MXPA98003137A

MXPA98003137A - Mouth-release of insulinotropic peptides like gluca

Info

Publication number: MXPA98003137A
Application number: MXPA/A/1998/003137A
Authority: MX
Inventors: D Ebert Charles; J Heiber Sonia; K Gutniak Mark
Original assignee: Theratech Inc
Priority date: 1995-10-23
Filing date: 1998-04-22
Publication date: 1998-11-12

Abstract

The present invention relates to drug release systems and methods for administering an insulinotropic peptide similar to glucagon to the buccal mucosa for transmucosal drug delivery. The drug delivery systems comprise a medicament composition containing an effective amount of the glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer to improve the permeation of the glucagon-like insulinotropic peptide via oral glucose, and the means for maintaining the drug composition in a drug transfer relationship with the buccal mucosa. These systems may be in free form, such as creams, gels and ointments, or may consist of a device of a certain physical form such as tablets and pills. A preferred glucagon-like insulinotropic peptide is GLP-1 (7-36) ami

Description

MOUTH RELEASE OF INSULINOTROPIC PEPTIDES LIKE GLUCAGON BACKGROUND OF THE INVENTION This invention relates to compositions and methods for delivering medicaments, especially peptide medicaments, to a warm-blooded animal, by administration through the mucosa and, particularly, through the buccal mucosa of the oral cavity. . More specifically, the invention relates to compositions and methods for buccal release of glucagon-like insulinotropic peptides (GLIP) in the body. Traditionally there has been very little trial of evaluation of the membranes that the oral cavity as drug administration sites. Both the buccal and sublingual membranes offer advantages over other routes of administration. For example, drugs that are administered through the buccal and sublingual routes have a rapid onset of action, reach high levels in the blood, avoid the effect of the first step of the hepatic metabolism and avoid exposure of the drug to the fluids of the liver. gastrointestinal tract. Additional advantages include easy access to the membrane sites, so that the medication can be applied, located and removed easily. In addition, there is a good potential for prolonged release through the buccal membrane. M. Rathbone & J. Hadgraft, 74 Int '1 J. Qf Pharmaceutics 9 (1991). The administration through the buccal mucosa can be better accepted than the rectal dosage, for example, and in general avoids local toxic effects, as they have been a problem in the nasal administration. B. Aungst & N. Rogers, 53 Int'l J. Pharmaceutics 227, 228 (1989). The sublingual route has received much more attention than the oral route. The sublingual mucosa includes the membrane of the ventral surface of the tongue and the floor of the mouth, while the buccal mucosa constitutes the lining of the cheeks and lips. The sublingual mucosa is relatively permeable, thus providing rapid absorption and acceptable bioavailability of many medications. In addition, the sublingual mucosa is convenient, easily accessible and generally well accepted. This route has been clinically investigated for the release of a substantial amount of medication. This is the traditional route for the administration of nitroglycerin, and it is also used for buprenorphine and nifedipine. D. Harris & J. Robinson, 81 J. Pharmaceutical Sci. 1 (1992). However, the sublingual mucosa is not very suitable for sustained release systems because it lacks a smooth and relatively immobile mucosal space suitable for the union of a retentive release system. The buccal mucosa is less permeable than the sublingual mucosa, and the rapid absorption and high bioavailability seen with the sublingual administration of medications in general, is not obtained to the same extent by the buccal mucosa. D. Harris & J. Robinson, 81 J. Pharmaceutical Sic. 1, 2 (1192). The permeability of the oral mucosa is probably related to the physical characteristics of the tissues. The sublingual mucosa is thinner than the buccal mucosa, in this way, the permeability is greater for the sunblingual tissue. The palatal mucosa is intermediate in thickness, but is keratinized, and thus less permeable, while the sublingual and buccal tissues are non-keratinized. However, the oral mucosa seems more suited to the union of retentive release systems. The ability of molecules to permeate through oral mucosa also seems to be related to molecular size, lipid solubility and ionization. Small molecules, less than about 300 daltons, appear to cross mucous membranes more rapidly, as molecular size increases, however, permeability decreases rapidly. The compounds soluble in lipids are more permeable through the mucous membranes than the molecules not soluble in lipids. In this sense, the relative permeabilities of the molecules seem to be related to their partition coefficients. The degree of ionization of the molecules, which depends on the pKa of the molecule and the pH on the surface of the membrane, also greatly affects the permeability of the molecules. Maximum absorption occurs when the molecules are non-ionized or neutral in their electrical charge; absorption decreases as the degree of ionization increases. Therefore, loaded macromolecular drugs present the greatest challenge to absorption through the oral mucosae. Substances that facilitate the transport of solutes through biological membranes, which favor penetration, are well known in the technique of drug administration. V. Lee et al., 8 Critical Reviews in Therapeutic Drug Carrier Sms 91 (1991) [hereinafter "Critical Reviews"]. Penetration enhancers can be classified as: (a) chelators (eg, EDTA, citric acid, salicylates), (b) surfactants (eg, sodium dodecyl sulfate (? DS)), (c) non-surfactants (e.g., cyclic unsaturated ureas), (d) bile salts (e.g., sodium deoxycholate, sodium taurocholate), and (e) fatty acids (e.g., oleic acid, acylcarnitines, mono- and diglycerides). The effectiveness of the promoters in the transport of peptidic and non-peptidic drugs through the membranes seems to be positively correlated with the hydrophobicity of the promoter. Critical Reviews in 112. For example, the efficacy of bile salts in the intensification of insulin absorption through nasal membranes is positively correlated with the hydrophobicity of the steroid structure of bile salts. Critical Reviews in 115. In this way, the order of effectiveness is: deoxycholate < Chenodeoxycholate < choke < ursodeoxycholate. The conjugation of deoxycholate and cholate, but not of the derivatives of fusidic acid with glycine and taurine do not affect its intensifying potency. The release of heparin through the intestinal mucosa is not evident, as measured in terms of prolongation of the partial thromboplastin time or release of the activity of the lipase in plam, when administered through the colon of a mandrel. However, significant activity is detected when the bile salts, cholate or sodium deoxycholate are included in the formulation. Critical Reviews in 108. Various mechanisms of action of the penetration promoters have been proposed. These mechanisms of action, at least for peptide and protein drugs, include: (1) reduction of viscosity and / or elasticity of the mucosal layer, (2) facilitation of transcellular transport by increasing the fluidity of the lipid double layer of the membranes, (3) the facilitation of the paracellular transport modifying the close junctions between the epithelial cell layer, (4) overcoming the enzymatic barriers, and (5) the increase of the thermodynamic activity of the drugs. Critical reviews at 117-125. A large number of penetration promoters have been tested and have been found to be effective in facilitating the administration of the drug through the mucosa, but hardly any penetration promoting product has reached the market place. The reasons for this include the lack of a satisfactory safety profile regarding irritation, the reduction of barrier function and the damage of the protective mechanism of mucociliary clearance. Critical Reviews in 169-170. Furthermore, for a flattener to work properly, the flattering and drug combination is preferably held in position against the mucosal tissues for a sufficient period of time to allow penetration aided by the medicament enhancer through the mucous membrane . In transdermal and transmucosal technology, this is usually carried out by means of a patch or other device that adheres to the skin layer by means of an adhesive.

