypropyl cellulose and 4.6 g of magnesium stearate were added to the sieved material, followed by mixing and tableting.
비교예 3. 록소프로펜나트륨을 이용한 서방정제의 제조Comparative Example 3. Preparation of Sustained-Release Tablet Using Sodium Roxoprofen
록소프로펜나트륨 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.90 g of lysopropene sodium, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried at 60 ° C. until the weight loss of 2.0% or less was established. 25.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
비교예 4. 케토프로펜을 이용한 서방정제의 제조Comparative Example 4. Preparation of Sustained-Release Tablet Using Ketoprofen
케토프로펜 90g과 유당수화물 90g, 히드록시프로필셀룰로오스 4.6g을 혼합 후 물로 연합한 후, 60℃로 건조감량 2.0% 이하가 될 때까지 건조하여 20 메쉬 체를 이용하여 정립하였다. 정립물에 콜리돈에스알 25.0g, 스테아르산마그네슘 4.6g을 가하고 혼합한 후 타정하였다.90 g of ketoprofen, 90 g of lactose monohydrate, and 4.6 g of hydroxypropyl cellulose were mixed and then combined with water, dried at 60 ° C. until the weight loss of 2.0% or less was established, and was established using a 20 mesh sieve. 25.0 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material, mixed and compressed.
실험예 1. 고분자에 따른 위장영역에서 펠루비프로펜의 용출률 실험Experimental Example 1. Dissolution rate test of pelubiprofen in the gastrointestinal zone according to the polymer
펠루비프로펜을 서방화시킴에 있어, 비수용성 고분자와 수용성 고분자를 사용하는 경우, 위장영역에서의 약물방출의 차이를 평가하기 위해서, pH 1.2 용출액에서의 용출율(%)을 실험하였다. 상기 실시예 1 내지 6에서 제조한 정제와 비교예 1 및 2에서 제조한 정제를 가지고 하기와 같은 실험을 수행하였다. In the sustained release of pelubiprofen, the dissolution rate (%) in the pH 1.2 eluate was tested in order to evaluate the difference in drug release in the gastrointestinal tract, when the water-insoluble and water-soluble polymers were used. Experiments were performed with the tablets prepared in Examples 1 to 6 and the tablets prepared in Comparative Examples 1 and 2 as follows.
용출률 실험은 대한약전 일반시험법 중 용출시험 제1법(회전검체통법)에 따라 실험하였다. 구체적으로 용출액은 900㎖(pH 1.2액), 온도는 37 ± 0.5℃로 용출하였다. 실험 시작 1시간 및 2시간후 용출액을 취하여 0.45㎛ 필터로 여과하고 UV로 분석하였고, 그 결과를 표 1에 나타내었다.(단위 %)The dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 liquid) and at a temperature of 37 ± 0.5 ° C. 1 and 2 hours after the start of the experiment, the eluate was collected, filtered through a 0.45 μm filter, and analyzed by UV. The results are shown in Table 1. (Unit%)
표 1
시간 1 시간 2 시간
실시예 1 5.0 8.9
실시예 2 2.3 5.1
실시예 3 0.7 1.2
실시예 4 1.7 2.4
실시예 5 0.8 15.1
실시예 6 15.1 25.3
실시예 7 2.1 4.6
비교예 1 30.2 56.0
비교예 2 43.4 62.0
Table 1
time 1 hours 2 hours
Example 1 5.0 8.9
Example 2 2.3 5.1
Example 3 0.7 1.2
Example 4 1.7 2.4
Example 5 0.8 15.1
Example 6 15.1 25.3
Example 7 2.1 4.6
Comparative Example 1 30.2 56.0
Comparative Example 2 43.4 62.0
이상의 실험으로부터, 펠루비프로펜을 비수용성 고분자를 사용하여 서방화시키는 경우, 위장영역에서의 약물의 방출이 극히 제한됨을 알 수 있다. From the above experiments, it can be seen that the release of the drug in the gastrointestinal tract is extremely limited when the pelubiprofen is sustained by using the water-insoluble polymer.
