Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2001-07-30
2004-08-03
Tate, Chris (Department: 1654)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093700, C424S093100
Reexamination Certificate
active
06770276
ABSTRACT:
The invention refers to medical science and deals with insulin-containing medicine for peroral use and its derivation method.
PRECEDING LEVEL OF TECHNIQUE
Diabetes—is one of the most widespread severe diseases, the absolute or relative deficiency of pancreas hormone, insulin, of which underlies it.
Insulin is a half-peptide hormone with molecular mass 6000. It impacts all types of metabolism in any organism: increases the penetration of glucose into organism tissues, prompts its utilization, reduces content of glycogen in liver and increases its number in muscles, enhances the intensity of protein synthesis and slows decomposition of the latter.
The principal method for injection of insulin into a human organism is hypodermic and intramuscular injection of medication. The attempts of insulin injection in the most physiological and patient-suitable peroral way turned out to be unsuccessful, for insulin easily degrades under the influence of digestive ferments, the fact that leads to loss of its biological activity.
The main obstacle, occurred when creating peroral forms of insulin, is its low resistance to the behavior of proteolitic ferments of gastrointestinal tract
Over the last decade there were numerous attempts to create peroral forms of insulin, nevertheless, so far it was impossible to create the efficiently acting medicine, able to compete in terms of its active properties with insulin injected
The medicine of insulin for peroral use, which represents a water-oily micro-emulsion consisting of insulin, lipids and protease deterrent, is well known Micro-emulsion is then covered with carboxymethylcellulos (Cho Y. W., Flynn M., Lancet, 1989, #30, p. 1518 Saffran , Kurnar G. S.).
The substantial deficiency of this medicine along with the labor-intensive and expensive technology of manufacturing is the carrier—carboxymethylcellulos which is subject to influence of micro-organism as well as able to absorb a great number of insulin, as the result of which the form derived doesn't correspond with the requirements of the efficient peroral use of insulin.
There is a widespread notion about insulin-containing medicine consisting of the core with the content of insulin and auxiliary substances and capsule made of biodegrading medium polymer (Savarlar C., et al, A new approach to the oral administration of insulin and other peptide drugs, Science, 1986, v.233, pp.1081-1084).
The medicine is produced by injection of 1-40 mg of crystal insulin and 200 mg of stoichiometric impurity of 5-methoxisalicylic acid and sodium bicarbonate. Then the capsule (tablet) is covered with so-polymer of hydroxiethylmethacrylate and styrene, stitched with devinylazobenzene. The capsule is resistant to the effect of stomach medium and thin intestines, but gets decomposed in thick intestines under the influence of microorganisms existing there.
The deficiency of this medium is its low efficiency and undefined time for reaching maximum effect. Peroral injection of the said medicine, containing 1 unit of insulin, into rats leads to reduction of glucose concentration in blood by 20% within 9 hours after the injection At the same time the intramuscular injection of insulin solution in the dose 0,1 or 1,0 units causes the reduction in the level of glucose in blood by 39 and 63% respectively. The maximum hypoglycemic effect for certain animals is reached within the period from 1 to 9 hours, and for some animals the effect of reduction in glucose concentration is missing even in 10 hours after the injection of medicine.
A solid insulin-containing medicine, consisting of the core containing inhibitor of proteolitic ferments and auxiliary substances and stomach-resistant capsule (Ehud Ziv, Miriarn Kidron, Itanaar Raz et al., Oral administration of insulin of solid form to non-diabetic and diabetic dogs. Journal of Pharmaceutical Science 1994, x.83,#6, pp.792-794 and Kidron A, Krausz M., Raz I et al., The absorption of Insulin: from the intestine in dogs, Nenside. Surfactants. Deterg 1989, v.26, #5, pp.352-354) is well known.
The medicine contains the inhibitor of trypsin made of soy as the inhibitor of proteolitic ferments and sodium cholate and lactose—as auxiliary substances. Lactose is used as a non-active filler, and sodium cholate as a compound enabling to enhance the penetration of insulin through intestine walls.
The deficiency of this medicine is its low efficiency. Thus, when the medicine is injected in a peroral way into healthy dogs with the insulin dose 40 units/kg. of animal's weight, the maximum reduction in glucose concentration in animal's blood makes 18%, though with a hypodermic injection the similar hypoglycemic effect may be reached with the insulin dose 10 times lower. Besides, the abovementioned medicine containing the inhibitor of trypsin made of soy has a selective effect towards various types of animals, in other words, it is not a universal one. Thus, when used in a perotal way it reveals activity towards dogs and reveals no activity towards rats (Kidron A, Krausz M., Raz I et al., The absorption of Insulin: from the intestine in dogs, Nenside. Surfactants. Deterg. 1989, v.26, #5, pp.352-354).
An insulin-containing medicine, intended to treat patients with diabetes in a peroral way, which consists of the core sampling containing insulin, albuminous inhibitor of proteolitic ferments and represents a stitched hydrophilic polymer, modified by ovomukoide, and auxiliary substances and stomach-resistant capsule (Ru Nr.2117488 Cl, 20.08.98) is well known.
The medicine contains 10 UNITS of insulin per one tablet. The medicine ensures a statically trustworthy hypoglycemic effect on various types of mammals, including the human being, meaning it has a universal nature.
Moreover, doses required to reach the necessary therapeutic effect are comparable with the levels for injection insulin. But the said medicine possesses low resistant: properties, the term of experiment—up to 50 days as well as a comparatively low specific activity 20EA per 1 g of dry tablet.
The method for derivation of insulin-containing polymer hydro-gels, including immobilization of insulin in the volume of stitched polymer, modified by inhibitor of proteolitic ferments—ovomukoides (Ru Nr.2066551 Cl, 20.09.96).
The method enables to derive medicine, possessing activity, which makes 60-70% of the activity of insulin medicine during hypodermic injection. But the content of insulin in 1 g of hydro-gel is not high.
The closest to the invention proposed is the method for derivation of medicine for peroral use, including insulin incubation with erythrocytes in proportion 1-14:100 in the presence of stitching agent in final concentration 0.15-0.25% (Ru Nr.2058788 Cl, 20.04.96).
Consequently, medicine with the content 1000 E/1 g of dry mass has been derived with the storage period in lyophilized state—up to several years.
DISCLOSURE OF INVENTION
The task of the invention proposed is to create an insulin-containing medicine for peroral use, meaning resistant to the effect of proteolitic ferments in gastrointestinal tract with the increased insulin content in 1 g of dry substance, the fact that expands the potential for using the medicine in various medical forms.
The essence of the invention is as follows: insulin-containing medicine for peroral use represents insulin, immobilized on erythrocytes of fresh mammal blood in the presence of stitching agent in proportion %: insulin: erytces of fresh mammal blood 5-10:100 and auxiliary substance with the insulin content in lyophilized state 1250-2000 E of insulin per 1 g of dry mass.
The said medicine as an auxiliary substance may contain gelatin in the amount from 1 to 2,5%.
The said medicine includes erythrocytes excreted from the fresh pig, horse or human blood as erythrocytes during insulin immobilization
The said medicine may contain glutarite dialdehyde as a stitching agent.
The method for derivation of insulin-containing medicine for peroral use includes the excretion of erythrocytes from fresh mammal blood, their incubation with insulin in proportion mass
Jacobson & Holman PLLC
Otkrytoe Aktsionernoe Obschestvo “Quantum Satis”
Tate Chris
Winston Randall
LandOfFree
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