KR100567131B1 - Taste masking of oral ibuprofen and arginine solution - Google Patents
Taste masking of oral ibuprofen and arginine solution Download PDFInfo
- Publication number
- KR100567131B1 KR100567131B1 KR1020040000280A KR20040000280A KR100567131B1 KR 100567131 B1 KR100567131 B1 KR 100567131B1 KR 1020040000280 A KR1020040000280 A KR 1020040000280A KR 20040000280 A KR20040000280 A KR 20040000280A KR 100567131 B1 KR100567131 B1 KR 100567131B1
- Authority
- KR
- South Korea
- Prior art keywords
- ibuprofen
- arginine
- weight
- liquid composition
- bitter taste
- Prior art date
Links
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 title claims abstract description 58
- 229960001680 ibuprofen Drugs 0.000 title claims abstract description 58
- 239000004475 Arginine Substances 0.000 title claims abstract description 36
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 230000000873 masking effect Effects 0.000 title claims abstract description 13
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 title abstract description 5
- 235000019640 taste Nutrition 0.000 title description 10
- 239000000203 mixture Substances 0.000 claims abstract description 45
- 235000003599 food sweetener Nutrition 0.000 claims abstract description 29
- 239000003765 sweetening agent Substances 0.000 claims abstract description 29
- 235000019658 bitter taste Nutrition 0.000 claims abstract description 27
- 239000007788 liquid Substances 0.000 claims abstract description 25
- 108010011485 Aspartame Proteins 0.000 claims abstract description 14
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 claims abstract description 13
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 claims abstract description 8
- 235000010358 acesulfame potassium Nutrition 0.000 claims abstract description 8
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- 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
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Abstract
본 발명은 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물에 관한 것으로서, 보다 상세하게는 이부프로펜과 함께 주성분으로 사용된 아르기닌은 이부프로펜의 용해도를 증가시켜 액상제제의 쓴맛을 증가시키므로, 여기에 부형제로서 α, β및 γ-시클로덱스트린 및 이들의 복합체, 폴록사머 및 키토산에서 선택되는 1종 이상의 혼합물을 첨가하며, 고감미제로서 아세설팜칼륨과 아스파탐을 혼용하여 첨가함으로써 상기 프로피온산 유도체에 수반되는 얼얼하고 쓴 뒷맛을 투여초기부터 지속적으로 차폐할 수 있어서 제제의 복용시 거부감이 없고 보관시 안정한 새로운 제형으로서 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물에 관한 것이다.The present invention relates to an arginine-containing ibuprofen oral liquid composition masking bitter taste, and more particularly, arginine used as a main component with ibuprofen increases the solubility of ibuprofen to increase the bitter taste of the liquid formulation, , β and γ-cyclodextrin and complexes thereof, one or more mixtures selected from poloxamer and chitosan are added, and as a high sweetening agent, a mixture of acesulfame potassium and aspartame is used to freeze and bitter the propionic acid derivative. The present invention relates to a liquid composition for arginine-containing ibuprofen oral administration which masks the bitter taste as a new formulation which is able to continuously mask the aftertaste from the beginning of administration and has no objection when taking the preparation and is stable during storage.
이부프로펜, 아르기닌Ibuprofen, Arginine
Description
본 발명은 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물에 관한 것으로서, 보다 상세하게는 이부프로펜과 상기 이부프로펜의 가용화제로서 아르기닌을 사용하여 이부프로펜의 침전형성을 억제시켜 안정성을 부여하고, 여기에 부형제로서 α, β및 γ-시클로덱스트린 및 이들의 복합체, 폴록사머 및 키토산에서 선택되는 1종 이상의 혼합물을 첨가하며, 감미제로서 아세설팜칼륨과 아스파탐을 혼용하여 첨가함으로써 상기 프로피온산 유도체에 수반되는 얼얼하고 쓴 뒷맛을 투여초기부터 지속적으로 차폐할 수 있어서 제제의 복용시 거부감이 없고 보관시 안정한 새로운 제형으로서 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물에 관한 것이다.The present invention relates to a liquid composition for arginine-containing ibuprofen oral administration, which masks bitter taste, and more particularly, to provide stability by inhibiting precipitation formation of ibuprofen using arginine as a solubilizer of ibuprofen and ibuprofen, and as an excipient adds one or more mixtures selected from α, β, and γ-cyclodextrins and complexes thereof, poloxamer and chitosan, and freezes and bitters accompanying propionic acid derivatives by adding acesulpam potassium and aspartame as a sweetener The present invention relates to a liquid composition for arginine-containing ibuprofen oral administration which masks the bitter taste as a new formulation which is able to continuously mask the aftertaste from the beginning of administration and has no objection when taking the preparation and is stable during storage.
