CA1223200A - Pharmaceutical compositions containing insulin - Google Patents
Pharmaceutical compositions containing insulinInfo
- Publication number
- CA1223200A CA1223200A CA000454266A CA454266A CA1223200A CA 1223200 A CA1223200 A CA 1223200A CA 000454266 A CA000454266 A CA 000454266A CA 454266 A CA454266 A CA 454266A CA 1223200 A CA1223200 A CA 1223200A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- insulin
- oral administration
- sodium
- bile
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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
- A61K38/28—Insulins
-
- 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
- A61K38/55—Protease inhibitors
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
Abstract
PHARMACEUTICAL COMPOSITIONS CONTAINING INSULIN
ABSTRACT OF THE DISCLOSURE
The invention provides a pharmaceutical composition for the oral administration of insulin comprising insulin, a bile acid or alkali metal salt thereof, the bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor, the composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
ABSTRACT OF THE DISCLOSURE
The invention provides a pharmaceutical composition for the oral administration of insulin comprising insulin, a bile acid or alkali metal salt thereof, the bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor, the composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
Description
v the present invention) relates to a pharnlac~utlcal Calypso i lion controlling insulin. More particularly, the present invention relates to a pharmaceutical compoC.itior for the oral adnlinistration of insulin.
Insulin is a medicament particularly useful as a hype-glycaemic agent being widely used by patients suffering from diabetes and is the only treatment for juvenile diabetes Maltese.
In practice today insulin is administered only by injection. The everyday injection of insulin is very trickle-sonic and causes consid~rab'ie physical and even mental suffering for the patients. Several severe side effects such as lipodystrophy at the site of the injection, lipoatrophy, lipohyp~rtrophy or occasional hypoglycemia have been noted and reported to occur.
To avoid the daily injection of the drug, the insulin pump has been developed in the last decade. This pump, however, also suffers from some of the disadvantages of the daily injection. Since insulin is normally secreted unto the portal vein, normally the liver is exposed to a greater insulin con-cent ration than peripheral tissues. Insulin administered via the peripheral venous system to insulin-deficient diabetic patients results in a concentration of insulin in the portal vein almost equal to that in the peripheral circulation. The net result is hypoinsulinemia in the portal vein and the liver and hyperinsulinemia in the peripheral venous system. This may lead to an abnormal pattern of glucose disposal.
ZOO
he present inventiorl roulettes to a pharnlaceutical composition curtaining insulin. More particularly, the present invention relates to a pharmaceutical cGn~pOsiti~n for the oral administration of insulin.
Insulin is a n,edicament particularly useful as a hype-glycaemic agent being widely used by patients suffering from diabetes and is the only treatment for juvenile diabetes Maltese.
In practice today insulin is administered only by injection. The everyday injection of insulin is very trouble-some and causes considerable physical and even mental suffering for the patients. Several severe side effects such as lipodystropby at the site of the injection, lipoatrophy, lipohypertrophy or occasional hypoglycemia have been noted and reported to occur.
To avoid the daily injection of the drug, the insulin pump has been developed in the last decade. This pump, however, also suffers from some of the disadvantages of the daily injection. Since insulin is normally secreted into the portal vein, normally the liver is exposed to a greater insulin con-cent ration than peripheral tissues. Insulin administered via the peripheral venous system to insulin-deficient diabetic patients results in a concentration of insulin in the portal vein almost equal to that in the peripheral circulation. The net result is hypoinsulinemia in the portal vein and the liver and hyperinsulinemia in the peripheral venous system. This may lead to an abnormal pattern of glucose disposal.
In order to overcome the difficulties caused by injection of insulin rectal administration of insulin has recently beer proposed, studied and developed.
Cheshire et. at (J. Harm. Formed. 30, 806~80~, 197~), Bar-On et at (By. J. Pharmacy 73, 2'1-24, 1981), and others tested the hypo~lyceaemic affect of insulin mixed with polyp oxyethylen laurel ether or polyoxtethylene-20-cetyl ether by administering through the rectum. Zip et at (Life Sciences, 29, 803-809,1981) tested the same effect with insulin mixed with bile salts. The insulin effected the blood glucose levels, by reduction of approximately 50%, with dose of 48~/kg.
In a further article by Zip, Kid Ron, Bar-On and Berry (Life Sciences, 31, pp. 2837-2841, 1982) insulin was used as a motel for proteins in general to discover the theoretical question of protein absorption through the intestine and it was found that in the presence of the strong detergent effect of deoxycholic acid and soybean ~rypsin inhibitor, biologically active macrolnolecules such as insulin could be effectively absorbed from the intestine.
Similarly, in British Patent '1,563,311 there is described and clainled a pharmaceutical composition for rectal administer-lion which comprises insulin, a carrier suiting the composition for rectal administration, and an agent or increasing the rate of' absorption of the insulin into the body on rectal administrator of the composition, the agent comprising at least one material selected froth (a) non ionic polyoxyethylene ether surface active agents having an HUB value of 6 to 19 and wherein the average number of polyoxyethylene units is 4 to 30, (by anionic surface active agents, (c) cat ionic surface active agents (d) ampholytic surface active agents, (e) bile acids and (~) alkali metal salts of bile acids and amounting to 0.001 to 0.5 times the weight of the carrier. In U.S. Patents 4434159 and 4164573 there are described similar insulin containing pharmaceutical compositic~rls for rectal administration.
