KR0177306B1 - Composition of mixture of somatotropin and vitamins - Google Patents
Composition of mixture of somatotropin and vitamins Download PDFInfo
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- KR0177306B1 KR0177306B1 KR1019960003739A KR19960003739A KR0177306B1 KR 0177306 B1 KR0177306 B1 KR 0177306B1 KR 1019960003739 A KR1019960003739 A KR 1019960003739A KR 19960003739 A KR19960003739 A KR 19960003739A KR 0177306 B1 KR0177306 B1 KR 0177306B1
- Authority
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- South Korea
- Prior art keywords
- somatotropin
- composition
- vitamin
- vitamins
- present
- Prior art date
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- 229940088594 vitamin Drugs 0.000 title claims abstract description 27
- 239000011782 vitamin Substances 0.000 title claims abstract description 27
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 10
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- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 8
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 5
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- 229940046008 vitamin d Drugs 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
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- 241001465754 Metazoa Species 0.000 description 12
- 238000009472 formulation Methods 0.000 description 12
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 11
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- 108010006025 bovine growth hormone Proteins 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 5
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 5
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 description 5
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- 208000007101 Muscle Cramp Diseases 0.000 description 2
- VYGQUTWHTHXGQB-FFHKNEKCSA-N Retinol Palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-FFHKNEKCSA-N 0.000 description 2
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- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical compound O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 1
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- VYGQUTWHTHXGQB-UHFFFAOYSA-N Retinol hexadecanoate Natural products CCCCCCCCCCCCCCCC(=O)OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C VYGQUTWHTHXGQB-UHFFFAOYSA-N 0.000 description 1
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- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/07—Retinol compounds, e.g. vitamin A
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Endocrinology (AREA)
- Dermatology (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
본 발명은 생체내 활성을 갖는 소마토트로핀과 비타민의 합제 조성물에 관한 것으로, 소마토트로핀과 적어도 2종의 지용성 비타민이 혼합된 것을 특징으로 하는 소마토트로핀과 비타민의 합제 조성물은, 지금까지의 투여 수단으로서 가장 보편화된 주사 방법으로 체내에 주입할 수 있을 뿐 아니라, 별도로 투여하던 비타민 제제를 소마토트로핀과 함께 동시에 투여함으로써 이들의 상승효과를 얻을 수 있으며, 동물의 주사 횟수를 줄여 이에 따른 고통을 경감시키는 동시에, 주사 투여에 요하는 노동력도 절감시킬 수 있다.The present invention relates to a mixture composition of somatotropin and vitamin having in vivo activity, wherein the mixture composition of somatotropin and vitamin, characterized in that the mixture of somatotropin and at least two fat-soluble vitamins, As a means of administration up to now, not only can it be injected into the body by the most common injection method, but also a synergistic effect can be obtained by simultaneously administering a separately administered vitamin preparation together with somatotropin, This can alleviate the pain and reduce the labor required for injection.
Description
제1도는 a 및 b도는 난쟁이 래트에서 본 발명의 조성물에 의한 체중증가를 나타낸 그래프이고,1 is a and b is a graph showing the weight gain by the composition of the present invention in dwarf rats,
제2도는 젖소에서 본 발명의 조성물에 의한 산유량 증가를 나타낸 그래프이다.2 is a graph showing the increase in acid flow rate by the composition of the present invention in cows.
본 발명은 생체내 활성을 갖는 소마토트로핀과 비타민의 합제 조성물에 관한 것으로, 특히 소마토트로핀과 지용성 비타민의 적절한 혼합 조성물을 만들어 동물에 비경구적으로 투여함으로써, 이들을 별도로 투여해야 하는 번거로움을 해결하고, 두가지 약제의 지속성 효과 및 상승적 효과를 얻을 수 있도록 고안된 조성물에 관한 것이다.The present invention relates to a combination composition of somatotropin and vitamins having in vivo activity, and in particular, by making an appropriate mixed composition of somatotropin and fat-soluble vitamins and administering them parenterally to an animal, it is necessary to separately administer them. The present invention relates to a composition designed to solve the problem and to obtain a sustained effect and a synergistic effect of two drugs.