이부프로펜과 같은 NSAID 약물이 폴리에톡실화 비이온 또는 소르비탄 지방산 에스테르와 같은 계면활성제로 제형화되어 미셀 형성 조성물을 수득할 수 있다는 것이 유럽특허 제0274870호에 기재되어 있으며, 유럽특허 제0622072호에 인지질로 서 난황 레시틴, 대두 레시틴과 같은 물질을 사용하여 약물이 수성 제형 중의 리포좀에 캡슐화되는 리포좀의 형성이 제안되어 있다. It is described in EP 0274870 that NSAID drugs, such as ibuprofen, can be formulated with surfactants such as polyethoxylated nonions or sorbitan fatty acid esters to obtain micelle forming compositions, and in EP 0622072. Formation of liposomes has been proposed in which drugs are encapsulated in liposomes in aqueous formulations using substances such as egg yolk lecithin and soy lecithin as phospholipids.
미국특허 제4,684,666호에 이부프로펜이 다가알콜 점증제와 감미제가 50중량% 이상이고 pH가 7.0 내지 7.7인 수성 액체에 현탁한 이부프로펜 시럽이 기술되어있고, 유럽특허 제0298740 호에 이부프로펜이 주 현탁제인 크산탄 검, 미세결정성 셀률로즈, 나트륨 카르복시메틸 셀룰로스 및 폴리소르베이트 80에 의해 현탁액 속에 유지되며, pH를 3.5 내지 5.0으로 유지하고 미각차단제로 슈크로즈와 소르비톨 용액을 사용하였다고 기술하고 있으며, 유럽특허 제 0390369호에 완충용 산으로 시크르산과 인산, 감미제로 슈크로즈와 소르비톨을 20∼70% 함유하며 이부프로펜 조성물의 pH를 1.5 내지 3.5로 유지시켜야 한다고 기술하고 있다. U.S. Patent No. 4,684,666 describes ibuprofen syrup in which ibuprofen is suspended in an aqueous liquid having a polyhydric alcohol thickener and a sweetener of 50% by weight or more and a pH of 7.0 to 7.7, and European Patent No. 0298740 describes ibuprofen as the main suspending agent. It is described as being maintained in suspension by xanthan gum, microcrystalline cellulose, sodium carboxymethyl cellulose and polysorbate 80, maintaining pH between 3.5 and 5.0 and using sucrose and sorbitol solution as taste blocker, European patent No. 0390369 describes 20-70% of sucrose and sorbitol as buffer acids and sucrose and sorbitol as sweeteners and the pH of the ibuprofen composition should be maintained at 1.5 to 3.5.
국내특허 공개번호 특2002-0031382호에는 pH 의존 용해성을 가지는 MM/MAE(디메틸아미노에틸 메타크릴레이트 및 중성 메타크릴산 에스테르)와 셀룰로스 에스테르 중합체 혼합물로 역 장용성 코팅을 하고, 코팅된 성분이 들어있는 조성물의 pH를 5이상으로 유지하여 미각을 차폐하는 방법을 기술하고 있다.Korean Patent Publication No. 2002-0031382 discloses a reverse enteric coating with a mixture of MM / MAE (dimethylaminoethyl methacrylate and neutral methacrylic acid ester) and cellulose ester polymers having pH dependent solubility, and containing coated components. It describes a method of masking the taste by maintaining the pH of the composition above 5.
그러나, 유럽특허 제0274870호는 상당히 과량의 계면활성제를 필요로 하기 때문에 이부프로펜과 같은 비교적 높은 투여량의 약물에 대해서는 불만족스럽다.However, EP 0274870 is unsatisfactory for relatively high doses of drugs such as ibuprofen as it requires a significant excess of surfactant.
또한 유럽특허 제0622072호에서의 분산액은 하나 이상의 하이드록시산과 하나 이상의 아미노산을 함유하여 리포좀 분산액을 안정화시키지만, 2층 막 중의 약물의 캡슐화에는 착물 제조 단계가 필요하여 비교적 저가의 단순한 조성물을 어떻게 제공하는 지에 대해 전혀 제안하지 않는다.The dispersion in EP 0622072 also contains at least one hydroxy acid and at least one amino acid to stabilize the liposome dispersion, but encapsulation of the drug in the bilayer membrane requires a complex preparation step to provide a relatively inexpensive simple composition. I do not suggest at all.