Tolls the a~lministra-tiorl of insulin Roy the portal system of the human rectum in suppository form or further along the intestinal tract, e.g., by enema-likP introduction is suggested and taught by said articles and patent.
Nevertheless it has been found that only part of the insulin is absorbed through the portal system from the human rectum and rectal administration also represents a major in-convenience for the patient.
According to the present invention, there have now been developed pharmaceutical compositions for administering insulin which overcome all of the above-mentioned disadvantages of the prior art systems.
More specifically, there have now been discovered and provided according to the present invention pharmaceutical compositions for the oral administration of insulin comprising insulin 9 a bile acid or alkali metal salt thereof 9 said bile acid being selected from the group consisting of colic acid, chenodeoxycholic acid, taurocholic acid taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3~-monshydroxy-caloric acid, lithocholic acid 9 3u-hydroxy-12-ketocholic acid J
3~hydroxy-12-ketocholic acid, 12~-3~-dihydrocholic acid, and ursodesoxycholic acid, and a protozoa inhibitor, slid composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
Thus there have now been discovered pharmaceutical come positions containing insulin which can be administered orally and which have the same effect as naturally secreted insulin on the blood glucose levels. The insulin administered according to the I
present invention reaches the intestine arid is ~uic~.ly bored in the body through the intestine and through the purity system to the liver. This absorption route is the most convenient way to administer the drug and it resembles the physiological secretion of insulin by the pancreas, thus enabling delicate control of the blood glucose level and the metabolic activities of the liver and the peripheral organs controlled by insulin.
Various attempts have been made in the past to administer insulin orally. In one study it was shown that administration of liposome-entrapped insulin caused a significant reduction of blood glucose levels in diabetic rats (Dapergolas, G. and Gregoriadis, Lance ii, 824-827, 1976~. Pate and Reman (FOBS Letters, 62, 60-63, 1976) showed that insulin administered orally entrapped in liposomes is effective in diabetic rats.
Papahadjopoulos and Sjoka (U.S. patent No. 4,235,871) suggested to use liposomes to encapsulate insulin and Sears (U.S. patent No. 4,145,410) used synthetic phosphatidyl compounds to stabilize the liposomes against lipolysis.
Another approach for insulin enhanced activity is the addition of an adjutant such as choline (which is not a bile salt) to the insulin injections (U.S. patent 2563070). This is totally different from oral administration with bile salts since the bile salts in an oral composition enhance the absorption of insulin from the intestinal lumen to the blood circulation while with injectable solutions no such absorption takes place or is necessary and the function of chlorine which is different structurally and chemically from colic acid is entirely different in said patent and it intended to delay the insulin absorption.
Thus it will be realized that none of the said publications teaches or suggests the novel pharmaceutical composition of the I
present invention which includes the use of bile salts to promote the absorption of insulin, the use of protozoa inhibitors to protect insulin against proteoiysis and the use of enterocoating of the active mixture.
Human insulin including human insulin genetically reproduced or any insulin such as, for example, the insulin obtained from cows (bovine), pigs or whales can be used as the insulin for compositions of this invention. Furthermore, metal complexes of insulin such as the zinc complex of insulin as well as protamine zinc insulin and glob in zinc insulin may be also used as the insulin in compositions of this invention.
The protozoa inhibitor used in the compositions of the present invention can be any material which has the ability to inhibit any proteolytic activity.
-I-tactical ~xdmples of such yrotedse inhibitors include aprotinin (Trasilol (R) of Bayer, Pen~all~idine isetilionate, anti pain, tosylamide-phenylethyl-chlGromethyl kitten (TPOKj, phenylmethyl sulfonyfluoride (PMSF), pepstatin, trypsin inhibitor Acetone, Alcohols, guanidium, a2-macroglubulin, TUCK, Chelating agents of Zen, lodoacetate, al-antitrypsin, ETA, Zen, Antithromlbin III, leupeptin Trypsin inhibitor from soy bean, trypsin inhibitor fro hen egg white, trypsin inhibitor from chicken egg white, etc.
Some of the above protozoa inhibitors might be toxic in large doses and therefore, if chosen; the use and dosage thereof must be carefully screened and jested.
In especially preferred embodiments of the present invention said protozoa inhibitor is selected from the group consisting of aprotinin9 A2-macroglobulin, antithrombin III and trypsin inhibitor from sty bean or chicken egg white.
The most preferred protozoa inhibitor agents used in this invention are preferably Trasylol(R) in the amount of 1000 kiwi./
100 my pill, or 3 my soybean trypsin inhibitor or 10 my soybean flour.
The above-mentioned bile acids and alkali metal salts thereof used in the oral compositions of the present invention promote the absorption of the insulin from the intestinal tract and act do cdrri~s thoroughfare, Hoover, it Weds In~erestln~ end sur~risin~J
to note that deoxycholi~ acid, which was the acid of choice in the article in Life Sciences, Vol. 31, pp. 2837-2441 (19132) is unsuitable for use in the oral compositions of the present in-mention because of the damage which it causes to the cells of the intestinal wall.
The active concentration of bile acid or salt thereof is about 1-20 mg/ml and preferably about 5-15 mg/pill/one treatment.
It has also been surprisingly found that sodium shalt can simultaneously function both as the bile acid carrier of the insulin and the protozoa inhibitor agent and thus a compost-lion comprising insulin and sodium shalt in an enteric coating is especially preferred.