Oral adhesives are well known in the art. See, for example, Tsu et al., U.S. Patent 3,972,995; Lowey, U.S. Patent 4,259,314; Lowey United States Patent 4,680,323; Yukimatsu et al., U.S. Patent 4,740,365; Kwiatek et al., U.S. Patent 4,573,996; Suzuki et al., U.S. Patent 4,292,299; Suzuki et al., Patent United States 4,715,369; Mizobuchi et al., Patent United States 4,876,092; Fankhauser et al., U.S. Patent 4,855,142; Nagai et al., U.S. Patent 4,250,163; Nagai et al., U.S. Patent 4,226,848; Browing U.S. Patent 4,948,580; Schiraldi et al., Re-published United States Patent Re. 33,093; and J. Robinson, 18 Proc Intern. Symp. Control. I laughed Bioact. Mater., 75 (1991). Commonly, these adhesives consist of a matrix of a polymer or mixture of hydrophilic polymers, for example, soluble or inchable in water, which can adhere to a moist mucosal surface. These adhesives can be formulated as ointments, thin films, tablets, pills and other forms. Often these adhesives have had medications mixed with them to effect slow release or local release of a medication. However, some have been formulated to allow adsorption through the mucosa in the individual's circulatory system. Glucagon-like insulinotropic pepitoids, for example, GLP-1 (7-39) amide, are antidiabetogenic agents that are being investigated for treatment of diabetes mellitus, which have hitherto been administered intravenously, subcutaneously or by some other invasive route, and are too large for transdermal delivery. Diabetes mellitus afflicts almost 15 million people in the United States.

Approximately 15O has insulin-dependent diabetes (DDI, type 1 diabetes), which is considered to be caused by the autoimmune destruction of pancreatic islet beta cells. In these patients, insulin therapy is essential for life. Approximately 80., of patients have non-insulin dependent diabetes (NIDDM, type 2 diabetes), a heterogeneous disorder characterized by damage to insulin secretion and insulin resistance. Some patients who appear to have NIDDM may actually have a slowly progressive form of DMDI and eventually will be dependent on insulin. However, most patients with NIDDM can be treated without insulin. These are usually overweight and have the insulin resistance of obesity superimposed on the intrinsic insulin resistance of the disease. The lost of weight, especially in the early stages of the disease can restore normal blood glucose levels of these patients. Your diabetes can develop when the impact of combined insulin resistance exceeds the ability of your pancreatic beta cells to compensate. Plasma insulin levels in these patients, which are often higher than those of normal weight people who do not have diabetes, are not adequate for their obesity and hyperglycemia. People with NIDDM who are not obese may have a primary defect in insulin secretion in which elevations in plasma glucose levels cause not only insulin resistance but also further impairment of pancreatic beta cell function. J.E. Gerich, Oral Hypogluce ic Agents, 321, íjL Engl. J. Med., 1231 (1989). Patients with NIDDM are usually treated with diet modifications and sulfonylureas and / or diguanides. H.E. Lebovit? & M.N. Feinglos, Sulfonylurea Drugs: Mechanism of Antidiabetic Action and Therapeutic Usefulness, 1 Diabetes Care, 189 (1978). Oral hypoglycemic agents represent approximately all descriptions in the United States. J. E. Gerich, 321 N. Engl. J. Med, 1231 (1989). Unfortunately, approximately 11-36'-. of patients with NIDDM do not respond well to diet and sulphonylurea therapy after one year of treatment. At 5-7 years approximately half of the patients with NIDDM receiving sulfonylurea treatment need to start insulin therapy. These patients tend to be resistant to insulin, in this way, high doses of insulin are administered, which in turn gives rise to hyperinsulinemia, may play a role in the development of atherosclerosis. Bailliere's Clinical Endocrinology and Metabolism, 407-24 (M. Nattras &PJ Hale eds., (1988).) In warm-blooded animals and humans, GLIP stimulate insulin release, lower glucagon secretion, inhibit emptying gastric and improve glucose utilization MK Gutniak et al., Antidiabetogenic Effect of Glucagon-Like Peptide-1 (7-36) amide in normal Subjects and Patients with Diabetes Mellitus, 326 N. Engl. J. Med., 1316 (1992), DM Nathan et al., Insulinotropic Action of Glucagon-like Peptide-1 (7 (37) in Diabetes Care, 270 (1992); MA Exogenous Glucagon-Like peptide 1 (7-36 amide) in Type 2 ( Non-Insulin-Dependent) Diabetic Patients, 36 Diabetologia, 741 (1993) In addition, these drugs are inherently safe since insulinotropic effects are strictly glucose-dependent, thus limiting glycemia-type risk in response to therapeutic use of these MA Nauck et al., Normalization of Fasting Hyperglycemia by Exogenous Glucagon-Like Peptide 1 (7-36 amide) in Type 2 (Non-Insulin-Dependent) Diabetic Patients, 36 Diabetology 741 (1993). These properties make these peptides serious candidates for a therapeutic drug in the treatment of non-insulin dependent diabetes mellitus (NIDDM). GLP-1 (7-39) amide is a gastrointestinal hormone processed from the preproglucagon gene. The preproglucagon is a precursor of the polyprotein hormone that contains a signal peptide of 20 amino acids and a prohormone of 160 amino acids, proglucagon (PG). The PG has been shown to be processed differently in the pancreas and the intestine left by man. C. Orskov et al., Pancreatic and Intestinal Proccesing of Proglucagon in Man, 30 Diabetologia 874 (1987). In the pancreas, the main products are: (a) glucagon (PG 33-61 amino acids), (b) pancreatic peptide related to glicentin (PPRG) (PG 1-30 amino acids), and (c) a main fragment of pro glucagon designated as a large peptide (FPPG) (PG 72-158 amino acids) containing two glucagon-like sequences, the only pro-glucagon from the pancreatic peptide with known biological activity is glucagon. In the small intestine the main products of pro glucagon are: (a) enteroglucagon (PG 1-69 amino acids), which includes the amino acid sequence of glucagon, (b) GLP-1 (PG 78-107 amino acids), and (c) ) GLP-2 (PG 126-158 amino acids). C. Orskov et al., Proglucagon Products in Plasma of Noninsulin-dependent Diabetics and Nondiabetic Controls in the Fasting State and after Oral Glucose and Intravenous Arginine, 87 J. Clin. Invest., 415 (1991). A variant of GLP-1 (7-39) amide, known as GLP-1 (7-37), has been shown to have indistinguishable biological effects and metabolic pathways in healthy individuals, D. Gefel et al., Glucagon-Like Peptide-I Analogs: Effects on Insulin Secretion and Adenosine 3 ', 5' -Monophosphate Formation, 126, Endocrinology, 2164 (1990); C. Orskov et al., Biological Effects and Metabolic Rates of Glucagon-like Peptide 1 7-36 amide and Glucagonilike Peptide 1 7-37 in Healthy Sujects Are Indistinguishable, 42 Diabetes 658 (1993), but GLP-1 (7- 39) amide is the natural form in humans, C. Orskov et al., Complete Sequences of Glucago-Like Peptide-1 from Human and Pig Small Intestine, 264 J. Biol. Chem., 12826 (1989). For a long time it has been believed that an endocrine transmitter produced in the intestinal tract, or incretin, stimulates the secretion of insulin in response to food intake. Since GLP-1 (7-39) amide is released during a meal and after oral glucose administration and potentiates glucose-induced insulin release, this peptide can be an important incretin. J. M. Conlon, Proglucagon-derived Peptides: Nomenclature, Biosynthetic Relationships and Physiological Roles, 31 Diabetologia, 563 (1988); J.J. Holst et al., Truncated Glucagon-Like Peptide 1, An Insulin-releasing Hormone from the Distal Gut, 211 FEBS Lett. 169, (1987); M. Gutniak et al., Antidiabetogenic Effect of Glucagon-like Peptide 1, (7-37) amide in normal Subject and Patients with Diabetes Mellitus, 326, N. Engl. J. Med., 1316, (1992). An improved treatment regimen for patients with NIDDM who have a secondary deficiency for sulfonylurea should give satisfactory metabolic control without creating marked hyperinsulinemia. So far there have been no other serious candidates for a drug that can be used as this treatment. The glucagon-like insulinotropic peptides, such as GLP-1 (7-39) amide, seem to be the most promising treatment against diabetes. J. Eng., U.S. Patent No. 5,424,286; HE Bjorn et al., WO 9517510; J. A. Galloway et al., EP 658568; H. Agerbk et al., WO 9505848; D. E. Danley et al., EP 619322; G. C. Adrews, WO 9325579; Kirk et al., WO 9318785; D. I. Buckley et al., WO 9111457; J. F. Habener, US 5,115,666; J. F. Habener WO 9011296; J. F. Habener WO 8706941; J.F. Habener, United States Patent No. 5,120,712. It has previously been found that the combination therapy of a GLIP and a sulfonylurea exerts a synergistic effect on glycemia and insulin release. S. Efendic et al., WO 9318786. R. Baker et al., U.S. Patent No. 5,362,496, describes oral dosage forms for nicotine mucosal administration in smoking cessation therapy. These dosage forms include pills, capsules, gum, tablets, ointments, gel, membranes and powder, which usually remain in contact with the mucosal membrane and disintegrate and dissolve rapidly to allow immediate absorption. J. Kost et la. In U.S. Patent No. 4,948,587 describes the improvement of the release of the drug through the buccal mucosa using ultrasound. F. Theeuwes e'z al. in U.S. Patent No. 5,298,017, describes the electrotransport of drugs, including peptides, through the buccal membrane. J. L. Hasla et al. in U.S. Patent No. 4,478,822, it shows a drug delivery system that can be used for buccal delivery, wherein the drug is combined with a polymer that is liquid at room temperature and semisolid or gel at body temperature. T. Higuchi et al., U.S. Patent No. 4,144,317, discloses a body formed for the release of the medicament wherein the medicament is contained in an ethylene-vinyl acetate copolymer. A. Zaffaroni, United States Patent No.