유럽특허 제0298740호와 제030369호는 이부프로펜이 pH 5 내지 6이상에서 급격히 용해도가 상승한다는 것에 근거한 것으로 보이나, 이부프로펜이 현탁상태이므로 용해된 상태로 환자에게 투여되는 경우에 비해 약리효과가 현저히 떨어진다는 문제점을 가지고 있다.European Patent Nos. 0298740 and 300369 show that ibuprofen has a sharp increase in solubility above pH 5-6, but the pharmacological effect of ibuprofen is significantly lower than that when administered to a patient in a dissolved state. I have a problem.
상기에서 언급한 미각차폐된 이부프로펜 액제의 경우 종래의 기술들이 공개되어 있으나, 이부프로펜과 아르기닌을 함유하는 액제의 경우는 보고를 찾기가 쉽지 않은 형편이다. 이의 원인은 수용성인 아르기닌이 이부프로펜의 용해도를 향상시키므로 약물의 경구투여시 이부프로펜의 용해를 잠시 억제 시키거나 할 수 없기 때문에 미각차폐에 상당히 어려움이 있다.Conventional techniques have been disclosed in the case of the above-mentioned taste-blocked ibuprofen solution, but it is difficult to find a report in the case of a solution containing ibuprofen and arginine. The reason for this is that water-soluble arginine improves the solubility of ibuprofen, so it is difficult to shield the taste because it cannot temporarily inhibit the dissolution of ibuprofen during oral administration of the drug.
이에 본 발명의 발명자들은 상기와 같은 기존 제제화의 단점을 극복하고 동시에 안정화된 아르기닌 함유 이부프로펜 액상 조성물 및 이를 함유하는 시럽제를 개발하고자 한다. Therefore, the inventors of the present invention are to overcome the disadvantages of the conventional formulation as described above and to develop a stabilized arginine-containing ibuprofen liquid composition and a syrup containing the same.
본 발명에서는 아르기닌에 의해 이부프로펜이 용해된 상태 즉, 쓴맛이나 얼얼한 느낌이 현저한 상태에서 이부프로펜 특유의 얼얼함과 쓴맛을 아세설팜칼륨과 아스파탐을 포함하는 고감미제를 사용하여 차폐시키고자 하였으며, 부형제와 점증제의 선택사용으로 장기간 보존시에도 침전과 같은 문제점이 없는 안정화된 제제를 제조할 수 있음을 알게되어 본 발명을 완성하였다. In the present invention, ibuprofen is dissolved by arginine, that is, the bitterness or tingling sensation in the state of remarkable bitterness and bitterness was tried to mask using a high sweetener containing acesulfame potassium and aspartame, excipient and increment The present invention has been completed by knowing that selective use of the agent can produce a stabilized formulation without problems such as precipitation even during long term storage.
따라서, 본 발명은 프로피온산 유도체에 수반되는 얼얼하고 쓴 뒷맛을 투여초기부터 지속적으로 차폐할 수 있어서 제제의 복용시 거부감이 없고 보관시 안정한 새로운 제형으로서의 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물을 제공하는데 그 목적이 있다.
Accordingly, the present invention provides a liquid composition for arginine-containing ibuprofen oral administration that masks the bitter taste as a new formulation that is stable in storage and can be continuously shielded from the beginning of administration of the frozen and bitter aftertaste accompanying propionic acid derivatives. Its purpose is to.
본 발명은 부형제, 감미제, 점증제, 향료 및 색소 중에서 선택된 보조제를 포함하는 경구 투여용 액상 제제에 있어서, 이부프로펜 1 ∼ 3 중량%와 아르기닌 1 ∼ 3 중량%를 주성분으로 하고, β-시클로덱스트린 10 ∼ 15 중량%, 아스파탐과 아세설팜칼륨이 9 ∼ 7 : 1 ∼ 3 중량비로 혼합된 고감미제 0.2 ∼ 0.5 중량%, 감미제 55 ∼ 85 중량%, 점증제 0.1 ∼ 0.3 중량% 및 잔부량의 정제수를 포함하는 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물을 특징으로 한다.The present invention relates to a liquid preparation for oral administration comprising an adjuvant selected from excipients, sweeteners, thickeners, flavorings and pigments, wherein 1-3 parts by weight of ibuprofen and 1 to 3% by weight of arginine are the main components, and β-cyclodextrin 10 To 15% by weight, 0.2 to 0.5% by weight of high sweetener mixed with aspartame and acesulfame potassium in a ratio of 9 to 7: 1 to 3, 55 to 85% by weight of sweetener, 0.1 to 0.3% by weight of thickener, and the balance of purified water Characterized by arginine-containing ibuprofen oral liquid composition masking the bitter taste, including.