실험예 2. 고분자에 따른 소장영역에서 펠루비프로펜의 용출률 실험Experimental Example 2. Dissolution rate test of pelubiprofen in the small intestine region according to the polymer
펠루비프로펜을 비수용성 고분자와 수용성 고분자를 사용하여 서방화시켰을 때의, 소장영역에서의 약물방출의 차이를 평가하기 위해서, pH 6.8 용출액에서의 용출율(%)을 실험하였다. 상기 실시예 1 내지 6에서 제조한 정제와 비교예 1 및 2에서 제조한 정제를 가지고 하기와 같은 실험을 수행하였다. The dissolution rate (%) in the pH 6.8 eluate was tested to evaluate the difference in drug release in the small intestine when the pelubiprofen was sustained by using a water-insoluble polymer and a water-soluble polymer. Experiments were performed with the tablets prepared in Examples 1 to 6 and the tablets prepared in Comparative Examples 1 and 2 as follows.
용출률 실험은 대한약전 일반시험법 중 용출시험 제1법(회전검체통법)에 따라 실험하였다. 구체적으로 용출액은 900㎖(pH 6.8액), 온도는 37 ± 0.5℃로 용출하였다. 실험 시작 1시간 및 2시간후 용출액을 취하여 0.45㎛ 필터로 여과하고 UV로 분석하였고, 그 결과를 표 2에 나타내었다.(단위 %)The dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ± (pH 6.8 liquid), the temperature of 37 ± 0.5 ℃. 1 and 2 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 μm filter and analyzed by UV, and the results are shown in Table 2. (Unit%)
표 2
시간 1 시간 2 시간 4 시간
실시예 1 39.7 88.7 95.5
실시예 2 24.1 60.4 80.4
실시예 3 19.5 55.1 70.5
실시예 4 74.8 99.8 99.2
실시예 5 89.3 94.3 95.4
실시예 6 15.3 53.9 75.8
실시예 7 36.9 75.4 95.1
비교예 1 33.9 60.8 83.0
비교예 2 34.6 61.2 81.2
TABLE 2
time 1 hours 2 hours 4 hours
Example 1 39.7 88.7 95.5
Example 2 24.1 60.4 80.4
Example 3 19.5 55.1 70.5
Example 4 74.8 99.8 99.2
Example 5 89.3 94.3 95.4
Example 6 15.3 53.9 75.8
Example 7 36.9 75.4 95.1
Comparative Example 1 33.9 60.8 83.0
Comparative Example 2 34.6 61.2 81.2
이상의 실험으로부터, 펠루비프로펜을 비수용성 고분자를 사용하여 서방화시키는 경우, 소장영역에서 약물방출이 지속적으로 유지됨을 알 수 있다.From the above experiments, it can be seen that the drug release is continuously maintained in the small intestine when the pelubiprofen is sustained by using a water-insoluble polymer.
실험예 3. 콜리돈에스알 비율에 따른 펠루비프로펜의 용출률 실험Experimental Example 3. Dissolution rate test of pelubiprofen according to the ratio of collidone
콜리돈에스알 비율에 따른 펠루비프로펜의 서방화 조성물의 소장영역에서의 방출패턴을 알아보기 위해서 pH 6.8 용출율(%)을 실험하였다. In order to determine the release pattern in the small intestine region of the sustained release composition of pelubiprofen according to the ratio of collidone R, pH 6.8 dissolution rate (%) was tested.
상기 실시예 1 및 7 내지 9에서 제조한 정제를 가지고 하기와 같은 실험을 수행하였다. The following experiment was performed with the tablets prepared in Examples 1 and 7 to 9.
용출률 실험은 대한약전 일반시험법 중 용출시험 제1법(회전검체통법)에 따라 실험하였다. 구체적으로 용출액은 900㎖(pH 6.8액), 온도는 37 ± 0.5℃로 용출하였다. 실험 시작 1시간, 2시간 및 4시간후 용출액을 취하여 0.45㎛ 필터로 여과하고 UV로 분석하였고, 그 결과를 표 3 및 도 1에 나타내었다.(단위 %)The dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ± (pH 6.8 liquid), the temperature of 37 ± 0.5 ℃. After 1 hour, 2 hours and 4 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 μm filter and analyzed by UV, and the results are shown in Table 3 and FIG. 1 (unit%).