No. 3,948,254, describes the release of the medicament via the mouth with a device having a microporous wall surrounding a closed reservoir containing a medicament and a solid carrier of the medicament. The pores contain a medium that controls the rate of drug release. In view of the foregoing, it will be appreciated that compositions and methods for prolonged buccal release of insulinotropic glucagon-like peptides, such as GLP-1 (7-39) amide, will be significant advances in the art.

OBJECTIVES AND SUMMARY OF THE INVENTION An object of the present invention is to provide a dosage form and method for administering a GLIP that allows easy accessibility to the administration site. It is also an object of the present invention to provide a dosage form and method for administering a GLIP that favors the high acceptance and comfort of a patient. Another object of the invention is to provide a dosage form and method for administering a GLIP that allows the localization of dosage forms over a prolonged period in order to maximize the absorption of the drug. Yet another object of the invention is to provide a dosage form and method for administering a GLIP that provides acceptable compatibility of the dosage form with the tissue. These and other objects are achieved by providing a drug delivery system for delivering through the mouth an insulinotropic peptide similar to glucagon in a buccal mucosa of a person, the system consisting of: (a) a medicament composition containing an amount effective of a glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer to improve the permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the composition of the medicament in a transfer ratio of the medicament with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation. The drug release system is preferably incorporated in any device of a certain physical form, such as a tablet, patch, or pill, or in free form, such as a gel, ointment, cream or gum. Preferred devices of determined physical form, such as a tablet or patch, the means for maintaining the composition of the medicament in relation to the transfer of the medication with the buccal mucosa is an adhesive. The preferred permeation promoter is a member selected from the group consisting of compounds that disrupt the cell envelope, solvents, steroidal detergents, bile salts, chelators, surfactants, non-surfactants, fatty acids and mixtures thereof. A preferred organic solvent is a member selected from the group consisting of a C 1 or C alcohol, and a diol of C or C 4, DMSO, DMA, DMF, 1-n-dodecyl-cyclazacycloheptan-2-one , N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures thereof. A compound that disrupts the preferred cellular envelope is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate. , glycerol monolaurate, propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof. A preferred bile salt is a steroidal detergent which is selected from the group consisting of natural and synthetic salts of the coltanic acid and mixtures thereof.

A preferred tablet, according to the invention, consists of an adhesive layer containing a hydrophilic polymer with a surface adapted to contact a first tissue of the oral cavity and adhere to it when wetted and an opposite surface in contact with and adhering to an adjacent layer of the drug / promoter that contains the permeation enhancer and the glucagon-like insulinotropic peptide, the medicament / facer layer adapted to be in contact with and in transfer relationship of the medicament with the buccal mucosa when the adhesive layer contacts and adheres to the first tissue, preferably the gingival tissue. Preferably, the hydrophilic polymer comprises at least one member selected from the group consisting of hydroxypropylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethylcellulose, carboxymethyl cellulose, dextran, gaur [sic] gum, polyvinylpyrrolidone, pectins, starches, gelatins, casein, acrylic acid polymers, acrylic acid ester polymers, acrylic acid copolymers, vinyl polymers, vinyl copolymers, vinyl alcohol polymers, alkoxy polymers, polyethylene oxide polymers, polyethers and mixtures thereof. It is also preferred that the adhesive layer further contains 1 or more members selected from the group consisting of fillers, rattle excipients, lubricants, flavors and colorants, and that the drug / facer layer also contains one or [sic] selected members. of the group consisting of excipients for tableting, fillers, flavorings, taste masking agents, colorants, stabilizers, inhibitors enci adores [sic] and lubricants. A preferred glutagon-like insulinotropic peptide is GLP-1 (7-39) amide. This tablet is described and claimed in the United States Patent Application Serial No. (Presented on the same date hereof) Another form of bi-layer tablet that can be used suitably is described in US Pat. No. 5,346,701. Another preferred device of determined physical form is a trans-oral patch, which may be a matrix patch or a reservoir patch. In a preferred matrix patch, the glucagon-like insulinotropic peptide and the permeation enhancer are suspended or dispersed in the adhesive. In a preferred reservoir patch, the glucagon-like insulinotropic peptide and the permeation enhancer are contained in the reservoir. Common for matrix and deposit patches are those illustrated in U.S. Patent Nos. 4,849,224; 4,983,395; 5,122,383; 5,202,125; 5,212,199; 5,227,169; 5,302,395; 5,346,701.

The medicament composition of the present invention may also further contain an effective amount of a sulfonylurea. A method of releasing an insulinotropic peptide similar to glucagon, for the release of the drug through the mouth in the buccal mucosa of a person, involves contacting the buccal mucosa with a delivery system, the method consists of: a) a medicament composition containing an effective amount of the glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer to promote permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the composition of the medicament in relation to drug transfer with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation; and maintaining the delivery system in contact with said mucosa for a sufficient time to release an effective amount of the peptide towards the individual. A method of treating diabetes consists in administering a glucagon-like insulinotropic peptide for the trans-oral release to the buccal mucosa of a person, the method consists of contacting the buccal mucosa with the delivery system, the method consists of: a) a medicament composition containing an effective amount of the glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer to enhance the permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the drug composition in relation to the transfer of the drug with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation; and keeping the release system in contact with the mucosa for a sufficient time to release an effective amount of the peptide to said person.

BRIEF DESCRIPTION OF THE DRAWINGS The figure shows a schematic cross-sectional view of a dosing tablet form of two layers, according to the present invention, wherein the layer containing the medicament is in a transfer ratio of the medicament with the mucosa. oral. Figure 2 shows a schematic cross-sectional view of a matrix patch embodiment having an optional adhesive layer, according to the present invention. Figure 3 shows a schematic cross-sectional view of a liquid reservoir patch, according to the present invention. Figure 4 shows the results of blood glucose determinations for fasting persons who were given a placebo (dotted line) or GLP-1 (7-39) amide (solid line) by buccal administration of the bilayer tablet, according to the present invention. Figure 5 shows the results of plasma insulin determinations for people who were given a placebo (O) or GLP-1 (7-39) amide (•) by buccal administration of a bilayer tablet according to the present invention. Figure 6 shows the results of plasma glucagon determinations for people who were given a placebo (0) or GLP-1 (7-39) amide (•) by buccal administration of a bilayer tablet according to the present invention. Figure 7 shows the results of plasma GLP-1 (7-39) amide determinations for people who received a placebo (dotted line) or drug (solid line) by buccal administration of a bilayer tablet according to the present invention.