The amount of insulin in a composition is 20-50u/kg in rats and expected to be about 0.5-3u/kg in humans. Preferred dosages for humans are about l-2u/kg/treatment with three treatments a day, however sustained release microencapsulat10n could allow treatment to be reduced to once or twice a day.
The enterocoating and possible micro encapsulation of the mixture provides protection for the insulin against decomposition in the stomach and for the slow release of the mixture consistuents in the intestinal tract.
The enterocoating is carried out by methods known per so in the art, e.g., according to Rumania Pharmaceutical Sciences, p. 1614-1615 (1975, Thea Ed. Meek Pub. Co.) and Theory and Practice of Industrial Pharmacy, Blackman, Liberian Caning, p. 116-117, 371-374 (1976~ end Ed) as us the enteric micro-encapsulation (Theory and Practice of Industrial Pharmacy ibid, pp. 420-4383.
One of the findings of the present invention is that there is different rate of absorption of the different constituents of the present composition from the intestinal lumen into the blood stream. The absorption of the bile acid is very fast, eulogy., more than 50% of colic acid is absorbed during 30 minutes while only 5-10% of the insulin is absorbed during 60 minutes.
For this reason a dry Regimen involvirlg ing~stiorl of a pair of pills at spaced intervals, e.g., a second pill eon-twining a higher concentration of bile acid to be taken half en, hour after the first Jill is contemplated as is microencapsulatior of different constituents with spaced time release coatings to enhance the absorption of the insulin into the system.
While the invention will now by described in connection with certain preferred embodiments in the following examples it will be understood that it is not intended to limit the invention to these particular embodiments. On the contrary it is intended to cover all alternatives, modifications and equivalents as may by included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the par-ticklers shown are by way of example and for purposes of if-lustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood descrip-lion of formulation procedures as jell as of the principles and conceptual aspects of the invention EXAM LYE 1.
An enterocoated capsule was prepared for oral administration of insulin to a diabetic dog. Table 1 shows Plasma 1~1 levels and glucose levels with administration.
I
_ _ Composition Test Formulatiorl Time GlucoseInsulir of -this invention No. (Mix) no Mel .
1 . i nsul i n 7 . 3u/ky 0 36 . 7 15 Oral administration shalt 30 my 15 33.9 0 soybean - 30 34.4 6 -trpsin inhibit ion 45 34,6 6 20 my 60 33.8 12 in two capsules 75 29.1 23 (enterocoated) 105 23.7 36 135 21.8 22 ~65 16.1 3 210 15.8 0 240 11.5 0 270 12.1 0 300 10.2 0 330 7.5 0 360 9.3 0 I
COMPARISON TABLE II
Test Formulation Time GlucoseInsL,lin No . ( My n . ) mm l~m/ml Insulin 0.5u/kg 0 28.7 0 ion 23.3 73 i n tramuscul en 20 ' 21 . 5 76 injection 30' 19.9 213 45' 15.6 2~0 60' 12.9 81 75' 10,9 120 90 ' 8 . 5 I
120' 6.5 50 150' 6.4 I
180' 6.5 25 - it-~L~f~3~0 POISON EXAMPLE A
_, .
A solution was roared ion direct intestinal administration of 0.5 ml in final volume.
In the rat.
TABLE III
Test Formulation Percent decrease into. of No. blood glucose Animals tested _ mix mint mix Compositions 1. Insulin 24u/kg of this sodium shalt 1% -33 11 5 invention. Trasylol 3000 KIWI.
Injection in saline of 0.5 ml in-to the 2. Insulin 24u/kg ilium sodium shalt 1% -23 -19 ~10 4 in saline 3. Insulin 24 u/kg sodium shalt 0.5'~0 -18 -24 -2 6 Trasylol 3000 KIWI.
in saline 4. Insulin 48u/kg sodium shalt 1b -34 -20 ~10 10 in saline 5. Insulin 48u/kg sodium shalt 1/0 -55 -50 I 6 Trasylol 1000 u in satin 6. Insulin 4~u/ky sodium shalt 1% -61 -66 -25 6 Trasylol 3000u in saline 7. Insulin 48u/kg sodium shalt 1/0 -35 -28 -~14 6 Soybean trypsin-inhibitor 3 my in saline 8. Insulin 48u/kg sodium torchlit I -7 -2 ~27 in saline 9. Insulin 48u/kg sodium torchlit 1% -28 -20 +21 Trasylol 1000 KIWI.
in saline '11 TABLE 1II (Continued) Lo 30 Test Formulation Percent decrease in lo. of No. blood glucose Animals tested 60 l20 240 mix mix mix lo Insulin 48 u/kg sodium torchlit l% 39 -36 I 7 Trasylol 3000 KIWI.
in saline 11. Insulin 48u/kg Sodium torchlit 1% -15 -12 +21 6 Soybean trypsin-inhibitor 3 my in saline lo. Insulin 48u/kg Trasylol 3000 KIWI. -33 -30 +4 6 in saline Control- 13. Insulin 48u/kg -5 -6 +25 6 intestinal in saline administration o As is clear -froth the tales the effect of intestir,~l administration of insulin on blood glucose levels is similar to the effect of insulin inquietude to the animals The effect it similar when insulin is given orally to the dog or directly into the intestine of the rat.
EnterQcoating provides the sufficient shelter against the destruction of the insulin in the stomach and delays its effect for one hour in the dog.
Now the following examples illustrate practically the pharmaceutical compositions of insulin for oral use embodying this invention, wherein the dosage of insulin employed are for the human bodies.