이와 같은 본 발명을 조성성분별로 구체적으로 설명하면 다음과 같다.The present invention will be described in detail for each component as follows.
본 발명은 이부프로펜과 함께 주성분으로 사용된 아르기닌은 이부프로펜의 용해도를 증가시켜 액상제제의 쓴맛을 증가시키므로, 여기에 부형제로서 α, β및 γ-시클로덱스트린 및 이들의 복합체, 폴록사머 및 키토산에서 선택되는 1종 이상의 혼합물을 첨가하며, 고감미제로서 아세설팜칼륨과 아스파탐을 혼용하여 첨가함으로써 상기 프로피온산 유도체에 수반되는 얼얼하고 쓴 뒷맛을 투여초기부터 지속적으로 차폐할 수 있어서 제제의 복용시 거부감이 없고 보관시 안정한 새로운 제형 으로서 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물에 관한 것이다.In the present invention, arginine used as a main component with ibuprofen increases the solubility of ibuprofen and increases the bitter taste of the liquid formulation, and thus is selected from α, β, and γ-cyclodextrin and their complexes, poloxamers, and chitosan as excipients. By adding one or more mixtures and adding acesulfame potassium and aspartame as a high sweetening agent, the frozen and bitter aftertaste accompanying propionic acid derivatives can be continuously masked from the beginning of administration, so there is no objection when taking the preparation and it is stored. As a new stable formulation, it relates to an arginine-containing ibuprofen oral liquid composition masking bitter taste.
먼저, 본 발명의 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물은 프로피온산 유도체 1 ∼ 3 중량%와 수용성 염기성 유기화합물 1 ∼ 3 중량%를 주성분으로 하고, 부형제 10 ∼ 15 중량%, 고감미제 0.2 ∼ 0.5 중량%, 감미제 55 ∼ 85 중량%, 점증제 0.1 ∼ 0.3 중량%, 향료 및 색소 적량 및 잔부량의 정제수를 포함하여 구성된다.First, the arginine-containing ibuprofen orally administered liquid composition masking the bitter taste of the present invention contains 1 to 3% by weight of propionic acid derivative and 1 to 3% by weight of a water-soluble basic organic compound, and 10 to 15% by weight of an excipient, and a high sweetener 0.2 to It consists of 0.5 weight%, 55-85 weight% of sweeteners, 0.1-0.3 weight% of thickeners, a fragrance | flavor and a pigment | dye quantity, and remainder of purified water.
먼저, 프로피온산 유도체는 이부프로펜, 나프록센 베녹사프로펜, 나프록센 나트륨, 플루르비프로펜, 페노프로펜, 펜부프로펜, 케토프로펜 인도프로펜, 피르프로펜, 카르포펜, 옥사프로펜, 프라노프로펜, 미크로프로펜, 티옥사프로펜, 수프로프로펜, 알미노프로펜, 티아프로펜산, 츨루프로펜 및 부클록신산 중에서 선택된 것을 사용할 수 있다. 본 발명의 상세한 설명에서는 상기한 프로피온산 유도체 중에서도 이부프로펜을 위주로 하여 설명한다.First, propionic acid derivatives are ibuprofen, naproxen benoxapropene, naproxen sodium, flurbiprofen, phenopropene, fenbuprofen, ketoprofen indopropene, pirpropene, carpopene, oxapropene, It can be used selected from pranopropene, micropropene, thioxapropene, supropene, aminopropene, thiapropenic acid, zlupropene and buclosinic acid. In the detailed description of the present invention, ibuprofen will be mainly described among the propionic acid derivatives described above.
상기한 이부프로펜은 전체 경구투여 액상 조성물 중량에 대하여 1 ∼ 3 중량% 사용하며, 이때 사용량이 1 중량% 미만이면 이부프로펜으로 얻을 수 있을 것으로 예상되는 약효 항진통성, 항염증성 및 항발열성을 얻을 수 없으며, 3 중량%를 초과하면 위장장애, 신장독성 등의 문제점을 일으킬 수 있다. The ibuprofen is used in an amount of 1 to 3% by weight based on the total weight of the oral liquid composition, and when the amount is less than 1% by weight, the antifungal, anti-inflammatory and antipyrogenic properties expected to be obtained by ibuprofen cannot be obtained. If it exceeds 3% by weight, it can cause problems such as gastrointestinal disorders and kidney toxicity.