Figure 8 shows the results of plasma GLP-1 determinations for fasting people who received the drug by cutaneous administration in various doses: (*) placebo; (m) 0.15 nmol / kg; (A) 0.50 nmol / kg; (X) 1.50 nmol / kg; (*) 4.50 nmol / kg ..

DETAILED DESCRIPTION OF THE INVENTION Before the compositions and methods present for buccal administration of a glucagon-like insulinotropic peptide are analyzed and described, it should be understood that this invention is not limited to the specific formulations, process steps and materials described herein as these formulations, process steps and materials may vary in some way, it should also be understood that the terminology used it is used herein for the purpose of describing only the specific embodiments and is not proposed as limiting since the scope of the present invention will be limited only by the appended claims and the equivalents thereof. It should be noted that, when used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents, unless the context clearly dictates otherwise. Thus, for example, reference to a bilayer tablet containing "an insulinotropic peptide similar to glucagon includes a mixture of two or more of these peptides, reference to" an adhesive "includes reference to one or more of these adhesives. and the reference to "a bile salt" includes reference to a mixture of two or more bile salts.In the description and claim of the present invention the following terminology will be used according to the definitions set forth below. herein, "glucagon-like insulinotropic peptide" or "GLIP" means insulinotropic peptides that exhibit substantial similarity to the amino acid sequence with glucagon, such as GLP-1 C-39) amide and precursors, analogs and fragments thereof. wherein the precursors, analogs and fragments have insulinotropic or insulin-stimulating activity.These precursors, analogs and fragments include the lipitides having the primary sequence of GLP-1 (7-36) amide wherein one or more L-amino acid residues are coupled to the C terminal or N-terminal thereof, eg, GLP-1 (7-37 ); wherein the C-terminal contains a carboxyl group, an amide or substituted amide, an ester or salt; and combinations of these. Also included in the definition are peptides substantially homologous to GLP-1 (7-39) amide and analogs thereof, so long as these analogous peptides also contain insulinotropic activity. When used herein, "substantially homologous" refers to peptides that maintain functionality despite differences in the primary structure from the peptides to which they are compared. For example, a substantially homologous peptide of GLP-1 (7-39) amide is one that maintains the functionality as an insulinotropic agent although it may include additional amino acid residues or it may be a truncating, deleting variant or substitution variant thereof. A substitution variant is one that contains a conservative substitution of one or more amino acid residues. A conservative substitution is a substitution of an amino acid residue for another in which the functionality of the peptide is maintained, in this case, the functionality as an insulinotropic agent. Amino acid residues that belong to certain groups of conservative substitution can sometimes be replaced by another amino acid residue in the same group. A classification of conservative substitution groups is as follows: (a) Pro ,; (b) Ala, Gly; (c) Ser, Thr; (d) Asn, Gln,; (e) Asp, Glu; (f) His; (g) Lys, Arg; (h) Cys; (i) He, Leu, Met, Val; and (j) Phe, Trp, Tyr, M. Jiménez-Montano & L. Zamora-Cortina, Envolutionary model for the generation of amino acid sequences and its application to the study of mammal alpha-hemoglobin chains, Proc. VII Int'l Biophysics Congress, Mexico City (1981). Another classification is described in M. Dayhoff et al., Atlas of Protein Sequence and Structure 1978 (Nat'l Biomed, Res. Found., Washington, D.C.), which is incorporated herein by reference. Other variations that are considered substantially homologous include the substitution of D-amino acids for naturally occurring L-amino acids, the substitution of amino acid derivatives as those containing additional side chains, and substitution of non-standard amino acids, ie, a-amino acids that are rare or not found in proteins. The primary structure of a substantially homologous peptide in this manner is limited only by its functionality. When used herein, "peptide" means peptides of any length and includes proteins. The terms "polypeptide" and "oligopeptide" are used herein without any particular size limitation proposed, unless a specific size is otherwise established. When used herein, "chemical promoter," "penetration enhancer," "permeation enhancer," and the like may include all promoters that increase the flow of a permeant, drug or other molecule through the mucosa. and it is only limited by functionality. In other words, it is proposed that all the compounds that disrupt the cell envelope, solvents, steroidal detergents, bile chelating salts, surfactants, non-surfactants, fatty acids and any other chemical promoting agent are included. The flow of a drug or analyte through the mucosa can be increased by changing the resistance (the diffusion coefficient) or the driving force (the gradient by diffusion) the flow can be improved by using the so-called enhancers or facilitators of the penetration or permeation or chemicals. The permeation facilitators comprise two categories of principal components, that is, the compounds to be disordered. the cell envelope and the solvents or binary systems that contain both the compounds that mess up the cell envelope and the solvents. However, as already described, other categories of permeation facilitators are known., such as steroidal detergents, bile salts, chelators, surfactants, non-surfactants and fatty acids. The compounds that disrupt the cell envelope are known in the art to be useful in topical pharmaceutical preparations and also function in the administration of drugs through the skin or mucosa. It is thought that these compounds help the dermal penetration by disrupting the lipid structure of the stratum corneum cell envelopes. A list of these compounds is described in the Patent Application European 43 4338, published June 13, 1982, which is incorporated herein by reference. Any compound that disrupts the cell envelope is considered useful for the purposes of this invention. Examples of the compounds that disrupt the cell envelope are those represented by the formula: RX wherein R is a straight chain alkyl of about 7 to 16 carbon atoms, a non-terminal alkenyl of about 7 to 22 carbon atoms or a branched chain alkyl of about 13 to 22 carbon atoms, and X is -OH, -COOCH-, -COOC; Hr ,, - OCOCHjr -SOCH ?, P (CH¿) 0, COOCíH4OCíH «OH, COOCH (CHOH), CH¿OH, -COOCH2CHOHCH3, -COOCH..CH (OR ") CHOR", - (OCH, CH mOH, -COOR ', O -CONR', where R is -H, - CHJ # -C¿H5, -C¿H7 or -C¿H4OH; R "is -H, or a non-terminal alkenyl of about 7 to 20 carbon atoms; and m is 2-6, with the proviso that, when R "is an alkenyl and X is -OH or -COOH, there is at least one double bond in the cis-configuration Suitable solvents include water, diols, such as propylene glycol and glycerol, mono-alcohols, such as ethanol propanol and higher alcohols; DMSO; dimethylformamide; N, N-dimethylacetamide; 2-pyrrolidone; N- (2-hydroxyethyl) pyrrolidone, N-methylpyrrolidone, 1-dodecylazacyclooptan-2-one and other alkyl-azacycloalkyl-2-ones (azones) substituted at the n-position and the like. U.S. Patent 4,537,776, Cooper, issued August 27, 1985, contains an excellent compendium of prior art information and background that details the use of certain binary systems for permeant enhancement. Because this description is very complete, the information and terminology used herein is incorporated herein by reference. In the same way, the application of European Patent 43 438, mentioned above, teaches the use of diols selected as solvents together with a broad category of compounds that disrupt the cell envelope for the administration of pharmacologically active lipophilic compounds. Due to the details in the description of the compounds that disrupt the cell envelope and the diols, this description of European Patent Application 43 4328 is also incorporated herein by reference. A binary system for improving the penetration of metoclopramide is described in the application of UK Patent GB 2,153,223 A, published on August 21, 1995, and consists of a monovalent alcohol ester of an aliphatic monocarboxylic acid of C8-32 ( unsaturated and / or branched if C18-32) or a mono aliphatic alcohol of C6-24 (unsaturated and / or branched if C14-24) and a N-cyclic compound such as 2-pyrrolidone, N-methylpyrrolidone and the like. Combinations of the promoters consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are described in US Pat. No. 4,973,468 as promoting the transdermal release of steroids such as progesterones and estrogens. A double enhancer consisting of glycerol monolaurate and ethanol for transdermal drug delivery is shown in U.S. Patent 4,820,720. US Patent 5,006,342 mentions numerous facilitators for the transdermal administration of medicaments consisting of esters of fatty acids or ethers of fatty alcohols of C alcan to C "alkanediols, wherein each acid / fatty alcohol portion of the ester / ether is about 8 to 22 carbon atoms. US Pat. No. 4,863,970 shows the penetration enhancer compositions for topical application consisting of an active permeant contained in a penetration enhancing vehicle containing specific amounts of one or more compounds that disrupt the cell envelope, such as oleic acid. , oleyl alcohol and glycerol esters of oleic acid; a C3 or C3 alkanol and an inert diluent, such as water. Other permeation enhancers, not necessarily associated with binary systems, include DMSO or aqueous DM? O solutions as shown by Herschler, in US Pat. No. 3,551,554.; Hercheler, U.S. Patent 3,711,602; and Herschler, US Pat. No. 3,711,606, and the azones (substituted alkyl-azacycloalkyl-2-ones in the n-position) as noted by Cooper, US Pat. No. 4,557,943. When used herein "bile salts" means steroidal detergents which are neutral or synthetic salts of the colanic acid, for example, the salts of cholic and deoxycholic acid or combinations of these salts and also include the non-ionized acid form, the salts of conjugates of bile acid with glycine or taurine are preferred, taurine salts being particularly preferred. Analogs of bile salts that have the same physical characteristics and also function as permeation promoters are also included in this definition. "NaTC" is the sodium salt taurocholate bile. "CHAP?" is the analogue of the bile salt, 3- [3-colamidopropyl) dimethylammonium] -1-propane sulfate, internal salt. When used herein, "transmucosal", "transbucal" in like terms means the passage of a glucagon-like insulinotropic peptide in and through the buccal mucosa to achieve effective therapeutic levels in blood or levels in deep tissue thereof. When used herein, "effective amount" means an amount of an insulinotropic peptide similar to glucagon that is non-toxic but sufficient to provide a selected systemic effect and performance at a reasonable benefit / risk ratio in the event of some medical treatment. An effective amount of a permeation enhancer, as used herein, means an amount selected to provide the selected increase in mucosal permeability, correspondingly, the desired depth of penetration, rate of administration and amount of medicament released. . When used herein, "adhesive", "adhesive" polymer, "mucoadhesive" or similar terms refers to hydrophilic polymers, natural or synthetic, which, by the designation of hydrophilic, may be soluble or water-insoluble and compatible. with the flattering ones and with the insulinotropic peptides similar to glucagon. These adhesives work by attaching the dosage forms to the mucous tissues of the oral cavity, such as the gingiva. These adhesives include hydroxypropyl cellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, carboxymethyl cellulose, dextran gaur [sic] gum, polyvinyl pyrrolidone, pectins, starches, gelatins, acrylic acid casein polymers, acrylic acid ester polymers, acrylic acid copolymers, vinyl polymers, vinyl copolymers, polymers of vinyl alcohols, alkoxy polymers, polyethylene oxide polymers, polyethers and mixtures thereof and the like. By "system", "drug delivery system", "transmucosal delivery system" or the like is meant a unit dosage form of a medicament composition that includes carriers, promoters and other components, whose drug composition is contained in or accompanied by by means of maintaining the composition of the medicament in a drug transfer relationship with the buccal mucosa.This means may be a patch, tablet, pill or other device of a certain physical form that is to be maintained against the buccal mucosa for administration continuous of the drug to this for systemic transport, or the medium can be formulated in free form to be applied directly to the buccal mucosa such as a cream, gel, gum, ointment and the like.The term "pill" includes pills, tablets, morsulus , "swivels", "swivels", "swivels", "swivels", "swivels", "swivels", "swivels", "swivels", "swells", "swells", "swells" selected at the time of application. "Certain physical form" means that the formulation has a form determined by a device. Preferably, the means used will be a device such as a tablet or a liquid deposit patch or matrix. A matrix patch contains the drug, the permeation enhancer and other optional ingredients in suspension or dispersed in an adhesive layer. A reservoir patch contains the medication, the permeation enhancer and other optional ingredients in a reservoir, which can be in the liquid form, or the liquid can be gelled or can be made thicker by an agent such as mineral oil, petroleum jelly and various aqueous gelling agents and hydrophilic polymers. This reservoir or matrix patch is placed in contact with the buccal mucosa and held in place by a suitable adhesive. In a reservoir patch, the composition of the medication is applied to the buccal mucosa through a permeable membrane that forms the floor of the reservoir that makes direct contact with the buccal mucosa. The method of application of the present invention may vary within limits, but necessarily includes the application of the selected medicament composition to the buccal mucosa, so that the release of the medicament begins and continues for a sufficient period of time to provide the Selected pharmacological or biological response.