All examples are for one pill or one capsule containing total weight of 100 my. The active compounds will be given in detail. The complimentary weight is of inert compounds like minutely or avicel 101.
Thus the active ingredients and the vehicle for oral administration of compositions according to the present in-mention are hereinafter set forth in tabular form:
tray on aureole ~LZ~3 I
Example Amount Nile Protozoa Vehicle Insulin Acid/Salt Inhibitor
Insulin is a medicament particularly useful as a hype-glycaemic agent being widely used by patients suffering from diabetes and is the only treatment for juvenile diabetes Maltese.
In practice today insulin is administered only by injection. The everyday injection of insulin is very trickle-sonic and causes consid~rab'ie physical and even mental suffering for the patients. Several severe side effects such as lipodystrophy at the site of the injection, lipoatrophy, lipohyp~rtrophy or occasional hypoglycemia have been noted and reported to occur.
To avoid the daily injection of the drug, the insulin pump has been developed in the last decade. This pump, however, also suffers from some of the disadvantages of the daily injection. Since insulin is normally secreted unto the portal vein, normally the liver is exposed to a greater insulin con-cent ration than peripheral tissues. Insulin administered via the peripheral venous system to insulin-deficient diabetic patients results in a concentration of insulin in the portal vein almost equal to that in the peripheral circulation. The net result is hypoinsulinemia in the portal vein and the liver and hyperinsulinemia in the peripheral venous system. This may lead to an abnormal pattern of glucose disposal.
ZOO
he present inventiorl roulettes to a pharnlaceutical composition curtaining insulin. More particularly, the present invention relates to a pharmaceutical cGn~pOsiti~n for the oral administration of insulin.
Insulin is a n,edicament particularly useful as a hype-glycaemic agent being widely used by patients suffering from diabetes and is the only treatment for juvenile diabetes Maltese.
In practice today insulin is administered only by injection. The everyday injection of insulin is very trouble-some and causes considerable physical and even mental suffering for the patients. Several severe side effects such as lipodystropby at the site of the injection, lipoatrophy, lipohypertrophy or occasional hypoglycemia have been noted and reported to occur.
To avoid the daily injection of the drug, the insulin pump has been developed in the last decade. This pump, however, also suffers from some of the disadvantages of the daily injection. Since insulin is normally secreted into the portal vein, normally the liver is exposed to a greater insulin con-cent ration than peripheral tissues. Insulin administered via the peripheral venous system to insulin-deficient diabetic patients results in a concentration of insulin in the portal vein almost equal to that in the peripheral circulation. The net result is hypoinsulinemia in the portal vein and the liver and hyperinsulinemia in the peripheral venous system. This may lead to an abnormal pattern of glucose disposal.
In order to overcome the difficulties caused by injection of insulin rectal administration of insulin has recently beer proposed, studied and developed.
Cheshire et. at (J. Harm. Formed. 30, 806~80~, 197~), Bar-On et at (By. J. Pharmacy 73, 2'1-24, 1981), and others tested the hypo~lyceaemic affect of insulin mixed with polyp oxyethylen laurel ether or polyoxtethylene-20-cetyl ether by administering through the rectum. Zip et at (Life Sciences, 29, 803-809,1981) tested the same effect with insulin mixed with bile salts. The insulin effected the blood glucose levels, by reduction of approximately 50%, with dose of 48~/kg.
In a further article by Zip, Kid Ron, Bar-On and Berry (Life Sciences, 31, pp. 2837-2841, 1982) insulin was used as a motel for proteins in general to discover the theoretical question of protein absorption through the intestine and it was found that in the presence of the strong detergent effect of deoxycholic acid and soybean ~rypsin inhibitor, biologically active macrolnolecules such as insulin could be effectively absorbed from the intestine.
Similarly, in British Patent '1,563,311 there is described and clainled a pharmaceutical composition for rectal administer-lion which comprises insulin, a carrier suiting the composition for rectal administration, and an agent or increasing the rate of' absorption of the insulin into the body on rectal administrator of the composition, the agent comprising at least one material selected froth (a) non ionic polyoxyethylene ether surface active agents having an HUB value of 6 to 19 and wherein the average number of polyoxyethylene units is 4 to 30, (by anionic surface active agents, (c) cat ionic surface active agents (d) ampholytic surface active agents, (e) bile acids and (~) alkali metal salts of bile acids and amounting to 0.001 to 0.5 times the weight of the carrier. In U.S. Patents 4434159 and 4164573 there are described similar insulin containing pharmaceutical compositic~rls for rectal administration.
Tolls the a~lministra-tiorl of insulin Roy the portal system of the human rectum in suppository form or further along the intestinal tract, e.g., by enema-likP introduction is suggested and taught by said articles and patent.
Nevertheless it has been found that only part of the insulin is absorbed through the portal system from the human rectum and rectal administration also represents a major in-convenience for the patient.
According to the present invention, there have now been developed pharmaceutical compositions for administering insulin which overcome all of the above-mentioned disadvantages of the prior art systems.