다음으로, 상기 프로피온산 유도체의 용출율을 향상시킬 수 있는 수용성 염기성 유기화합물을 사용한다. 상기 수용성 염기성 유기화합물은 아르기닌, 리 신 및 히스티딘 중에서 선택된 염기성 아미노산, 메글루민, 에글루민 및 유기성 아민염 등 중에서 선택된 1종 또는 2종 이상의 혼합물을 사용할 수 있다. 본 발명의 상세한 설명에서는 상기한 수용성 염기성 유기화합물 중에서도 아르기닌을 위주로 하여 설명하는데, 염기성 아미노산인 아르기닌은 생성된 NO(Nitric oxide)가 산화제로 작용하여 산소라디칼에 의한 위점막 보호작용을 하여 이부프로펜의 위장장애 등의 문제점을 해결할 수 있는 효과도 부여한다. Next, a water-soluble basic organic compound capable of improving the dissolution rate of the propionic acid derivative is used. The water-soluble basic organic compound may be used one or a mixture of two or more selected from basic amino acids selected from arginine, lysine and histidine, meglumine, eglumine and organic amine salts. In the detailed description of the present invention, the above-mentioned water-soluble basic organic compounds are mainly described with arginine, and the basic amino acid arginine is a gastrointestinal ibuprofen by protecting the gastric mucosa by oxygen radicals by acting as an oxidizing agent. It also gives the effect of solving problems such as disability.
상기한 아르기닌은 전체 경구투여 액상 조성물 중량에 대하여 1 ∼ 3 중량% 사용하며, 이때 사용량이 1 중량% 미만이면 이부프로펜의 가용화를 향상시킬 수 없다는 문제점이 있다.Arginine is used in an amount of 1 to 3% by weight based on the total weight of the oral administration liquid composition, and when the amount is less than 1% by weight, there is a problem in that solubilization of ibuprofen cannot be improved.
또한, 아르기닌의 사용으로 인하여 상기한 이부프로펜의 용해가 증가하게 되고, 이에 따라 이부프로펜의 쓴맛과 얼얼한 맛이 더욱 강하게 느껴지게 되어, 상기한 쓴맛 및 얼얼한 맛의 차폐의 필요성이 더욱 부각되게 된다. 본 발명에서는 상기한 쓴맛과 얼얼한 맛의 효율적인 차폐를 위하여 특정한 부형제와 고감미제의 사용을 필수구성요소로 하는 아르기닌을 함유한 이부프로펜 경구 투여 액상 조성물을 제공한다. In addition, the use of arginine increases the dissolution of ibuprofen, and thus the bitter and tingling taste of ibuprofen is more strongly felt, and the necessity of masking the bitter and tingling taste is further highlighted. The present invention provides a liquid composition for oral administration of ibuprofen containing arginine, which is an essential component of the use of specific excipients and high sweeteners for the effective masking of the bitter and tingling taste.
일반적으로 부형제는 쓴맛 차폐의 한 역할을 수행하는 성분으로, 본 발명에서는 상기한 부형제로서 α, β및 γ-시클로덱스트린 또는 이들의 복합체, 폴록사머, 키토산 및 키토올리고당 중에서 선택된 1종 또는 2종 이상의 혼합물을 사용한다. 본 발명에서는 상기한 β-시클로덱스트린을 필수구성요소로 포함한다.In general, an excipient is a component that plays a role of bitterness masking, and in the present invention, one or two or more selected from α, β, and γ-cyclodextrin or a complex thereof, poloxamer, chitosan, and chitooligosaccharide as the excipients described above. Use a mixture. In the present invention, the aforementioned β-cyclodextrin is included as an essential component.
상기한 부형제는 경구투여 액상 조성물 총중량에 대하여 10 ∼ 15 중량% 사용하며, 이때 사용량이 10 중량% 미만이면 고감미제와 함께 사용하여도 완전한 맛 차폐의 목적을 달성할 수 없으며, 15 중량%를 초과하면 완전히 용해되지 않아 제제학상의 문제점이 있다.The above-mentioned excipient is used in an amount of 10 to 15% by weight based on the total weight of the orally administered liquid composition, and when the amount is less than 10% by weight, even when used with a high sweetening agent, the purpose of complete taste masking may not be achieved, and more than 15% by weight If not completely dissolved there is a pharmaceutical problem.