Two-layer tablets for GLIP delivery In relation to figure 1, there is shown an illustrative dosage form, according to the present invention, for administering GLIP through the buccal mucosa. This dosage form is provided as a bilayer tablet 10 such that drug / adhesive interactions that inhibit efficient flow through the GLIP membrane through the mucosal tissue are greatly reduced or eliminated. The bi-layer tablet 10 consists of an adhesive layer 12 and an active layer or containing the medicament 14. The adhesive layer 12 is formulated to adhere to a mucosal surface in the oral cavity, so that the active layer 14 is in a ratio transfer of the drug with a tissue of the mucosa, such as the buccal mucosa, such that the drug passes through the mucosal tissue and is absorbed into the bloodstream of the person. In the illustrative embodiment of Figure 1, the tablet 10 is placed in the oral cavity so that the adhesive layer 12 adheres to a gingival (keratinized) surface 16 and the active layer 14 is in the drug transfer relationship with the buccal mucosa 18. Bilaye tablets are made by the compression techniques of normal tablets and layer on a suitable press. With reference to Figure 1, the bilayer tablets 10 consist of an adhesive layer 12 and an active or drug-containing layer 14, which may be of a different color to distinguish the layers for application purposes. The identification of the non-adhesive medicament containing layer 14 facilitates application by the patient and avoids the inadvertent adhesion of other oral tissues to the tablet. The adhesive layer 12 is prepared by dry blending the ingredients and compressing them into a tablet or by wet granulation of the ingredient mixture and then compressing according to accepted pharmaceutical techniques. In general, it has been found convenient to mix the polymer or polymers of the adhesive and any auxiliary of the formulation as fillers, rattle excipients, lubricants, flavors, colorants and the like and then compress the mixture in a press. The layer containing the active drug 14 is first prepared by intimately mixing the medicament with a permeation promoter and any other auxiliary of the formulation, such as excipients for tableting, dyes, flavorings, taste masking agents, stabilizers, inhibitors. enzymatic, lubricants and similar. This can be formulated as a dry matrix or can be carried out by conventional wet granulation and sieving techniques, followed by drying. In any case, the ingredients of the layer containing the medicament, mixed afterwards, are placed on top of the partially compressed adhesive layer and both layers are then compressed. A person with ordinary skill in the art will realize that the tablet herein can also be manufactured by first making the layer containing the medicament and then the adhesive layer. The compositions of the present invention will preferably be sized to provide between about 0.05 to 10 cm "of surface area for contacting the drug-containing layer with the mucosa.A preferred areas are between about 0.07 to 5 cm ^, being optimal the areas between approximately 0.18 and 5 cm ". The layer containing the medicament or activator will usually have a thickness of between about 0.1 and 3 mm, with thicknesses between about 0.5 and 2 mm being preferred. The following examples are illustrative of the methods for preparing bilayer tablets according to the present invention.