표 3
시간 1 시간 2 시간 4 시간
실시예8 71.5 96.4 98.1
실시예1 39.7 88.7 95.5
실시예9 35.2 70.7 94.5
실시예10 27.5 54.1 80.3
TABLE 3
time 1 hours 2 hours 4 hours
Example 8 71.5 96.4 98.1
Example 1 39.7 88.7 95.5
Example 9 35.2 70.7 94.5
Example 10 27.5 54.1 80.3
실험예 4. NSAIDs에 따른 용출률 실험Experimental Example 4. Dissolution rate experiment according to NSAIDs
실시예 1과 비교예 3, 4의 위장영역 및 소장영역에서의 용출률을 평가하기 위하여, pH 1.2 및 pH 6.8 용출액에서의 용출율(%)을 실험하였다. In order to evaluate the dissolution rates in the gastrointestinal and small intestine regions of Example 1 and Comparative Examples 3 and 4, the dissolution rates (%) in pH 1.2 and pH 6.8 eluates were tested.
용출률 실험은 대한약전 일반시험법 중 용출시험 제1법(회전검체통법)에 따라 실험하였다. 구체적으로 용출액은 900㎖(pH 1.2액 및 pH 6.8액), 온도는 37 ± 0.5℃, 패들의 회전속도는 100rpm으로 하여 용출하였다. 실험 시작 1시간, 2시간 및 4시간 후의 용출액을 취하여 0.45㎛ 필터로 여과하고 UV로 분석하였고, 그 결과를 표 4 및 도 2, 3에 나타내었다.(단위 %)The dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 and pH 6.8), at a temperature of 37 ± 0.5 ° C., and a rotational speed of the paddle at 100 rpm. After 1 hour, 2 hours and 4 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 μm filter, and analyzed by UV. The results are shown in Table 4 and FIGS. 2 and 3 (unit%).
표 4
pH 1.2 pH 6.8
시간 1 시간 2 시간 1 시간 2 시간 4 시간
실시예 1 5.0 8.9 39.7 88.7 95.5
비교예 3 55.1 72.1 73.5 93.7 99.8
비교예 4 65.8 77.9 64.4 85.6 94.5
Table 4
pH 1.2 pH 6.8
time 1 hours 2 hours 1 hours 2 hours 4 hours
Example 1 5.0 8.9 39.7 88.7 95.5
Comparative Example 3 55.1 72.1 73.5 93.7 99.8
Comparative Example 4 65.8 77.9 64.4 85.6 94.5
이상의 실험으로부터, 펠루비프로펜과 비수용성 고분자의 조합에 의해서 위장영역에서의 약물방출이 억제되며, NSAIDs에 속하는 다른 유효성분의 경우, 예를 들어, 케토프로펜 또는 록소프로펜등은 비수용성 고분자와 조합하여도 위장영역에서의 약물방출이 저하되지 않음을 알 수 있다.From the above experiments, drug release in the gastrointestinal tract is suppressed by the combination of pelubiprofen and a water-insoluble polymer, and in the case of other active ingredients belonging to NSAIDs, for example, ketoprofen or loxoprofen, etc. It can be seen that the drug release in the gastrointestinal tract does not decrease even in combination with the water-soluble polymer.
실험예 5. 시판중인 펠루비정과 펠루비프로펜 제어방출제제의 위장영역에서의 용출률 실험 Experimental Example 5 Dissolution Rate Experiment of Commercial Peluvicide and Pelubiprofen Controlled Release Agents in the Gastrointestinal Region
시판중인 펠루비정과 실시예 1의 위장영역에서의 용출률을 평가하기 위하여, pH 1.2 용출액에서의 용출양(mg)을 실험하였다. In order to evaluate the dissolution rate in commercially available Peluvi tablets and gastrointestinal zone of Example 1, the dissolution amount (mg) in pH 1.2 eluate was tested.
용출률 실험은 대한약전 일반시험법 중 용출시험 제1법(회전검체통법)에 따라 실험하였다. 구체적으로 용출액은 900㎖(pH 1.2액), 온도는 37 ± 0.5℃로 용출하였다. 실험 시작 0.5시간, 1시간, 2시간 후의 용출액을 취하여 0.45㎛ 필터로 여과하고 UV로 분석하였고, 그 결과를 표 5에 나타내었다.(단위 mg)The dissolution rate test was conducted according to the dissolution test method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. Specifically, the eluate was eluted at 900 ml (pH 1.2 liquid) and at a temperature of 37 ± 0.5 ° C. 0.5 hours, 1 hour, and 2 hours after the start of the experiment, the eluate was taken, filtered through a 0.45 μm filter, and analyzed by UV. The results are shown in Table 5 (unit mg).