본 발명은 상기 이부프로펜이 가지는 얼얼하고 자극적인 쓴맛을 효율적으로 차폐시키기 위하여 감미제를 사용하되, 특히 고감미제로서 아스파탐과 아세설팜칼륨을 필수구성성분으로 사용한다. 특히, 복용 초기에 감미가 적게 느껴지나 복용 후 감미가 지속적으로 느껴지는 아스파탐과 복용 초기에는 감미가 강하게 느껴지는 아세설팜칼륨 혼합물을 첨가할 경우 쓴맛의 차폐 효과를 더욱 크게 할 수 있으며, 아스파탐과 아세설팜칼륨 9 ∼ 7 : 1 ∼ 3 중량비로 혼합하여 사용하면 그 효과를 극대화 할 수 있다. 상기한 고감미제는 전체 경구투여 액상 조성물 중량에 대하여 0.2 ∼ 0.5 중량% 사용하며, 이때 사용량이 0.2 중량% 미만이면 쓴맛 차폐능이 좋지 못하고, 0.5 중량%를 초과하면 독성의 문제를 야기 시킬 수 있다.In the present invention, a sweetener is used to effectively mask the pungent and irritating bitterness of the ibuprofen, and in particular, aspartame and acesulfame potassium are used as essential components as a high sweetener. In particular, the addition of aspartame, which feels less sweet at the beginning but continues to feel sweet after taking, and acesulpam potassium mixture, which is strongly sweet at the beginning, can increase the masking effect of bitter taste. When used by mixing in a potassium potassium 9-7: 1 to 3weight ratio, the effect can be maximized. The high sweetener is used 0.2 to 0.5% by weight based on the total weight of the oral liquid composition, when the amount is less than 0.2% by weight bad bite shielding ability is bad, if it exceeds 0.5% by weight can cause toxicity problems.
이 외에도 감미제로는 말티톨, 이소말트, 소르비톨, 에리스리톨 및 글리세린 등 중에서 선택된 당 알코올과, 백당, 프락토올리고당, 대두올리고당, 자일로 올리고당 및 팔라치노스 올리고당 등 중에서 선택된 올리고당 중에서 선택된 1종 또는 2종 이상의 혼합물을 사용할 수 있다.In addition, sweeteners include one or two or more selected from sugar alcohols selected from maltitol, isomalt, sorbitol, erythritol and glycerin, and oligosaccharides selected from white sugar, fructooligosaccharide, soy oligosaccharide, xylo oligosaccharide and palatinose oligosaccharide. Mixtures can be used.
점증제는 이부프로펜의 쓴맛이 미각에 미치는 영향을 줄이는 효과를 나타내 고, 안정성이 우수하여 저온에서도 용액의 성질을 유지하며 침전물이 발생하지 않도록 하는 역할을 수행하는 성분으로서, 본 발명에서는 상기한 점증제로서 카르복시메틸 셀룰로오스나트륨, 히드록시프로필 메틸셀룰로오스, 하이드록시에틸 셀룰로오스, 젤라틴 및 폴리비닐 피롤리돈 등 중에서 선택된 1종 또는 2종 이상의 혼합물을 사용한다. 상기한 점증제는 전체 경구투여 액상 조성물 중량에 대하여 0.1 ∼ 0.3 중량% 사용하며, 이때 사용량이 0.1 중량% 미만이면 조성물의 안정성에 문제가 있고, 0.3 중량%를 초과하면 높은 점도로 인해 제제의 투여가 용이하지 않다는 문제점이 있다.Thickener is an ingredient that has the effect of reducing the effect of the bitter taste of ibuprofen on the taste, excellent stability and plays the role of maintaining the properties of the solution even at low temperatures, and do not generate precipitates, in the present invention, the thickener As the sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, gelatin, polyvinyl pyrrolidone and the like, one kind or a mixture of two or more kinds are used. The thickener is used in an amount of 0.1 to 0.3% by weight based on the total weight of the oral liquid composition, and when the amount is less than 0.1% by weight, there is a problem in the stability of the composition. There is a problem that it is not easy.
상기한 성분 외에, 향료, 색소 및 보존제 등의 본 발명의 해당 분야에서 통상적으로 사용하는 보조제를 사용자의 선택에 따라 적당량 사용할 수 있으며, 정제수를 사용하여 상기 성분들을 용해시킨 액상 조성물을 제조한다.In addition to the above components, adjuvants commonly used in the relevant fields of the present invention, such as perfumes, colorants, and preservatives, may be appropriately used according to a user's selection, and a liquid composition in which the above components are dissolved using purified water is prepared.
이하, 본 발명의 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물을 제조하는 방법을 간단하게 설명한다.Hereinafter, a method for preparing an arginine-containing ibuprofen oral liquid composition masking the bitter taste of the present invention will be described briefly.
