Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-08-08
2003-01-21
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S451000, C424S489000, C514S960000, C514S962000
Reexamination Certificate
active
06509035
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a medicament useful for treating hyperlipemia and a producing method thereof. More specifically, the present invention relates to an oral preparation of coenzyme A (CoA) and a producing method thereof.
BACKGROUND OF THE INVENTION
CoA is a ubiquitous active substance found in organisms and is consisted of pantothenic acid, adenine, ribose, cysteamine and phosphoric acid. It is the coenzyme for acetylation reaction in vivo, and plays an extremely important role in metabolism of carbohydrates, lipids and proteins. For example, it is essential for the process of tricarboxylic acid cycle, storage of hepatic glycogen, synthesis of acetylcholine, decrease of the amount of cholesterol, regulation of the level of plasma lipid and synthesis of steroids. CoA significantly alleviates the symptoms of anorexy and hypodynamia of patients and has been used as helper medicament for treatment of diseases such as arteriosclerosis, chronic arteritis, myocardial infarction, myocarditis, various liver diseases, leucopenia, thrombopenic purpura, acute anuria induced by chronic renal insufficiency, nephrotic syndrome, uremia, neonatal anoxia and diabetes acidosis, etc. Because CoA is susceptible to the dephosphorylation by phosphoesterase in enteric tract, the only route of CoA administration has been by injection up to now, which is pain and inconvenient for patients and increases cost. Therefore, the use of CoA is limited.
SUMMARY OF THE INVENTION
The object of the present invention is to overcome such disadvantages of exsisting CoA preparations. Therefore, the first aspect of the invention provides an oral absorbable CoA preparation with stable therapeutic effect; the second aspect of the invention provides a method for preparing the said CoA oral preparation; and the third aspect of the invention provides a use of the said CoA oral preparation for treating hyperlipemia; and the fourth aspect of the invention provides a method of treating hyperlipemin in an individual with the said CoA oral preparation.
DETAILED DESCRIPTION OF THE INVENTION
The Oral CoA preparation of the present invention can be tablet, capsule, powder, granule, and microcapsule consisting of 0.04-9.99% active ingredient CoA, 0.4-99.55% an antioxidant, 0.4-99.55% an acidic buffer or acidifier and 0-98.99% a pharmaceutically acceptable excipient(s).
The method for preparing the CoA oral preparation of the present invention, 1 portion of CoA was added to 20~800 portions of salt-free water, and then 0~20 portions of an antioxidant, 1~20 portions of an acidic buffer or acidifier, 0~40 portions of an extender were added to dissolve and then lyophilized to obtain the raw material (a lyophilized powder) for making the preparations of the invention. Based on the amount of CoA lyophilized powder, 1~2489 portions of an antioxidant, and 0~2489 portions of an acidic buffer or acidifier were added to the lyophilized powder and mixed uniformly, and then formulated with a pharmaceutical excipient(s) to form CoA oral tablet, capsule, granule, powder or microcapsule according to a conventional process.
Tablet, capsule, granule, powder and microcapsule of the present invention can be formulated according to following conventional process:
To the raw material as botained above containing one portion of CoA, 1~2489 portions of an antioxidant, 0~2489 portions of an acidic buffer or acidifier, and a suitable amount of binder, disintegrant and extender are added and mixed uniformly, then starch syrup is added. The resulting mixture then is granulated, tableted and dried to form tablets, each containing 10~500 units of CoA.
To the raw material as obtained above containing one portion of CoA, 1~2489 portions of an antioxidant, 0~2489 portions of an acidic buffer or acidifier, and a suitable amount of binder, disintegrant and extender are added and mixed uniformly. Then the resulting mixture as obtained can be packed as powder according to desired dosages. Alternathply a suitable amount of starch syrup can be added to the mixture followed by granulating, drying and sterile packing to form granules containing 10~500 units of CoA per package. Furthermore capsules with 10~500 units of CoA per capsule can be obtained after filling the dried granules into capsule shells and sealing.
To the raw material as obtaimed above containing one portion of CoA, 1~2489 portions of an antioxidant and 0~2489 portions of an acidic buffer or acidifier are added and then ground and mixed uniformly.
The resulting mixture is then added to a solution of ethyl cellulose (EC) in isopropanol and then EC microcapsules of CoA are obtained after spray drying.
The antioxidant of the invention can be any pharmaceutically acceptable one such as Vitamin C, sulfourea, glutathione, alanine, cystein, etc.
The acidic buffer of the invention can be any pharmaceutically acceptable one such as sodium dihydrogen phosphate, potassium dihydrogen phosphate; and the acidifier of the invention can be any pharmaceutically acceptable one such as citric acid, aspartic acid, glutamic acid, folic acid.
The pharmaceutically acceptable excipients useful for the invention include conventional binder such as starch, hydroxyl propyl starch, modified starch, pregelatinized starch, dextrin, sugar powder, microcrystalline cellulose, gelatin syrup, and PVP mucilago; disintegrant such as sodium carboxymethyl starch, starch and microcrystalline cellulose; lubricant such as modified starch, microcrystalline cellulose, micro-powder silicon gel and aluminum hydroxide; and extender such as starch and derivative thereof, celluloses and derivatives thereof, inorganic compounds, organic salts and hexonic acids or pentitols.
The clinical administration dosage of CoA of the invention is 10~500 units of CoA per day. One mg of pure CoA corresponds to 413 units, while commercially available CoA of pharmaceutical grade is of about 250 units per mg, i.e. 100 units of CoA weighs about 0.4 mg.
Enteric phosphoesterase usually can inactivate enteric CoA by dephosphorylation at its 3-position quickly. The optimal pH of phosphoesterase is 9.8. An oxidated type of CoA is more easily be inactivated than the reducted type. Although not bound by any theory, it is contemplated that the pvesent invention works by inhibiting the enzyme reaction process of the inactivation of enteric CoA. In the preparation of the present invention, an antioxidant was added in order to maintain the reducted state of CoA; and an acidic buffer or acidifier was added to form a slightly acidic micro-environment in enteric tract after oral administration of CoA, which lead to the inhibition of degradation of CoA by phosphoesterase so that CoA can be absorbed before inactivation. The oral preparation of the present invention therefore exerts similar biological effect as a injectable preparation.
Pharmacodynamic experiments using the CoA oral preparation of the present invention and an injectable preparation of CoA on thrombocytopenia:
1. Effect on Peripheral Platelet of Animal
Object: 10 experimental dogs were used and devided into 2 groups of 5 to which oral or injection preparations of CoA was adminisered, respectively. Their peripheral platelet samples were taken and tested at intervals to observe the differences between before and after administration.
Dosage of CoA: Oral administration group, 100 units per time, twice per day. Injection administration group, 35 units per time, twice per day.
Result: Statistical analysis were carried out on the changes of the number of platelets before and after the administration of CoA to dogs by individual comparison test. The results are shown in Table 1. It is noted that exogenous CoA can improve the level of platelet in experimental dogs in a short time either administered by oral or injection route. Average increment of 170,800/mm
3
was observed in the injection administration group on day 8 (P<0.01); while 133,000/mm
3
in the oral administration group on day 6 (P<0.05), and thereafter the level of platelet restored to its normal level gradually. It is proved
Fei Guijun
Ren Genfu
Evans Charesse
Ladas & Parry
Shanghai Materia Medica Bioengineering Institute
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