EXAMPLE 1 Two-layer tablets are prepared in the following manner.

An adhesive layer was prepared using 70 parts by weight of polyethylene oxide (Polyox 301N; Union Carbide), 20 parts by weight of polyacrylic acid (Carbopol 934P; B. F. Goodrich) and 10 parts by weight of a compressible loading material Xylitol / carboxymethylcellulose (Xylitab 200; Xyrofin). These ingredients were mixed by turning a container for 3 minutes. The mixture was then transferred to an evaporator tray and rapidly wet granulated with absolute ethanol to a semimasity-like consistency. This mass was immediately and rapidly pressed through a 14 mesh stainless steel screen (1.4 m holes), to which the wet granules adhered. The sieve was covered with perforated aluminum foil, and the moistened granules were dried overnight at 30 ° C. The dried granules were removed from the screen and then passed through a 20 mesh screen (0.85 mm holes) to further reduce the size of the granules. The particles that did not pass through the 20 mesh screen were crushed briefly with a mortar and pestle to reduce the amount of the fines and then passed through the 20 mesh screen. The resulting granules were then placed in a mixing vessel and 0.25 parts by weight of stearic acid and 0.06 parts by weight of mint flavor (Universal Flavors) were added and mixed to the granules. The final percentages by weight of the ingredients were as follows: 69.78Ü of polyethylene oxide, 9.97 '-. of compressible loading material Xylitol / carboxymethyl cellulose, 19.94o of polyacrylic acid, 0.25--. of stearic acid and 0.06 mint flavor. An amount of 50 mg of this mixture was placed in a 0.375 inch diameter die and precompressed in a Carver Press Model C with pressure of 0.25 metric tons for a time of 3 seconds to form the adhesive layer. The active layer was prepared by weighing 49.39 parts by weight of mannitol, 34.33 parts by weight of hydroxypropyl cellulose (Klucel LF, Aqualon, Wimilgton, Delaware) 15.00 parts by weight of sodium taurocholate (Aldrich, Milwaukee, Wisconsin) and was mixed by spinning a container for 3 minutes. The mixture was then transferred to an evaporator plate and rapidly wet granulated with absolute ethanol to a semi-mass-like consistency. This mass was immediately and rapidly pressed through a 14 mesh steel screen, to which the wet granules adhered. The sieve was covered with perforated aluminum sheet and the granules were dried at 30 ° C. The dried granulate was then passed sequentially through 20 mesh screens, 40 (0.425 mm holes) and 60 (0.25 mm holes) to further reduce the particle size. The particles that did not pass through a sieve were briefly crushed with a mortar and pestle to reduce the fines. The screened particles were weighed and then 0.91 parts by weight of GLP-1 (7-39) amide and 7 0.06 parts by weight of yellow # 6HT FD &C aluminum lacquer dye were mixed in sequence with the wet granulate by geometric dilution. The dried granulate was then placed in a mixing vessel and combined with 0.26 parts by weight of magnesium stearate (lubricant) and 0.06 parts by weight of peppermint flavor by spinning for 3 minutes. A 50 mg sample of this material was placed on top of the partially compressed adhesive layer and both layers were then compressed at a pressure of 1.0 ton for a time of 3 seconds to produce a bi-layer tablet suitable for buccal administration . This procedure resulted in a gingival tablet in which the active layer contained 0.91% by weight of GLP-1 / 7-36) amide, 15% by weight of NaTC, and 84.09% by weight of filler, lubricant, dye, formulation aids or flavoring agents.

Example 2 The procedure of Example 1 was followed with the exception that the amounts of the components of the active layer were varied to provide an active layer with a content of 65.30c by weight of mannitol, 34.33o of hydroxypropyl cellulose, 0.25'¿ of magnesium stearate, 0.06o of yellow aluminum lake dye # 6HT FD &C, and 0.06o of mint flavor. This procedure resulted in placebo tablets suitable for use in double-blind, in-vitro studies with human volunteers.

EXAMPLE 3 The procedure of Example 1 was followed to prepare a buccal tablet in which the active layer contained the same content but was prepared by mixing dry and not by wet granulation.

Buccal Mouth Patch for GLIP Administration Figure 2 shows one embodiment of an illustrative film patch for GLIP buccal administration, wherein patch 20 consists of an underlying medicament / flattener / polymer 21 layer and an outer layer of inert membrane 22 having the same diameter as the active layer 21. However, the external inert layer of a patch can extend beyond the outer periphery of the underlying active layer and have it contained in the lower surface of this, additional mucoadhesive (not sample) or, as shown in Figure 2, may have an optional cover 23 containing a mucoadhesive on the inner surface of the cover 23 that extends beyond the outer periphery of both active layers 21 and inert membrane layer 22. In this way, the active or internal layer is completely surrounded by the covering membrane that adheres to the mucosa and also ensures that the drug / flattering combination per It will be in the area of the oral mucosa in which it is applied until the portions of the drug / flattener have been adequately released. Optional cover 23 may also be a thermoselective membrane having a pore structure with desired molecular weight cutoff frequency (MWCO). In certain cases, it may be beneficial to have both the membrane 22 and the cover 23 both as MWCO membranes, each with a different MWCO value to control and vary the amount or degree of water or other materials passing through these membranes. Figure 3 shows a liquid reservoir patch, illustrative, which can be used according to the present invention to administer a glucagon-like insulinotropic peptide in the buccal mucosa. This liquid deposit patch is described in U.S. Patent No. 4,849,224, which is incorporated herein by reference. As described in this patent, these devices, such as the one generally shown at 24 in Figure 3, consist of a layer in the uppermost part of a supporting, heat-sealing film 26, which has a recess in the form of inverted cup, which serves as the reservoir 28 for the composition of the medicament. The lower side of the outer edge of the supporting film carries a ring-shaped layer 30 of a peripheral adhesive towards the reservoir. Underlying the reservoir, just inside the peripheral ring of adhesive is a membrane layer 32 which is permeable to the composition of the medicament. A removable, sealable interior liner 34 is under the membrane 32 and portions of the backing film 26. A sealable-release release liner 36 covers the entire underside of the unit and forms the base surface of the device. The device 18 has a thermal seal 38 between the membrane and the backing film. A device of the alternative liquid reservoir type that can be used in conjunction with the present invention is described in U.S. Patent No. 4,983,395, which is incorporated herein by reference.

Example 4 A formulation for buccal patch is prepared with a content of 400 μg of GLP-1 (7-39) amide using a dialysis membrane of 500 MWCO as a cover or outer layer. Into a vial, 278.3 μl of an aqueous solution of NaTC at 39 ° and 59 μl of aqueous solution of GLP-1 (7-39) amide at 1.2 ° by weight are added. The solutions are stirred together until a clear solution is formed. To this is added an ethanol solution containing 1130.8 μl of hydroxypropylcellulose at 19.85: with stirring until a homogeneous mixture is obtained. A portion of 718 μl of this mixture is then emptied onto a membrane of. dialysis of 500 MWCO, which has been dried in an oven at 70 ° C to produce a dry substrate, in a glass mold and allowed to cool overnight. The excess membrane is cut around the translucent homogenous active layer to produce a finished buccal patch with a surface area of approximately 5 cm. "The active layer of this patch contains 400 μg of GLP-1 (7-39) amide ( 4.8o by weight), 45 mg of NaTC (15o by weight) and 100.4 mg of hydroxypropylcellulose (34o by weight).