유전공학의 발달로 유전자 재조합 기술에 의해 대량 생산이 가능해진 소의 소마토트로핀은 현재 산유량을 증가시킬 목적으로 상업적으로 이용할 수 있게 되었고, 돼지 소마토트로핀은 사료 효율 개선과 육질 개선 방향으로 계속 연구가 진행되고 있는 상황이다.The development of genetic engineering has made cattle somatotropins available for mass production by genetic recombination technology now commercially available for the purpose of increasing production, and pig somatotropins continue to improve feed efficiency and meat quality. Research is ongoing.
생체내 활성을 갖는 소마토트로핀을 투여하는 방법으로서 현재까지 개발된 것은, 매일 투여하는 번거로움을 피하기 위해 과량의 소마토트로핀을 투여하여 단지 지속성 만을 연장시킨 제형이 대부분이다. 예를 들어, 대한민국 특허공고 제 89-2631 호에서는, 기존의 항생제 등 여러 가지 약물의 지속성 제형을 만들기 위해 보편적으로 사용되어 왔던 식물성 오일에 알루미늄 모노스테아레이트와 같은 항수화제를 첨가하여 오일을 교질(gel)화시키고, 여기에 전이 금속에 착화시킨 소마토트로핀을 균질혼합시켜 지속성 만을 연장시킨 제형을 개시하고 있다. 이와 유사한 예로서 유럽특허 제 314,421 호 및 대한민국 특허공개공보 제 87-1825 호 등에서는, 오일을 사용하여 소마토트로핀의 지속성 만을 연장시킨 제형들이 개시되었는데, 이들 역시 기존의 다른 약물에 적용되어온 유성 주사제 조성물에 단지 소마토트로핀 만을 치환시켜 적용한 제형들이다.What has been developed so far to administer somatotropin with in vivo activity is most of the formulations that only prolong persistence by administering excess somatotropin to avoid the hassle of daily administration. For example, Korean Patent Publication No. 89-2631 discloses that oils may be added to vegetable oils that have been commonly used to make long-lasting formulations of drugs, such as antibiotics, by adding an antihydrating agent such as aluminum monostearate. A formulation wherein the persistence is only extended by homogenizing the gelation and somatotropin complexed to the transition metal is disclosed. As a similar example, European Patent No. 314,421 and Korean Patent Publication No. 87-1825 have disclosed formulations that extend only the sustainability of somatotropin with oil, which has also been applied to other drugs. These formulations are applied by replacing only somatotropin with the injection composition.
지속성을 위해 오일을 사용하지 않은 기술로서는, 대한민국 특허출원 제 90-1689 호 및 제 90-23104 호에서 초산 토코페롤과 부형제를 사용한 예를 개시하고 있다. 그러나, 이 때 초산 토코페롤은 단지 지속성 만을 연장시키기 위한 부형제로서 사용되어 생리적으로 필요한 용량보다 과량 첨가되기 때문에, 기온이 떨어지는 겨울에는 초산 토코페롤의 점도가 증가하여 투여하는데 불편하다는 문제점이 초래되었다.As a technique that does not use oil for sustainability, Korean Patent Application Nos. 90-1689 and 90-23104 disclose examples of using tocopherol acetate and excipients. However, at this time, tocopherol acetate is used as an excipient for prolonging only the persistence and is added in excess of the physiologically necessary dose, resulting in a problem of increasing the viscosity of tocopherol acetate in the winter when the temperature is low, which is inconvenient to administer.
이 밖에 다른 기술에서는 대부분 소마토트로핀의 지속성을 연장하고자 이식 제형의 고형 조성물들을 적용하고 있다. 대표적인 기술로서 대한민국 특허공고 제 92-5660 호 및 제 90-6886 호 등에서는 고가의 삼투압 펌프 장치를 수술을 통하여 이식시키거나, 특별한 이식 기구를 사용하여 압착 제조된 소마토트로핀을 동물 체내에 이식시켜 지속성을 확보하려 하였다. 그러나, 이러한 이식 기술들은 동물에 적용하기 힘들 뿐 아니라, 동물들이 느끼는 이물감도 크다는 단점이 있다.In addition, most of the other techniques apply the solid compositions of the implant formulation to extend the persistence of somatotropin. As a representative technique, Korean Patent Publication Nos. 92-5660 and 90-6886 disclose that an expensive osmotic pump device is implanted through surgery, or a somatotropin produced by compression using a special implantation apparatus is implanted into an animal body. We tried to secure the sustainability. However, these transplant techniques are not only difficult to apply to animals, but also have a disadvantage of having a large sense of foreign object.