More specifically, there have now been discovered and provided according to the present invention pharmaceutical compositions for the oral administration of insulin comprising insulin 9 a bile acid or alkali metal salt thereof 9 said bile acid being selected from the group consisting of colic acid, chenodeoxycholic acid, taurocholic acid taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3~-monshydroxy-caloric acid, lithocholic acid 9 3u-hydroxy-12-ketocholic acid J
3~hydroxy-12-ketocholic acid, 12~-3~-dihydrocholic acid, and ursodesoxycholic acid, and a protozoa inhibitor, slid composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
Thus there have now been discovered pharmaceutical come positions containing insulin which can be administered orally and which have the same effect as naturally secreted insulin on the blood glucose levels. The insulin administered according to the I
present invention reaches the intestine arid is ~uic~.ly bored in the body through the intestine and through the purity system to the liver. This absorption route is the most convenient way to administer the drug and it resembles the physiological secretion of insulin by the pancreas, thus enabling delicate control of the blood glucose level and the metabolic activities of the liver and the peripheral organs controlled by insulin.
Various attempts have been made in the past to administer insulin orally. In one study it was shown that administration of liposome-entrapped insulin caused a significant reduction of blood glucose levels in diabetic rats (Dapergolas, G. and Gregoriadis, Lance ii, 824-827, 1976~. Pate and Reman (FOBS Letters, 62, 60-63, 1976) showed that insulin administered orally entrapped in liposomes is effective in diabetic rats.
Papahadjopoulos and Sjoka (U.S. patent No. 4,235,871) suggested to use liposomes to encapsulate insulin and Sears (U.S. patent No. 4,145,410) used synthetic phosphatidyl compounds to stabilize the liposomes against lipolysis.
Another approach for insulin enhanced activity is the addition of an adjutant such as choline (which is not a bile salt) to the insulin injections (U.S. patent 2563070). This is totally different from oral administration with bile salts since the bile salts in an oral composition enhance the absorption of insulin from the intestinal lumen to the blood circulation while with injectable solutions no such absorption takes place or is necessary and the function of chlorine which is different structurally and chemically from colic acid is entirely different in said patent and it intended to delay the insulin absorption.
Thus it will be realized that none of the said publications teaches or suggests the novel pharmaceutical composition of the I
present invention which includes the use of bile salts to promote the absorption of insulin, the use of protozoa inhibitors to protect insulin against proteoiysis and the use of enterocoating of the active mixture.
Human insulin including human insulin genetically reproduced or any insulin such as, for example, the insulin obtained from cows (bovine), pigs or whales can be used as the insulin for compositions of this invention. Furthermore, metal complexes of insulin such as the zinc complex of insulin as well as protamine zinc insulin and glob in zinc insulin may be also used as the insulin in compositions of this invention.
The protozoa inhibitor used in the compositions of the present invention can be any material which has the ability to inhibit any proteolytic activity.
-I-tactical ~xdmples of such yrotedse inhibitors include aprotinin (Trasilol (R) of Bayer, Pen~all~idine isetilionate, anti pain, tosylamide-phenylethyl-chlGromethyl kitten (TPOKj, phenylmethyl sulfonyfluoride (PMSF), pepstatin, trypsin inhibitor Acetone, Alcohols, guanidium, a2-macroglubulin, TUCK, Chelating agents of Zen, lodoacetate, al-antitrypsin, ETA, Zen, Antithromlbin III, leupeptin Trypsin inhibitor from soy bean, trypsin inhibitor fro hen egg white, trypsin inhibitor from chicken egg white, etc.
Some of the above protozoa inhibitors might be toxic in large doses and therefore, if chosen; the use and dosage thereof must be carefully screened and jested.
In especially preferred embodiments of the present invention said protozoa inhibitor is selected from the group consisting of aprotinin9 A2-macroglobulin, antithrombin III and trypsin inhibitor from sty bean or chicken egg white.
The most preferred protozoa inhibitor agents used in this invention are preferably Trasylol(R) in the amount of 1000 kiwi./
100 my pill, or 3 my soybean trypsin inhibitor or 10 my soybean flour.
The above-mentioned bile acids and alkali metal salts thereof used in the oral compositions of the present invention promote the absorption of the insulin from the intestinal tract and act do cdrri~s thoroughfare, Hoover, it Weds In~erestln~ end sur~risin~J
to note that deoxycholi~ acid, which was the acid of choice in the article in Life Sciences, Vol. 31, pp. 2837-2441 (19132) is unsuitable for use in the oral compositions of the present in-mention because of the damage which it causes to the cells of the intestinal wall.
The active concentration of bile acid or salt thereof is about 1-20 mg/ml and preferably about 5-15 mg/pill/one treatment.
It has also been surprisingly found that sodium shalt can simultaneously function both as the bile acid carrier of the insulin and the protozoa inhibitor agent and thus a compost-lion comprising insulin and sodium shalt in an enteric coating is especially preferred.
The amount of insulin in a composition is 20-50u/kg in rats and expected to be about 0.5-3u/kg in humans. Preferred dosages for humans are about l-2u/kg/treatment with three treatments a day, however sustained release microencapsulat10n could allow treatment to be reduced to once or twice a day.
The enterocoating and possible micro encapsulation of the mixture provides protection for the insulin against decomposition in the stomach and for the slow release of the mixture consistuents in the intestinal tract.
The enterocoating is carried out by methods known per so in the art, e.g., according to Rumania Pharmaceutical Sciences, p. 1614-1615 (1975, Thea Ed. Meek Pub. Co.) and Theory and Practice of Industrial Pharmacy, Blackman, Liberian Caning, p. 116-117, 371-374 (1976~ end Ed) as us the enteric micro-encapsulation (Theory and Practice of Industrial Pharmacy ibid, pp. 420-4383.