Example 5 Trophies for GLIP administration A trocaine or lozenge for oral administration of a glucagon-like insulinotropic peptide is prepared by incorporating 400 μg of GLP-1 (7-39) amide into an elaborate mass of a sugar and mucilage and also it contains 15'¿ by weight of NaTC, and then the mixture is air-dried as is well known in the troponis making art.

EXAMPLE 6 Dosage form in free form to administer GLIP A dosage form in free form for administering a glucagon-like insulinotropic peptide is made by incorporating 400 μg of GLP-1 (7-36) amide into a liquid mixture containing about 15 ' In weight of NaTC and 85o in weight of water. To 12 μl of this mixture S3 adds 0.15 g of Carbopol 1342 acrylic acid copolymer. This mixture is homogenized to result in a gelled drug composition.

In vivo test of the GLIP administration Example 7 This example describes a double-blind, placebo-controlled, cross-over comparison with random assignment for the treatment sequence. Eight healthy volunteers were selected for this in vivo study of blood levels of glucose, insulin, glucagon and GLP-1 (7-39) amide in response to having received a bilayer tablet with medication, with a content of 400 μg of GLP -1 (7-36) amide or a placebo, compared according to Examples 1 and 2, respectively. The inclusion criteria for volunteers was normal glucose tolerance, weight within 22 < BMI < 26, informed consent to participate in the study and age between 20 and 60 years. The exclusion criterion was decreased glucose tolerance (2-hour glucose tolerance test), OGTT, gastrointestinal symptoms, medication or ongoing disease, acute infection, abnormal laboratory variables (hemoglobin, hematocrit, leukocytes, creatinine, bilirubin, calcium, potassium, sodium, alkaline phosphatase, ga-GT,? GOT, SGPT, cholesterol and triglycerides), and blood pressure greater than 185 mmHg systolic and / or 90 mmHg diastolic.The numbers of the individuals were assigned to people in the order in which they were listed in the study The number assigned to each person determined the sequence of treatment received People who received the treatment sequence 1 were treated with medication followed by placebo and the people who received the treatment sequence 2 they were treated with placebo followed by medication, and people were asked not to consume food the night before treatment. línica people were given the bilayer tablet with medication or with placebo. At time 0, the bilayer tablet was applied to the gingiva with the active layer in contact with the tissue of the lip or the inside of the cheek and the people were placed in resting position. The bilayer tablet was removed after 4.5 hours. No food was allowed until a standard meal was provided after 4.5 hours and no snacks were allowed at any time. The standard meal contained 550 kcal, with 28c, 22o and 50% of the energy coming from proteins, fat and carbohydrates, respectively. The test continued until 8 hours after the application of the bicap tablet and people left the hospital after 9 hours. At the clinic, a nurse administered the medication to the people and they were under observation at all times. Any symptom or sensation of disturbance or diminution of the well-being of the people during the experiments was carefully documented. The normal safety variables were determined under fasting conditions before each experiment. Blood glucose was checked frequently and glucose infusion was available due to some case of hypoglycaemia (<2.5 mmol / 1). If any person experienced symptoms of hypoglycemia, an additional blood glucose determination would be taken for safety reasons. An elimination period of 1-4 days was allowed between each experiment. The study was completed within 6 weeks after the inclusion of the first volunteer. Blood samples were taken for pharmacokinetic analysis 10 minutes before the application of the drug and at 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 120, 150, 180, 210, 240, and 270 minutes and 6 and 8 hours after the application of the medicine. The samples were frozen until tested for the content of GLP-1 (7-36) amide by radioin a double antibody assay (RIA). The content of the peptide in the bilayer tablet samples was also analyzed by HPLC. The mean blood glucose, insulin, glucagon and GLP-1 (7-36) amide concentrations were calculated by the area under the curve (AUC) using the trapezoidal rule. The maximum concentration (Cmax), the half-life (T?,) And the time for the maximum blood level (Trt? Ax), were calculated for GLP-1 (7-36) amide based on the levels of the peptide in plasma. The results were tested for the normal distribution. A two-tailed t-test was carried out for the normally distributed samples and a Wilcoxon rank-sum test was used for the data that did not have a normal distribution. All statistical tests used a significance level of 0.05.

Figure 4 shows the results of blood glucose determinations for people who received the placebo (dotted line) or medication (solid line). For the placebo group, blood glucose levels remained relatively constant from 10 minutes before the application of the bilayer tablet until 270 minutes after the application of the tablet. During the same time period, the blood glucose levels of people who received GLP-1 (7-36) amide decreased compared to the placebo group 20 minutes after application of the drug, reached a lower level of approximately 3 mmol / L at approximately 50 minutes and return to a normal level at approximately 90 minutes. The blood glucose levels of the two groups are indistinguishable after feeding. These data show that oral administration of GLP-1 (7-36) amide with the bilayer tablet, according to the present invention, results in significantly reduced blood glucose levels compared to placebo controls. Figure 5 shows the results of plasma insulin determinations for individuals who were given the placebo (0) or the drug (•). For the placebo group, plasma insulin levels remain relatively constant or decrease slightly during the course of 10 minutes before administration of the bilayer tablet until 270 minutes after administration of the tablet. For the group that received GLP-1, the plasma insulin level suddenly increases from a normal level to 10 minutes after administration of the drug, to a level of approximately 3 times normal at 15 minutes after administration. The maximum plasma insulin level is reached approximately 20 minutes after administration of GLP-1 (7-36) amide, and the level rapidly decreases to normal at approximately 50 minutes. On the other hand, the insulin levels of the drug group follow the insulin levels of the placebo group. Thus, administration of GLP-1 (7-36) amide results in a rapid increase in plasma insulin concentration followed by a rapid decrease, both within one hour of drug administration. Figure 6 shows the results of plasma glucagon determinations for people who were given the placebo (O) or the drug (•). For the placebo group, the plasma glucagon level decreases in a slow and stable manner from the 10 minutes prior to the administration of the bilayer tablet until 270 minutes after administration of the tablet. For the drug group, the plasma glucagon level decreases suddenly from time 0 until a significantly lower level than the placebo group is reached approximately 30 minutes later and then the level suddenly rises to a significantly higher level than the placebo group, peaking at approximately 60-75 minutes after administration. From this maximum, the level of glucagon in plasma decreases continuously until it tracks the level of the placebo group beginning about 150 minutes after the administration of the drug. These data show that oral administration of GLP-1 (7-36) amide rapidly reduces plasma glucagon levels below those of the placebo group and then raises them higher than normal levels before they reach normal levels, another approximately 150 minutes after administration. Figure 7 shows the results of determinations of plasma GLP-1 (7-36) amide for people who were given the placebo (dotted line) or medication (solid line). For the placebo group, the amount of GLP-1 (7-39) amide in the plasma remains almost constant at a very low level from 10 minutes before the administration of the drug until 270 minutes after the administration thereof. After the food, the level of GLP-1 (7-36) measured in plasma rises and then decreases continuously over time. For the drug group, the plasma GLP-1 (7-39) amide level rises suddenly beginning at 5 minutes after administration and reaches a maximum approximately 30 minutes after administration. The level of GLP-1 (7-39) amide then decreases rapidly to approximately 90 minutes after administration and then decreases more slowly to a level following the placebo group track beginning at approximately 150 minutes. After food, the level of GLP-1 (7-39) amide is approximately the same as that of the placebo group. These results show that oral administration of GLP-1 (7-39) amide results in rapid absorption through the buccal mucosa into the blood stream and that elevated levels of GLP-1 (7-39) amide remain in blood until approximately 150 minutes after administration. Taken together, these data show that oral administration of GLP-1 (7-39) amide with the bilayer tablet of the present invention results in rapid absorption into the bloodstream that results in a pronounced rise in the amount of plasma insulin and a corresponding decrease in the amount of glucose in the blood. In addition, the blood glucose level does not result in hypoglycemia, probably due to the aforementioned glucose dependence of the insulinotropic effects of the drug.