먼저, 수용성 염기성 유기화합물로서 아르기닌 등을 적량의 정제수에 완전히 용해시키고, 별도의 용기에 시클로덱스트린류, 폴록사머, 키토산 또는 키토올리고당과 같은 부형제 중 선택된 1종 이상을 충분히 용해시킨다. 또한, 상기와는 별도의 용기에 선택된 감미제를 충분히 용해시켜서 준비한다.First, arginine or the like as a water-soluble basic organic compound is completely dissolved in an appropriate amount of purified water, and at least one selected from excipients such as cyclodextrins, poloxamers, chitosan or chitooligosaccharides is sufficiently dissolved in a separate container. In addition, the selected sweetener is sufficiently dissolved and prepared in a container separate from the above.
상기 감미제를 용해시킨 용액에 상기 아르기닌과 부형제를 각각 용해시킨 용 액을 함께 넣고, 여기에 이부프로펜을 첨가하여 45 내지 75 ℃에서 충분히 교반하여 투명한 용액을 제조한다.Into the solution in which the sweetener was dissolved, a solution in which arginine and an excipient were dissolved, was added together, and ibuprofen was added thereto, followed by sufficiently stirring at 45 to 75 ° C. to prepare a transparent solution.
여기에 미리 용해시켜둔 점증제나 색소, 향료 등의 통상의 보조제를 첨가하고 정제수로 100 ml를 채워 상기 본 발명에서 목적하는 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물을 제조한다.Ordinary supplements such as thickeners, pigments and fragrances previously dissolved therein are added thereto, and 100 ml of purified water is used to prepare an arginine-containing ibuprofen orally administered liquid composition shielding the bitter taste desired in the present invention.
본 발명의 쓴맛을 차폐한 아르기닌 함유 이부프로펜 경구투여 액상 조성물은 이부프로펜 특유의 얼얼한 쓴맛을 효율적으로 차폐하여 복용시 거부감이 없고, 보관 안정성이 우수하게 개선된다.Arginine-containing ibuprofen oral liquid composition for masking the bitter taste of the present invention effectively masks the bitter taste peculiar to ibuprofen, there is no rejection when taken, and storage stability is improved.
이하, 본 발명을 실시예에 의거하여 구체적으로 설명하겠는바, 본 발명이 다음 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by the following Examples.
실시예 1 ∼ 3 및 비교예 1 ∼ 2Examples 1-3 and Comparative Examples 1-2
다음 표 1에 나타낸 바와 같은 조성성분 및 함량으로 칭량하여 아르기닌, 부형제, 감미제를 정제수에 용해시킨 용액을 각각 제조한 다음, 상기 감미제 용액에 이부프로펜, 아르기닌 용액, 부형제 용액을 첨가한 다음 45 또는 75 ℃이하에서 충분히 교반하여 투명한 용액으로 제조하였다. 상기 제조한 투명한 용액에 미리 용해시켜둔 점증제, 색소, 향료, 보존제를 첨가하고 정제수로 100 ml를 채워 시럽제를 제조하였다. Next, to prepare a solution in which arginine, excipients and sweeteners were dissolved in purified water by weighing the ingredients and contents as shown in Table 1, and then adding ibuprofen, arginine solution, and excipient solution to the sweetener solution at 45 or 75 ° C. Stirring well below, to prepare a clear solution. A syrup was prepared by adding a thickener, a pigment, a fragrance, and a preservative previously dissolved in the transparent solution prepared above, and filling 100 ml with purified water.
상기와 같이 조제된 조성물의 쓴맛 차폐 정도를 확인하기 위해 적어도 5인 이상의 사람에게 투여한 결과, 본 발명의 실시예 중 특히 아세설팜칼륨과 아스파탐을 혼합하여 사용한 실시예 1의 경우에는 복용 초기 아세설팜칼륨의 감미와 아스파탐의 지속적으로 느껴지는 감미에 의해 이부프로펜의 얼얼한 쓴맛이 효율적으로 차폐되어 그 쓴맛과 얼얼함을 나타내지 않았다.As a result of administering to at least five or more persons to confirm the degree of bitterness masking of the composition prepared as described above, in the case of Example 1, especially in the case of Example 1 in which acesulfame potassium and aspartame were mixed, The sweet bitter taste of ibuprofen was effectively masked by the sweet taste of cesulfame potassium and the persistent sweetness of aspartame, indicating no bitterness.
반면, 고감미제로서 사용된 아세설팜칼륨과 아스파탐 중 1종만을 사용한 실시예 2, 3에서는 초기 또는 뒷맛에서 얼얼함과 쓴맛이 느껴졌으며, 고감미제가 제외된 비교예 2는 이부프로펜 특유의 얼얼함이 강하게 나타났다.On the other hand, in Examples 2 and 3 using only one type of acesulpam potassium and aspartame used as a high sweetening agent, tingling and bitterness were felt in the initial or aftertaste, and Comparative Example 2 without the high sweetening agent was strongly characterized by ibuprofen-specific freezing. appear.