본 발명자들은 이상 언급한 바와 같은 소마토트로핀 지속성 제형의 문제점을 고려하여 이를 해결하고자 연구한 결과, 소마토트로핀에 지용성 비타민을 적정 비율로 혼합한 후 제형화시킴으로써, 지금까지의 투여 수단으로서 가장 보편화된 주사 방법을 통하여 체내에 주입할 수 있을 뿐 아니라, 일회의 주사로 이들 소마토트로핀과 비타민 제제를 한꺼번에 투여하여 상승효과를 얻을 수 있게 되었다.The present inventors have studied to solve this problem in consideration of the problems of somatotropin sustained-release formulation as mentioned above, and then formulated after mixing the fat-soluble vitamin in somatotropin in an appropriate ratio, as a means of administration so far In addition to being injected into the body through the most common injection methods, a single injection can be used to achieve a synergistic effect by administering these somatotropin and vitamin preparations at once.
즉, 본 발명의 목적은 지금까지의 투여 수단으로서 가장 보편화된 주사 방법으로 체내에 주입할 수 있을 뿐 아니라, 별도로 투여하던 비타민 제제를 소마토트로핀과 함께 동시에 투여함으로써 이들의 상승효과를 얻을 수 있으며, 동물의 주사 횟수를 줄여 이에 따른 고통을 경감시키는 동시에, 주사 투여에 요하는 노동력도 절감시킬 수 있도록 한 소마토트로핀 제제를 제공하는 것이다.In other words, the object of the present invention is not only can be injected into the body by the most common injection method as a means of administration so far, but also synergistic effects can be obtained by simultaneously administering the vitamin preparation previously administered together with somatotropin. The present invention also provides a somatotropin preparation that can reduce the number of injections of animals, thereby reducing pain, and at the same time reducing the labor required for injection administration.
상기 목적을 달성하기 위하여 본 발명에서는 소마토트로핀과 적어도 2종의 지용성 비타민이 혼합된 것을 특징으로 하는 소마토트로핀과 비타민의 합제 조성물을 제공한다.In order to achieve the above object, the present invention provides a mixture composition of somatotropin and vitamins, characterized in that somatotropin and at least two fat-soluble vitamins are mixed.
이하 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 조성물에서 소마토트로핀에 혼합되는 비타민은, 예를 들어 비타민 A, D 및 E와 같은 지용성 비타민으로서, 소마토트로핀과 같은 단백질 약물이 수분과 결합할 때 불안정화되는 점을 극복할 수 있다는 점에서 혼합 제형 제조에 유리한 약물이 된다.The vitamins mixed with somatotropin in the compositions of the present invention are, for example, fat-soluble vitamins such as vitamins A, D and E, which overcome the instability of protein drugs such as somatotropin when combined with water. It can be an advantageous drug for the preparation of mixed formulations.
이러한 제형상의 장점에 덧붙여, 비타민 A는 망막에서 빛을 감수하는 세포인 간체와 원추체 중에 존재하는 감광색소 로돕신(rhodopsin)과 아이오돕신(iodopsin)에 관련하여 시각 특히 암순응을 높이는 작용을 한다. 또한, 점막의 이상 건조와 변성, 각화, 손상, 안구 건조증 및 각막 연화증을 개선하고 질병에 대한 저항력을 증가시키는 역할을 하며, 이 밖에도 상피조직의 유지, 골 및 치아의 성장에 필수요소이며 성장 촉진 작용도 갖는 것으로 알려져 있다.In addition to the benefits of this formulation, vitamin A acts to enhance visual compliance, particularly dark adaptation, in relation to the photosensitizing rhodopsin and iodopsin present in the light-sensitive cells in the retina, the hepatic and cones. It also plays a role in improving abnormal dryness and degeneration of the mucous membranes, keratinization, damage, dry eye and corneal softening, and increased resistance to disease.In addition, it is essential for the maintenance of epithelial tissue, bone and tooth growth, and growth. It is also known to have an action.