One of the findings of the present invention is that there is different rate of absorption of the different constituents of the present composition from the intestinal lumen into the blood stream. The absorption of the bile acid is very fast, eulogy., more than 50% of colic acid is absorbed during 30 minutes while only 5-10% of the insulin is absorbed during 60 minutes.
For this reason a dry Regimen involvirlg ing~stiorl of a pair of pills at spaced intervals, e.g., a second pill eon-twining a higher concentration of bile acid to be taken half en, hour after the first Jill is contemplated as is microencapsulatior of different constituents with spaced time release coatings to enhance the absorption of the insulin into the system.
While the invention will now by described in connection with certain preferred embodiments in the following examples it will be understood that it is not intended to limit the invention to these particular embodiments. On the contrary it is intended to cover all alternatives, modifications and equivalents as may by included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the par-ticklers shown are by way of example and for purposes of if-lustrative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood descrip-lion of formulation procedures as jell as of the principles and conceptual aspects of the invention EXAM LYE 1.
An enterocoated capsule was prepared for oral administration of insulin to a diabetic dog. Table 1 shows Plasma 1~1 levels and glucose levels with administration.
I
_ _ Composition Test Formulatiorl Time GlucoseInsulir of -this invention No. (Mix) no Mel .
1 . i nsul i n 7 . 3u/ky 0 36 . 7 15 Oral administration shalt 30 my 15 33.9 0 soybean - 30 34.4 6 -trpsin inhibit ion 45 34,6 6 20 my 60 33.8 12 in two capsules 75 29.1 23 (enterocoated) 105 23.7 36 135 21.8 22 ~65 16.1 3 210 15.8 0 240 11.5 0 270 12.1 0 300 10.2 0 330 7.5 0 360 9.3 0 I
COMPARISON TABLE II
Test Formulation Time GlucoseInsL,lin No . ( My n . ) mm l~m/ml Insulin 0.5u/kg 0 28.7 0 ion 23.3 73 i n tramuscul en 20 ' 21 . 5 76 injection 30' 19.9 213 45' 15.6 2~0 60' 12.9 81 75' 10,9 120 90 ' 8 . 5 I
120' 6.5 50 150' 6.4 I
180' 6.5 25 - it-~L~f~3~0 POISON EXAMPLE A
_, .
A solution was roared ion direct intestinal administration of 0.5 ml in final volume.
In the rat.
TABLE III
Test Formulation Percent decrease into. of No. blood glucose Animals tested _ mix mint mix Compositions 1. Insulin 24u/kg of this sodium shalt 1% -33 11 5 invention. Trasylol 3000 KIWI.
Injection in saline of 0.5 ml in-to the 2. Insulin 24u/kg ilium sodium shalt 1% -23 -19 ~10 4 in saline 3. Insulin 24 u/kg sodium shalt 0.5'~0 -18 -24 -2 6 Trasylol 3000 KIWI.
in saline 4. Insulin 48u/kg sodium shalt 1b -34 -20 ~10 10 in saline 5. Insulin 48u/kg sodium shalt 1/0 -55 -50 I 6 Trasylol 1000 u in satin 6. Insulin 4~u/ky sodium shalt 1% -61 -66 -25 6 Trasylol 3000u in saline 7. Insulin 48u/kg sodium shalt 1/0 -35 -28 -~14 6 Soybean trypsin-inhibitor 3 my in saline 8. Insulin 48u/kg sodium torchlit I -7 -2 ~27 in saline 9. Insulin 48u/kg sodium torchlit 1% -28 -20 +21 Trasylol 1000 KIWI.
in saline '11 TABLE 1II (Continued) Lo 30 Test Formulation Percent decrease in lo. of No. blood glucose Animals tested 60 l20 240 mix mix mix lo Insulin 48 u/kg sodium torchlit l% 39 -36 I 7 Trasylol 3000 KIWI.
in saline 11. Insulin 48u/kg Sodium torchlit 1% -15 -12 +21 6 Soybean trypsin-inhibitor 3 my in saline lo. Insulin 48u/kg Trasylol 3000 KIWI. -33 -30 +4 6 in saline Control- 13. Insulin 48u/kg -5 -6 +25 6 intestinal in saline administration o As is clear -froth the tales the effect of intestir,~l administration of insulin on blood glucose levels is similar to the effect of insulin inquietude to the animals The effect it similar when insulin is given orally to the dog or directly into the intestine of the rat.
EnterQcoating provides the sufficient shelter against the destruction of the insulin in the stomach and delays its effect for one hour in the dog.
Now the following examples illustrate practically the pharmaceutical compositions of insulin for oral use embodying this invention, wherein the dosage of insulin employed are for the human bodies.
All examples are for one pill or one capsule containing total weight of 100 my. The active compounds will be given in detail. The complimentary weight is of inert compounds like minutely or avicel 101.