저장 안정성은 -5 ℃ 및 상온에서 보관하여 침전상태를 평가하였으며, 본 발명의 실시예 1 ∼ 3 의 경우 -5 ℃, 상온에서 보관 동안 침전물의 형성 없이 안정한 액상을 유지하였으나, 비교예 1의 경우는 아세설팜칼륨과 아스파탐을 혼합하여 사용하였지만 부형제로서 사용한 폴록사머가 완전히 용해되지 않을뿐더러 침전물이 생기는 등의 상이 불안정한 문제점을 나타내었다.The storage stability was measured at -5 ℃ and room temperature to evaluate the precipitation state, in the case of Examples 1 to 3 of the present invention was maintained at a stable liquid phase without the formation of a precipitate during storage at -5 ℃, room temperature, Comparative Example 1 Although acesulpam potassium and aspartame were used in a mixed state, the poloxamer used as an excipient not only completely dissolved, but also exhibited an unstable phase such as a precipitate.
상기에 나타난 결과와 같이 본 발명의 감미제로 단맛이 초기에 감지되는 아세설팜칼륨과 단맛의 감지가 늦지만 오래 지속되는 아스파탐을 혼용함으로서, 프로피온산 특유의 얼얼함과 쓴맛을 갖는 약물의 경구투여 시 투여 초기부터 환자가 느끼는 불쾌감을 지속적으로 차단할 수 있다.As shown in the above results, by using acesulpam potassium potassium which is initially detected as a sweetener and aspartame which is delayed in detection of sweetness but as a long-lasting sweetener, the oral administration of a drug having a tingling and bitter taste peculiar to propionic acid may be administered. From the outset, the discomfort that the patient feels can continue to be blocked.
또한 적절한 점증제로서 고분자 폴리머를 사용하여, 이부프로펜의 쓴맛이 미각에 미치는 영향을 줄이는 효과를 나타내고, 안정성이 우수하여 저온에서도 용액의 성질을 유지하며 침전물이 발생하지 않아, 타 이부프로펜 시럽제제에 비해 뛰어난 쓴맛 차폐 능력 및 안정한 액상제제를 제공하여 복용이 편리하고 뛰어난 약효발현 효과를 기대할 수 있다.
In addition, by using a polymeric polymer as an appropriate thickener, it exhibits the effect of reducing the effect of the bitter taste of ibuprofen on taste, excellent stability, and maintains the properties of the solution even at low temperatures, and does not generate precipitates, which is superior to that of ibuprofen syrup By providing bitterness shielding ability and stable liquid preparation, it is easy to take and can expect excellent drug expression effect.
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US5024997A (en) * | 1990-06-22 | 1991-06-18 | American Home Products Corporation | Palatable ibuprofen solutions |
US5597583A (en) * | 1992-04-10 | 1997-01-28 | Smithkline Beecham P.L.C. | Pharmaceutical composition |
US5866162A (en) * | 1993-08-10 | 1999-02-02 | Smithkline Beecham P.L.C. | Pharmaceutical composition containing a drug/β-cyclodextrin complex in combination with an acid-base couple |
EP1312355A1 (en) * | 2001-11-20 | 2003-05-21 | Apr Applied Pharma Research S.A. | Water-soluble non-effervescent pharmaceutical compositions comprising non-steroidal anti-inflammatory drugs |
KR20030041577A (en) * | 2001-11-20 | 2003-05-27 | 디디에스텍주식회사 | Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations |
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US5024997A (en) * | 1990-06-22 | 1991-06-18 | American Home Products Corporation | Palatable ibuprofen solutions |
US5597583A (en) * | 1992-04-10 | 1997-01-28 | Smithkline Beecham P.L.C. | Pharmaceutical composition |
US5866162A (en) * | 1993-08-10 | 1999-02-02 | Smithkline Beecham P.L.C. | Pharmaceutical composition containing a drug/β-cyclodextrin complex in combination with an acid-base couple |
EP1312355A1 (en) * | 2001-11-20 | 2003-05-21 | Apr Applied Pharma Research S.A. | Water-soluble non-effervescent pharmaceutical compositions comprising non-steroidal anti-inflammatory drugs |
KR20030041577A (en) * | 2001-11-20 | 2003-05-27 | 디디에스텍주식회사 | Solid dispersions containing substituted cyclodextrin and insoluble drug and their preparations |
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