비타민 D는 항구루병 인자로서 결핍시 구루병, 골연화증, 골위약증 및 테타니 등이 나타날 수 있는데, 특히 임신 또는 수유증의 동물, 어린 동물에서 비타민 D의 수요는 중요하며, 먹이로부터 섭취가 불충분할 경우에는 주사로 투여해 줄 필요가 있다.Vitamin D is an anti-epileptic factor, which can lead to rickets, osteomalacia, osteopenia and tetany, especially when there is a need for vitamin D in pregnant or lactating animals and young animals, and insufficient intake from food. It needs to be administered by injection.
또한, 비타민 E는 동물에 있어서 정상적인 생식 과정을 도와주고 근육 발달 이상을 예방해 주며, 뇌연화증, 근육활동 불규칙, 근 경축, 운동 실조 및 강직성 경련을 예방할 수 있다. 이 밖에도 비타민 E는 젖소에서 가장 문제가 되고 있는 유방염을 예방하는 데에도 기여하는 것으로 알려져 있는데, 주로 초산 토코페롤 형태로 적용된다.In addition, vitamin E helps normal reproductive processes in animals and prevents muscle developmental abnormalities, and can prevent encephalomalacia, muscle activity irregularities, muscle spasms, ataxia and tonic spasms. In addition, vitamin E is known to contribute to the prevention of mastitis, which is the most problematic in cows, mainly applied in the form of tocopherol acetate.
이들 지용성 비타민 중, 특히 비타민 A 및 D는 과량 적용시 부작용이 발생될 수 있으므로 주의를 요한다. 소마토트로핀은 현재 2주에 한번씩 연속해서 주사하므로 지속적인 투여에도 부작용이 발생되지 않고 이 비타민들의 효과 및 소마토트로핀의 효과를 극대화시킬 수 있는 용량을 결정하여 제형을 제조할 필요가 있다.Of these fat-soluble vitamins, in particular vitamins A and D require caution because side effects can occur when applied in excess. Somatotropin is currently injected once every two weeks, so there is no side effect even with continuous administration, and it is necessary to prepare a dosage form to determine the dose to maximize the effects of these vitamins and the effect of somatotropin.
본 발명의 조성물에 사용되는 소마토트로핀은 소나 돼지의 소마토트로핀일 수 있으며, 천연의 것이거나 유전자 재조합 방식에 의해 생산된 것일 수도 있다.Somatotropin used in the composition of the present invention may be somatotropin of cattle or pigs, may be natural or produced by genetic recombination.
본 발명의 조성물에 있어서, 소마토트로핀은 전체 조성물의 20 내지 35 중량%로 함유되는 것이 바람직하며, 비타민 A는 소마토트로핀 1g 당 500,000 내지 2,000,000 단위, 비타민 D는 소마토트로핀 1g 당 75,000 내지 300,000 단위, 그리고 비타민 E는 소마토트로핀 1g 당 1,200 내지 3,500 단위의 비율로 혼합되는 것이 바람직하다.In the composition of the present invention, somatotropin is preferably contained in 20 to 35% by weight of the total composition, vitamin A is 500,000 to 2,000,000 units per gram of somatotropin, vitamin D per gram of somatotropin 75,000 to 300,000 units, and vitamin E is preferably mixed in a ratio of 1,200 to 3,500 units per gram of somatotropin.
본 발명의 조성물 제조시, 소마토트로핀은 레시틴 등과 함께 균질화시켜 미세입자로 만든 다음 동결건조시키고, 이어서 다른 비타민들과 균질 혼합시킴으로써, 소마토트로핀과 비타민의 합제 조성물을 제조할 수 있다.In preparing the composition of the present invention, somatotropin may be homogenized with lecithin to make microparticles and then lyophilized, followed by homogeneous mixing with other vitamins, thereby preparing a combination composition of somatotropin and vitamin.
이하, 본 발명을 실시예에 의거하여 더욱 상세하게 설명한다. 단, 하기의 실시예는 본 발명의 예시일 뿐 본 발명이 이들 만으로 제한되는 것은 아니다.EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail based on an Example. However, the following examples are only examples of the present invention, and the present invention is not limited thereto.
