Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Liposomes
Reexamination Certificate
1999-09-22
2001-07-03
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Liposomes
C424S450000, C424S489000, C514S012200, C514S633000, C514S725000, C426S072000, C426S073000, C426S074000, C530S399000
Reexamination Certificate
active
06254884
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical composition which comprises bioactive somatotropin and at least two kinds of lipid-soluble vitamins, and more particularly to a parenterally administered pharmaceutical composition which can solve inconvenience of administering somatotropin and lipid-soluble vitamins respectively and which shows the sustained effect of somatotropin and the synergic effect of somatotropin and lipid-soluble vitamins.
BACKGROUND OF THE INVENTION
Recently, somatotropin has been produced massively by using genetic engineering techniques. Bovine somatotropin has been commercialized to increase the productivity of milk and porcine somatotropin has been commercialized to improve feed conversion ratio and to improve meat quality and so on.
Most of bioactive somatotropin formulations developed until now are the sustained-releasing type that a large amount of somatotropin is administered and released slowly only to avoid the inconvenience of daily administration. For examples, U.S. Pat. No. 5,411,951 and U.S. Pat. No. 5,474,980 disclose the sustained-releasing composition produced by adding a gelling agent such as aluminum monostearate into vegetable oil, and by gelatinizing oil by heating, and by mixing somatotropin homogeneously. These techniques have been already used to prepare sustained-releasing composition of antibiotics (U.S. Pat. No. 2,491,537, U.S. Pat. No. 2,507,193, U.S. Pat. No. 3,016,330), pamoate salts of oxazepin (U.S. Pat. No. 3,676,557) or relaxin (U.S. Pat. No. 2,964,448), parathyroid stimulating hormone (U.S. Pat. No. 3,869,549), luteinizing hormone releasing factor (U.S. Pat. No. 4,256,737), gonadotropin (U.S. Pat. No. 3,852,422) and insulin (U.S. Pat. No. 2,143,590, U.S. Pat. No. 2,174,862, U.S. Pat. No. 2,920,014, U.S. Pat. No. 3,102,077) and the like.
There are similar techniques for preparing sustained-releasing type by using oil. For example, EP 211691 discloses that somatotropin is mixed with wax and oil complex and EP 213851 suggests that sustained-releasing formulation is prepared by mixing somatotropin with oil and glyceride release-modifying agent available commercially. And EP 314421 discloses that sustained-releasing somatotropin composition is prepared by adding absorption-controlling material such as calcium stearate and dextran to oil. But this is a formulation that active ingredient has been substituted with somatotropin in the known oil-injection formulation.
In addition, the sustained-releasing techniques without using oil have been attempted. For example in EP 193917 somatotropin was mixed with water-soluble polysaccharides such as starch and dextrin to improve the sustained-releasing effect. But this formulation has shorter releasing time than other formulations mixed with oil and the somatotropin is unstable with water-soluble ingredients.
Another technique which does not use oil to prolong the releasing time has been described in U.S. Pat. No. 5,520,927. It discloses the formulation of tocopherol acetate and a release-delaying agent. However, in this case tocopherol acetate is used only for delaying the release of drug.
Different techniques from the above-mentioned have been attempted for sustained-releasing somatotropin formulations. U.S. Pat. No. 4,861,580 discloses sustained-releasing somatotropin formulation is prepared as a liposome type by using lipid-soluble material such as phosphatidyl choline, phosphatidyl ethanolamine and alpha-tocopherol hemisuccinate tris salt. And in U.S. Pat. No. 4,675,189 sustained-releasing somatotropin formulation was prepared as a microcapsule type by using bio-compatible polymer. And in U.S. Pat. No. 4,857,506 sustained-releasing somatotropin formulation is prepared as a multiple water-in oil-in water emulsion. But these are inadequate to be commercialized since the processes are so complex and high technologies are required. Furthermorer the recovery rate to produce the desirable somatotropin is too low to be commercialized. In addition the somatotropin formulations prepared by the process are not stable and can not show the desirable sustained-release effect.
By using quite different methods, solid formulations which are implantable were prepared for improving the sustained-release of drugs. These techniques have been described in U.S. Pat. No. 4,452,775, U.S. Pat. No. 4,761,289, U.S. Pat. No. 4,765,980, U.S. Pat. No. 4,786,501, U.S. Pat. No. 4,863,736, U.S. Pat. No. 5,035,891, U.S. Pat. No. 5,198,422, U.S. Pat. No. 5,228,697, U.S. Pat. No. 5,356,635, U.S. Pat. No. 5,595,752 and EP 246540, 462959, PCT/US92/01877, PCT/US91/08129, PCT/US90/01340, PCT/AU87/00139 and the like. In these techniques solid somatotropin compositions were prepared and implanted into the animal body by surgical operation or by using special instruments which are expensive. The implanting techniques make it possible to release the desirable amount of bioactive somatotropin during the desirable period. However, the implanting process is too difficult to be performed and animals also feel uncomfortable due to the foreign substance.
The inventors of the present invention have conducted the intensive research for the sustained-release formulation of somatotropin to solve the above-mentioned problems. The inventors have found that somatotropin mixed with lipid-soluble vitamins at proper proportions shows the excellent sustained-release effect and additionally the synergic effect of the active ingredients by administering parenterally.
SUMMARY OF THE INVENTION
The object of the present invention is to provide the pharmaceutical compositions, when it is parenterally administered, which comprises somatotropin and at least two kinds of lipid-soluble vitamins, which has such a sustained-release effect that it reduces the pain and the labor cost due to the frequent injections and such a synergic effect of the active ingredients that it increases the productivity of milk in dairy cattle and reproduction efficiency and it decreases the somatic cell count in the milk, the incidence of mastitis and metabolic diseases of cattle.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides pharmaceutical compositions which comprises somatotropin and at least two kinds of lipid-soluble vitamins.
The lipid soluble vitamins which are used in the present invention contain vitamin A, vitamin D and vitamin E which are preferably used in preparing protein drugs since they make protein drugs such as somatotropin stable by preventing protein drugs from binding with water.
In addition to the above-stated advantage of the formulations, the vitamins have its own bioactivities described below.
Particularly, vitamin A promotes the sense of vision especially the adaptability to darkness which is related with rhodopsin and iodopsin of rod cell and cone cell sensing light on the retina. It can also improve abnormal dryness, denaturalization, keratinization and damage of mucosal membrane, ophthalmoxerosis and ophthalmomalacia and increase the resistance against various diseases. In addition, it has been reported to be an essential element in maintaining epidermal tissue and helping the growth of bone and teeth and it plays a great role as a growth stimulating hormone.
Vitamin D is an anti-rickets factor. When it is deficient, rickets, osteomalacia, osteopsathyrosis, tetany and the like can be caused. Since vitamin D is especially important for pregnant or lactating animals or and infant animals, it is necessary to administer by injection when it is deficient by provender.
Vitamin E is related to white muscle diseases. When it is deficient, white muscle diseases are caused, which partly changes the color of muscle fiber into gray and makes the muscles atrophied. The muscle atrophy provokes symptoms such as losing flexibility, stiffening and paralyzing of muscle. As the disease progresses, it becomes difficult to breathe. Resultantly animals having severe symptoms of the muscle atrophy became unable of lactation. Vitamin E is a anti-sterility vitamin for overcoming the sterility and it also promotes growth rat
Chang Byoung Sun
Kim Doo
Kim Nam Joong
Ryoo Jephil
Bachman & LaPointe P.C.
Dudash Diana
LG Chemical Ltd.
Sharareh Shannam
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