표 5
시간 0.5 시간 1 시간 2 시간
펠루비정 27.3 28.6 29.8
실시예 1 1.5 2.3 4.0
Table 5
time 0.5 hour 1 hours 2 hours
Peluvijeong 27.3 28.6 29.8
Example 1 1.5 2.3 4.0
이상의 실험으로부터, 시판중인 펠루비정과 비교 시 펠루비프로펜을 비수용성 고분자를 사용하여 서방화시키는 경우, 위장영역에 약물이 노출되는 양이 약 7.5배 감소하는 것을 알 수 있다..From the above experiments, it can be seen that the amount of drug exposure to the gastrointestinal tract is reduced by about 7.5-fold when pelubiprofen is sustained by using a water-insoluble polymer as compared with commercially available peluvicide.
위 실험으로부터, 펠루비프로펜을 비수용성고분자로 서방화시키는 경우, 위장영역에서의 약물의 방출이 제한되고, 소장영역에서의 방출이 지속적으로 이루어짐을 알 수 있으며, 따라서, 위장관 부작용의 발현을 극소화시킴과 동시에 1일 2회 투여에 의해서 통증 조절을 효율적으로 조절할 수 있음을 알 수 있다. From the above experiments, it was found that when sustained release of pelubiprofen with water-insoluble polymers, the release of the drug in the gastrointestinal tract is restricted and the release in the small intestine continually occurs, thus minimizing the expression of gastrointestinal side effects. At the same time, it can be seen that pain control can be efficiently controlled by administration twice a day.
실험예 6. 동물실험 결과(Beagle)Experimental Example 6. Animal Test Results (Beagle)
펠루비정과 펠루비서방정의 동물실험(pharmacokinetics) 결과, 1일 3회 30mg씩 투약한 펠루비정과 1일 2회 45mg씩 투약한 펠루비서방정의 AUC는 각각 2470, 2515μg/L·hr으로 유사한 결과를 나타내었다.(도 4)The pharmacokinetics of Peluvi tablets and Peluviser tablets showed similar results with Peluvisi tablets administered 30mg 3 times a day and Peluviser tablets administered 45mg twice a day with 2470 and 2515μg / L · hr, respectively. (Fig. 4)

Claims (4)

  1. 펠루비프로펜과 방출제어고분자를 포함하는 약제학적 조성물에 있어서, 상기 방출제어용 고분자가 비수용성 고분자인 것을 특징으로 하는 약제학적 조성물.A pharmaceutical composition comprising felubipropene and a release controlling polymer, wherein the release controlling polymer is a water-insoluble polymer.
  2. 제 1항에 있어서, 상기 조성물은 위장영역(pH 1.2 용출액)에서 2시간 동안 30% 미만으로 용출되는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition of claim 1, wherein the composition is eluted at less than 30% for 2 hours in the gastrointestinal tract (pH 1.2 eluate).
  3. 제 2항에 있어서, 상기 조성물은 소장영역(pH 6.8 용출액)에 있어서 2시간 동안 50% 이상 용출되는 것을 특징으로 하는 약제학적 조성물.The pharmaceutical composition according to claim 2, wherein the composition is eluted at least 50% in the small intestine region (pH 6.8 eluate) for 2 hours.
  4. 제 2항 또는 제 3항에 있어서, 상기 비수용성 고분자는 카보머, 카르복시메칠셀룰로오스 칼슘, 셀룰로오스아세테이트프탈레이트, 메칠셀룰로오스, 히드록시프로필메칠셀룰로오스프탈레이트로부터 선택되는 셀룰로오스유도체, 미결정납, 백납, 카르나우바납, 경납 및 유화납으로부터 선택되는 왁스류, 메타아크릴레이트 코폴리머, 에칠셀룰로오스, 폴리비닐아세테이트, 콜리돈에스알 및 이들의 혼합물로 이루어진 군으로부터 선택되는 것을 특징으로 하는 약제학적 조성물.The cellulose derivative according to claim 2 or 3, wherein the water-insoluble polymer is selected from carbomer, carboxymethyl cellulose calcium, cellulose acetate phthalate, methyl cellulose, hydroxypropyl methyl cellulose phthalate, lead, microcrystalline lead, white lead and carnauba wax. Pharmaceutical composition, characterized in that the selected from the group consisting of waxes, methacrylate copolymers, ethyl cellulose, polyvinylacetate, collidone AL and mixtures thereof selected from braze and lead.
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