[실시예 1]Example 1
소 소마토트로핀(LG화학 바이오텍 연구소) 용액(60.6 ㎎/㎖) 500㎖에 레시틴 10g을 넣고 30 분동안 균질 혼합기로 혼합한 다음, 미세 분쇄기에 넣고 입자 크기가 200㎛ 이하가 될 때까지 분쇄시켰다. 이 현탁액을 0.22㎛ 필터를 통과해 멸균시킨 후 동결 건조기에 넣고 동결 건조시키는데, 동결 건조병을 사용하여 진공 상태 100 mtorr 이하, 온도 -70℃에서 3일동안 실시하였다. 동결건조가 끝난 가루형태의 소마토트로핀은 가열형 수분측정기로 수분함량 측정시 1.4%로 나타났다.10 g of lecithin was added to 500 ml of bovine somatotropin (LG Chem. Biotech Research Institute) solution, mixed with a homogeneous mixer for 30 minutes, then placed in a fine grinder and ground until the particle size was 200 μm or less. I was. The suspension was sterilized through a 0.22 μm filter, placed in a freeze dryer and lyophilized. The freeze drying bottle was used for 3 days at a vacuum of 100 mtorr or lower and a temperature of −70 ° C. The freeze-dried powdered somatotropin showed 1.4% when the moisture content was measured by a heated moisture meter.
별도로 비타민 A 팔미테이트 267g(1g=1,000,000 unit, 점조성 용액, BASF)과 비타민 D31g(1 ㎎=40,000 unit, 분말 형태, Sigma)를 칭량하여 마그네틱 바를 사용해서 용해 혼합시켰다.Separately, 267 g of vitamin A palmitate (1 g = 1,000,000 units, viscous solution, BASF) and 1 g of vitamin D 3 (1 mg = 40,000 units, in powder form, Sigma) were weighed and dissolved using a magnetic bar.
동결 건조된 소 소마토트로핀 6.7g에 비타민 E 아세테이트 9.5g(1 ㎎=1.36 unit, 점조성 용액, ROCHE), 및 위에서 준비한 비타민 A 와 비타민 D3혼합액 5.03g을 넣고 균질 혼합기를 사용하여 균질 혼합시킨 후, 조성물의 기포를 제거하기 위해 진공 챔버에 6시간 동안 넣어 기포를 제거하였다.To 6.7 g of freeze-dried bovine somatotropin, 9.5 g of vitamin E acetate (1 mg = 1.36 unit, viscous solution, ROCHE), and 5.03 g of the vitamin A and vitamin D 3 solution prepared above were added and homogenized using a homogeneous mixer. After mixing, the mixture was placed in a vacuum chamber for 6 hours to remove bubbles from the composition.
위와 같이 제조한 조성물이 주사에 적합한지 알아보기 위해, 상온과 4℃에서 하루동안 보관한 후 주사능 시험을 행하였다. 주사능 시험은, 3㎖ 일회용 주사기에 본 조성물 2 ㎖ 씩을 채우고 15 게이지 3/4 인치 바늘을 장착한 후 3㎏의 추로 누를 때, 조성물이 주사기를 다 빠져나온 시간을 측정하였다. 주사능 결과를 표 1에 나타내다.In order to find out whether the composition prepared as described above is suitable for injection, the test was performed after storing at room temperature and 4 ° C. for one day. The injectability test measured the time that the composition exited the syringe when a 3 ml disposable syringe was filled with 2 ml of the present composition, fitted with a 15 gauge 3/4 inch needle and pressed with a 3 kg weight. Injectable results are shown in Table 1.
[실시예 2]Example 2
실시예 1과 같은 방법으로 조성물을 제조하되, 동결 건조된 소 소마토트로핀을 6.7g, 비타민 E 아세테이트를 12g, 그리고 비타민 A와 비타민 D3혼합액을 2.5g 혼합하였다. 주사능 결과는 표 1에 나타내었다.The composition was prepared in the same manner as in Example 1, but 6.7 g of freeze-dried bovine somatotropin, 12 g of vitamin E acetate, and 2.5 g of a mixture of vitamin A and vitamin D 3 were mixed. Injectable results are shown in Table 1.