Thus the active ingredients and the vehicle for oral administration of compositions according to the present in-mention are hereinafter set forth in tabular form:
tray on aureole ~LZ~3 I
Example Amount Nile Protozoa Vehicle Insulin Acid/Salt Inhibitor
2. 100 IT 15 my sodium Shelley - Pnterocoated capsule
3. 100 IT 15 my sodium shalt aprotinin enterocoated 1000 KIWI. capsule
4. loo IT 15 my. sodium shalt aprotinin enterocoated 3000 KIWI. capsule
5. 100 IT 15 my. sodium shalt 5 my soybean enterocoated trypsin inhibitor capsule
6 100 IT I my. sodium shalt - enterocoated pills
7. 100 IT 15 my. sodium shalt aprotinin enterocoat~d 1000 KIWI. pills
8. 100 IT 15 my. sodium shalt aprotinin enterocoated 3000 KIWI. pills
9. 100 IT 15 my. sodium shalt 5 my chicken egg enterocoated white pills trypsin inhibitor
10. 100 IT 15 my sodium Tory- appertain enterocoated shalt 1000 KIWI. capsule
11. 100 IT 15 my. sodium Tory- aprotinin enterocoated shalt 3000 KIWI. capsule
12. 100 IT 15 my. sodium Tory- 5 my soybean enterocoated shalt trypsin inhibitor capsule
13. lo IT 15 my. sodium Tory- aprotinin enterocoated shalt 1000 KIWI. pills
14. 100 IT 15 my. sodium Sheehan- aprotinin enterocoated deoxychola-te 1000 KIWI. capsule
15. 100 IT 15 my. sodium Sheehan- aprotinin enterocoated deoxycholate 3000 KIWI. capsule
16. 100 IT 15 My. sodium Sheehan- 5 my soybean enterocoated deoxycholate trypsin inhibitor capsule Lo I V
Exude out Byway Russ Yo-yo Insulin Acid/Sdlt Irlhi~itor I 100 IT 15 my. sodium Sheehan- aprotinin enterocoated deoxycholate 1000 KIWI. pills 18. 100 IT 15 my. sodium Sheehan- aprotinln enterocoated deoxycholate 30C0 KIWI. pills 19. 100 IT 15 my sodium ennui- 5 my. subdural enterocoated deoxycholate trypsin inhibitor pills En The following interocoa~ed tablets were prepared in the following manner:
Component I Example 21 Insulin 2 my 2 my Sod. Shalt 15 my 15 my Trasilol - 1000 U
Lactose Hydrous US 144 my 150 my Starch NO 36 my 30 my Magnesium Stewart NO 3 my 3 my Eudragit L-100 polymer of Acrylic and Muth~crylic Acid Esters) 4 my 4 my Talc NO 4 my 4 my Polyethylene luckily 6000 NO Jo L_ 0 Total 208.4 my 208.4 my Method of Preparation:
(a) In order to homogeneously disperse the active components tr;turations with lactose for each component were individually prepared. Gradual dry mixing of all the components was then performed. The components are then mechanically pressed to form tablets of 9 mm diameter;
(b) A solution of the enterocoating polymer is then prepared by solving the polymer in a ethylene chloride isopropyl alcohol mixture. The tablets are coated by spraying the solution within a mildly warmed jar whole the tablets roll.
The solvent vapors are continuously aspirated.
Testis the Tablets The dissolution of the tablets was then tested according to US XX. The tablets were found to be stable for two hours in gastric juices. Why n they are then transfer-red to intestinal juices, they dissolve therm in less than 1/2 an hour.
Trade no It will be eviderlt to those skilled in the art that -the invention is not limited to the details of the foregoing illustrative embodiments and examples end that the present invention may be embodied in other specific forms without departincJ froth the essential attributes thereof, and it is, therefore, desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come with the meaning and range of equivalency of the claims are, therefore, intended to be embraced therein.
Exude out Byway Russ Yo-yo Insulin Acid/Sdlt Irlhi~itor I 100 IT 15 my. sodium Sheehan- aprotinin enterocoated deoxycholate 1000 KIWI. pills 18. 100 IT 15 my. sodium Sheehan- aprotinln enterocoated deoxycholate 30C0 KIWI. pills 19. 100 IT 15 my sodium ennui- 5 my. subdural enterocoated deoxycholate trypsin inhibitor pills En The following interocoa~ed tablets were prepared in the following manner:
Component I Example 21 Insulin 2 my 2 my Sod. Shalt 15 my 15 my Trasilol - 1000 U
Lactose Hydrous US 144 my 150 my Starch NO 36 my 30 my Magnesium Stewart NO 3 my 3 my Eudragit L-100 polymer of Acrylic and Muth~crylic Acid Esters) 4 my 4 my Talc NO 4 my 4 my Polyethylene luckily 6000 NO Jo L_ 0 Total 208.4 my 208.4 my Method of Preparation:
(a) In order to homogeneously disperse the active components tr;turations with lactose for each component were individually prepared. Gradual dry mixing of all the components was then performed. The components are then mechanically pressed to form tablets of 9 mm diameter;
(b) A solution of the enterocoating polymer is then prepared by solving the polymer in a ethylene chloride isopropyl alcohol mixture. The tablets are coated by spraying the solution within a mildly warmed jar whole the tablets roll.
The solvent vapors are continuously aspirated.
Testis the Tablets The dissolution of the tablets was then tested according to US XX. The tablets were found to be stable for two hours in gastric juices. Why n they are then transfer-red to intestinal juices, they dissolve therm in less than 1/2 an hour.
Trade no It will be eviderlt to those skilled in the art that -the invention is not limited to the details of the foregoing illustrative embodiments and examples end that the present invention may be embodied in other specific forms without departincJ froth the essential attributes thereof, and it is, therefore, desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come with the meaning and range of equivalency of the claims are, therefore, intended to be embraced therein.
Claims (4)
1. A pharmaceutical composition for the oral administration of insulin comprising insulin, a bile acid or alkali metal salt thereof, said bile acid being selected from the group consisting of cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, glycochenocholic acid, 3.beta.-monohydroxychloric acid, lithocholic acid, 3.alpha.-hydroxy-12-ketocholic acid, 3.beta.-hydroxy-12-ketocholic acid, 12.alpha.-3.beta.-dihydrocholic acid, and ursodesoxycholic acid, and a protease inhibitor, said composition being provided with an enterocoating to assure passage through the stomach and release in the intestine.