[실시예 3]Example 3
실시예 1과 같은 방법으로 조성물을 제조하되, 동결 건조된 소 소마토트로핀을 6.7g 비타민 E 아세테이트를 7g, 그리고 비타민 A 와 비타민 D3혼합액을 7.5g 사용하였다. 주사능 결과는 표 1에 나타내었다.To prepare a composition in the same manner as in Example 1, 7g of 6.7g vitamin E acetate and 7.5g of a mixture of vitamin A and vitamin D 3 was used as lyophilized bovine somatotropin. Injectable results are shown in Table 1.
[실시예 4]Example 4
실시예 1과 같은 방법으로 조성물을 제조하되, 동결 건조된 소 소마토트로핀을 6.7g, 비타민 E 아세테이트를 4.5g, 그리고 비타민 A와 비타민 D3혼합액을 10g 사용하였다. 주사능 결과는 표 1에 나타내었다.The composition was prepared in the same manner as in Example 1, but 6.7 g of freeze-dried bovine somatotropin, 4.5 g of vitamin E acetate, and 10 g of a mixture of vitamin A and vitamin D 3 were used. Injectable results are shown in Table 1.
[비교예][Comparative Example]
실시예 1과 같은 방법으로 조성물을 제조하되, 동결 건조된 소 소마토트로핀을 6.7g, 그리고 비타민 E 아세테이트 14.5g 만을 사용하였다. 주사능 결과는 표 1에 나타내었다.To prepare a composition in the same manner as in Example 1, only 6.7g of lyophilized bovine somatotropin, and 14.5g of vitamin E acetate were used. Injectable results are shown in Table 1.
상기 표 1에서 보듯이, 소마토트로핀을 적어도 2종의 비타민과 혼합한 실시예 1 내지 4의 경우는 상온 뿐 아니라 저온에서도 주사능이 양호사였으나, 초산 토코페롤 만을 혼합한 비교예의 경우는 저온에서 주사능이 매우 불량하여 동물에 투여하는데 지장이 있을 정도였다.As shown in Table 1, in the case of Examples 1 to 4 in which somatotropin was mixed with at least two vitamins, the injection ability was good at low temperature as well as at room temperature, but the comparative example in which only tocopherol acetate was mixed was used at low temperature. The injection performance was so poor that it could interfere with the administration to the animals.
[실시예 5]Example 5
소 소마토트로핀 대신 돼지 소마토트로핀을 사용하여 실시예 1 내지 4 및 비교예와 같이 제조된 조성물로 동물실험을 실시하였는데, 유전적으로 난쟁이중이 유발된 랫트(dwarf rat)을 사용하여 실험하였다.Animal experiments were carried out using the composition prepared as in Examples 1 to 4 and Comparative Example using porcine somatotropin instead of bovine somatotropin, using a dwarf rat genetically induced dwarf rat It was.
난쟁이 랫트는 생후 8 주령, 무게 100g 내외인 암컷을 사용하였으며 물과 사료는 자유 급식시켰고, 한 조성물당 4마리씩을 한 케이지에 넣고 실험하였다. 랫트에 조성물을 투여하기 전 3일 동안 무게를 측정하여 각 개체의 기준 체증으로 삼았으며, 각 조성물 0.04 ㎖(돼지 소마토트로핀 10 ㎎ 해당량)씩을 랫트의 복측 피하에 주사하고, 투여 후 7일동안 매일 일정한 시간에 무게를 측정하였다. 대조군으로는, 아무것도 투여하지 않은 난쟁이 랫트 4마리에 대하여 시험 기간 동안 무게를 측정하였다. 조성물 투여후에 축적된 무게 증가(cumulative weight gain)를 표 2에 나타내었다.Dwarf rats were females 8 weeks old, weighing about 100 g, and were fed freely with water and feed. Weighing for 3 days prior to administration of the composition to the rat was used as the reference weight of each individual, 0.04 ml (10 mg equivalent of pig somatotropin equivalent) of each composition was injected into the rat subcutaneous subcutaneous, 7 after administration Weighed at a constant time each day for days. As a control, 4 dwarf rats that received nothing were weighed during the test period. The cumulative weight gain accumulated after administration of the composition is shown in Table 2.
제1a도 및 1b도는 난쟁이쥐에서 본 발명의 조성물에 의한 체증증가를 나타낸 그래프이다.1a and 1b is a graph showing the increase in weight by the composition of the present invention in dwarf rats.
상기 표 2 및 제1도에서 보듯이, 본 발명의 조성물은 투여 7일 째에는 대조군에 비하여 약 40% 전후의 체중 증가를 보였다.As shown in Table 2 and Figure 1, the composition of the present invention showed a weight gain of about 40% before and after 7 days compared to the control.
[실시예 6]Example 6
실시예 1 및 비교예에서 제조한 조성물을 사용하여, 착유중인 홀스타인 젖소 24마리에 대하여 산유량 증가 시험을 실시하였다.Using the compositions prepared in Example 1 and Comparative Example, an increased milk flow test was performed on 24 milking Holstein cows.
젖소 24마리를 산차와 착유 일수를 고려하여 각각 8마리씩 군분리하였으며, 아무 것도 투여하지 않은 대조군, 실시예 1의 비타민 ADE와 혼합된 소 소마토트로핀 제형 500㎎(250㎎/㎖)을 투여한 군, 그리고 나머지 한 그룹은 비교예의 제형을 같은 용량 주사하였다. 투여는 2주 간격으로 4회 꼬리 양쪽 미측 겸부 피하에 주사하였다. 투여 전 2주간의 일일 산유량을 측정하여 각 개체의 기준산유량을 삼았으며, 투여후 산유량을 측정해서 투여전 산유량과 비교하여 산유량 증가율을 계산하였다. 결과는 표 3에 나타내었다.24 cows were divided into 8 groups each in consideration of maternity and milking days, and 500 mg (250 mg / ml) of the bovine somatotropin formulation mixed with the vitamin ADE of Example 1, the control group which was not administered at all, was administered. One group and the other group received the same dose injection of the formulation of the comparative example. Dosing was injected subcutaneously in both tail caudal humerus, four times at two week intervals. The daily milk flow was measured for 2 weeks before administration, and the base oil flow rate of each individual was measured. The results are shown in Table 3.
제2도는 젖소에서 본 발명의 조성물에 의한 산유량 증가를 나타낸 그래프이다.2 is a graph showing the increase in acid flow rate by the composition of the present invention in cows.
상기 표 3 및 제2도에서 보듯이, 본 발명의 조성물은 투여 7 내지 8 주째에는 대조군에 비하여 약 30% 정도의 산유량 증가를 보였다.As shown in Table 3 and Figure 2, the composition of the present invention showed an increase in milk flow of about 30% compared to the control at 7 to 8 weeks of administration.
한편, 소마토트로핀에 초산 토코페롤만을 혼합한 조성물의 경우에는 난쟁이 랫트에 있어서 체중 증가 효과나 소에 있어서 산유량 증가 효과는 본 발명의 조성물과 유사하였으나, 주사능이 불량하다는 점에서는 바람직하지 못하였다.On the other hand, the composition of somatotropin mixed with only tocopherol acetate, the weight gain effect in the dwarf rats and the effect of increasing the acid flow rate in the cow was similar to the composition of the present invention, but was not preferable in terms of poor injection ability.
이상에서 살펴 본 바와 같이 소마토트로핀과 적어도 2종의 비타민을 포함하는 본 발명의 합제 조성물은, 상온에서나 저온에서도 주사능이 양호하였으며, 성장 촉진 및 소의 산유량 증진에 대해서도 우수한 작용이 있음을 알 수 있었다.As described above, the mixture composition of the present invention comprising somatotropin and at least two vitamins has good injection ability even at room temperature or at low temperature, and shows that it has an excellent effect on promoting growth and enhancing the yield of cow. there was.
또한, 실제 동물에 사용시 소마토트로핀과 비타민 복합제형이 따로 따로 주사되고 있다는 점을 고려한다면, 본 발명의 소마토트로핀과 복합 비타민의 합제 조성물은 이러한 번거로움을 해소할 수 있으며, 문헌적으로 이미 알려진 바와 같이 복합 비타민을 동물에 투여해 줌으로써 대상동물의 건강 상태에 도움을 줄 수 있다는 이점도 갖는다.In addition, considering that the somatotropin and vitamin complex formulations are separately injected when used in real animals, the combination composition of the somatotropin and the complex vitamin of the present invention can solve this inconvenience, and As is already known, by administering a multi-vitamin to the animal can also benefit the health of the target animal.
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