2. A pharmaceutical composition for the oral administration of insulin according to claim 1 wherein said protease inhibitor is selected from the group consisting of aprotinin A2-macroglobulin,, antithrombin III and trypsin inhibitor from soy bean or chicken egg white.
3. A pharmaceutical composition for the oral administration of insulin according to claim 1 comprising sodium cholate as both the bile acid and the protease inhibitor.
4. A pharmaceutical composition for the oral administration of insulin according to claim 1 wherein the components of said composition are microencapsulated and enterocoated to provide for timed release of ingredients in the intestine.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL68769 | 1983-05-23 | ||
| IL68769A IL68769A (en) | 1983-05-23 | 1983-05-23 | Pharmaceutical compositions containing insulin for oral administration |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1223200A true CA1223200A (en) | 1987-06-23 |
Family
ID=11054289
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000454266A Expired CA1223200A (en) | 1983-05-23 | 1984-05-14 | Pharmaceutical compositions containing insulin |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US4579730A (en) |
| EP (1) | EP0127535B1 (en) |
| JP (1) | JPH0678238B2 (en) |
| AT (1) | ATE49125T1 (en) |
| CA (1) | CA1223200A (en) |
| DE (1) | DE3480903D1 (en) |
| DK (1) | DK167240B1 (en) |
| IL (1) | IL68769A (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK98342C (en) * | 1959-06-16 | 1964-03-31 | Henry Marinus Dr Christensen | Process for the preparation of an insulin preparation for oral application. |
| JPS5257313A (en) * | 1975-11-07 | 1977-05-11 | Yamanouchi Pharmaceut Co Ltd | Manufacture of micellar insuline emulsion preparations |
| DE2640707C3 (en) * | 1976-09-10 | 1980-01-24 | Karl Dr.Med. 7302 Ostfildern Theurer | Process for the production of medicinal preparations with a content of protein and peptide solutions which can be absorbed in the intestine |
| JPS5940137B2 (en) * | 1976-10-14 | 1984-09-28 | 武田薬品工業株式会社 | Pharmaceutical composition for oral administration |
| JPS5821622A (en) * | 1981-07-28 | 1983-02-08 | Kowa Co | Remedy for diabetes |
| EP0071433A1 (en) * | 1981-07-28 | 1983-02-09 | Kowa Company, Ltd. | Medicine for the treatment of diabetes |
| FR2515960A1 (en) * | 1981-11-06 | 1983-05-13 | Alkhouri Fallouh Nazir | Biodegradable nano:capsules contg. biologically active cpd. - having envelope of polymerised alkyl cyanoacrylate |
| IL68769A (en) * | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
-
1983
- 1983-05-23 IL IL68769A patent/IL68769A/en unknown
-
1984
- 1984-05-09 DK DK229484A patent/DK167240B1/en not_active IP Right Cessation
- 1984-05-09 US US06/608,462 patent/US4579730A/en not_active Expired - Fee Related
- 1984-05-14 CA CA000454266A patent/CA1223200A/en not_active Expired
- 1984-05-21 DE DE8484401049T patent/DE3480903D1/en not_active Expired - Fee Related
- 1984-05-21 AT AT84401049T patent/ATE49125T1/en not_active IP Right Cessation
- 1984-05-21 EP EP84401049A patent/EP0127535B1/en not_active Expired - Lifetime
- 1984-05-23 JP JP59104386A patent/JPH0678238B2/en not_active Expired - Lifetime
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| US10881714B2 (en) | 2008-03-26 | 2021-01-05 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| US11660327B2 (en) | 2008-03-26 | 2023-05-30 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
| US10350162B2 (en) | 2008-05-05 | 2019-07-16 | Oramed Ltd. | Methods and compositions for oral administration of exenatide |
| US10398762B2 (en) | 2012-01-03 | 2019-09-03 | Oramed Ltd. | Methods and compositions for treating diabetes |
| US11395848B2 (en) | 2012-01-03 | 2022-07-26 | Oramed Ltd. | Methods and compositions for treating diabetes |
| US10342764B2 (en) | 2012-02-01 | 2019-07-09 | Oramed Ltd. | Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same |
| US10933022B2 (en) | 2012-02-01 | 2021-03-02 | Oramed Ltd. | Protease inhibitor-containing compositions, compositions comprising same, and methods for producing and using same |
| US10967051B2 (en) | 2013-01-03 | 2021-04-06 | Oramed Ltd. | Methods and compositions for treating NAFLD, hepatic steatosis, and sequelae thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| US4579730A (en) | 1986-04-01 |
| IL68769A0 (en) | 1983-09-30 |
| EP0127535A3 (en) | 1987-01-14 |
| ATE49125T1 (en) | 1990-01-15 |
| DK167240B1 (en) | 1993-09-27 |
| JPS6069028A (en) | 1985-04-19 |
| IL68769A (en) | 1986-02-28 |
| DK229484A (en) | 1984-11-24 |
| JPH0678238B2 (en) | 1994-10-05 |
| EP0127535B1 (en) | 1990-01-03 |
| DK229484D0 (en) | 1984-05-09 |
| EP0127535A2 (en) | 1984-12-05 |
| DE3480903D1 (en) | 1990-02-08 |
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