Example 8 In this example, the relative bioavailability of GLP-1 (7-39) amide by buccal administration is compared to GLP-1 administered subcutaneously. This was done in comparison with the published data. Two studies that provide intravenous infusion data in fasting individuals are available in: DM Nathan et al., Insulinotropic Action of Glucagon-like Peptide-1- (7-37) in Diabetic and Nondiabetic Subjects, 15 Diabetes Care 270 (1992 ); C. Orskov et al., Biological Effects and Mstabolic Rates of Glucagonlike Peptide-1-7-36 Amide and Glucagonlike Peptide-1 7-37 in Healthy Subjects is Indistinguishable, 42 Diabetes 658 (1993). Both studies mention an approximate elimination of 15 ml / min / kg. A study by M. A. Nauck on subcutaneous administration of GLP-1 to fasting people illustrates the changes in pharmacokinetics with the dose (figure 8). This may be due to changes in bioavailability with dose, changes in elimination with the dose or a combination of both effects. At any speed, the regression analysis of all the results indicates an elimination of approximately 40 ml / min / kg, consistent with the bioavailability of 38o by cutaneous administration in relation to intravenous administration. The data summarized in Figure 7 were analyzed by the AUC to provide a calculation of relative bioavailability by buccal administration compared to subcutaneous administration. These data are shown in table 1.

These data show a relative bioavailability of 27o compared to the data in Figure 8.

Claims

CLAIMS 1.
A drug delivery system for the trans-oral release of an insulinotropic glucagon-like peptide in the buccal mucosa of an individual, the system consists of: (a) a medicament composition containing an effective amount of an insulinotropic peptide similar to glucagon and an effective amount of a permeation enhancer, to favor the permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the composition of the medicament in a transfer ratio of the medicament with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation. of claim 1, wherein the system comprises a device of a certain physical form
3. The medication administration system of claim 2, wherein the device of physical form determined is a member selected from the group consisting of a patch and a tablet, and where the maintenance medium is an adhesive.
4. The drug delivery system of claim 3, wherein the permeation enhancer is a member that is selected from the group consisting of compounds that disrupt the cell envelope, solvents, steroidal detergents, bile salts, chelators, surfactants, non-surfactants , fatty acids and mixtures of these.
5. The drug delivery system of claim 4, wherein the device of physical form determined is a tablet.
The medicament delivery system of claim 5, wherein the tablet contains an adhesive layer comprising a hydrophilic polymer with a surface adapted to contact a first tissue of the oral cavity and adhere thereto when wetted and an opposing surface contacts and adheres to an adjacent layer of the medicament / enhancer containing a permeation promoter and the glucagon-like insulinotropic peptide, the drug / adjuvant layer adapted to be in contact and in drug transfer relationship with the buccal mucosa when the adhesive layer makes contact and adheres to the first tissue.
The drug delivery system of claim 6, wherein the permeation enhancer is a bile salt comprising a steroidal detergent consisting of a member of the group comprising the natural and synthetic salts of the colanic acid and mixtures of these .
8. The drug delivery system of claim 7, wherein the hydrophilic polymer comprises at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, ethylcellulose, carboxymethylcellulose, dextran, gaur gum. [sic], polyvinyl pyrrolidone, pectins, starches, gelatins, casein, acrylic acid polymers, acrylic acid ester polymers, acrylic acid copolymers, vinyl polymers, vinyl copolymers, vinyl alcohol polymers, alkoxy polymers, polymers of polyethylene oxide, polyethers and mixtures thereof.
9. The drug delivery system of claim 8, wherein the adhesive layer further contains 1 or more members that are selected from the group consisting of fillers, excipients for tableting, lubricants, flavors and colorants, and wherein The medicament / enhancer layer further contains one or [sic] members selected from the group consisting of excipients for rattling, fillers, flavorings, taste masking agents, colorants, stabilizers, enzymatic inhibitors and lubricants.
The drug delivery system of claim 9, wherein the biliary salt enhancer is a salt of a bile acid conjugate with taurine
11. The drug delivery system of claim 10, wherein the hydrophilic polymer comprises a mixture of polyethylene oxide and polyacrylic acid.
12. The drug delivery system of claim 11, wherein the first tissue is gingival tissue.
The drug delivery system of claim 12, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
14. The drug delivery system of claim 13, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
The medicament delivery system of claim 4, wherein the determined physical form device is a matrix patch
16. The drug delivery system of claim 15, wherein the organic solvent is a member that is selected of the group consisting of a C 1 or C 2 alcohol, and C 3 or C 4 diol, DMSO, DMA, DMF, 1-n-dodecyl-cyclazacycloheptan-2-one, N-methylpyrrolidone, N- (2- hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures of these; the compound that disrupts the cell envelope is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate , propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid and mixtures of these.
17. The drug delivery system of claim 16, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
18. The drug delivery system of claim 17, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
19. The drug delivery system of claim 4, wherein the device of physical form determined is a liquid reservoir patch and wherein the composition of the medicament is contained in this reservoir.
20. The drug delivery system of claim 19, wherein the organic solvent is a member selected from the group consisting of a C¿ or C alcohol alcohol and Cj or C4 diol, DMSO, DMA, DMF, 1 -n-dodecyl-cyclazacycloheptan-2-one, N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures thereof; the compound that disrupts the cell envelope is a member selected from the member consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, monolaurate glycerol, propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid and mixtures of these.
21. The drug delivery system of claim 20, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
22. The drug delivery system of claim 21, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
23. The drug delivery system of claim 4, wherein the device of physical form determined is a trochus.
24. - The drug delivery system of claim 23, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogues and fragments thereof .
25. The drug delivery system of claim 24, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
26. The drug delivery system of claim 1, wherein the formulation is in free form for application to the buccal mucosa and is a member selected from the group consisting of a gel, gum, cream and ointment.
27. The drug delivery system of claim 25, wherein the penetration enhancer is a member selected from the group consisting of organic solvents, compounds that disrupt the cell envelope, steroid detergents, bile salts, chelators. , surfactants, non-surfactants, fatty acids and mixtures of these.
28. The drug delivery system of claim 26, wherein the organic solvent is a member selected from the group consisting of a C2 or C2 alcohol and C3 or C4 diol, DMSO, DMA, DMF, 1-n -dodecyl-cyclazacyclo-heptan-2-one, N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures thereof; the compound that disrupts the cell envelope is a member selected from the member consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, monolaurate glycerol, propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid and mixtures of these.
29. The drug delivery system of claim 28, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogues and fragments thereof.
30. The drug delivery system of claim 28, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
31. The drug delivery system of claim 1, wherein the medicament composition further contains a sulfonyl urea.
32. A method of releasing a glucagon-like insulinotropic peptide for delivery of the drug through the mouth into the buccal mucosa of an individual, the method comprising contacting the buccal mucosa with a delivery system consisting of: a) a medicament composition containing an effective amount of a glucagon-like insulinotropic peptide and an effective amount of a permeation enhancer, to promote permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the composition of the medicament in a transfer ratio of the medicament with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation.
33. The method of claim 32, wherein the system comprises a device of determined physical form.
34. The method of claim 33, wherein the device of physical form determined is a member that is selected from the group consisting of a patch and a tablet, and wherein the maintenance means is an adhesive.
35. The method of claim 34, wherein the permeation enhancer is a member selected from the group consisting of compounds that disrupt the cell envelope, solvents, steroidal detergents, bile salts, chelators, surfactants, non-surfactants, acids fatty acids and mixtures of these.
36. The method of claim 35, wherein the device of physical form determined is a tablet.
37. The method of claim 36, wherein the tablet contains an adhesive layer comprising a hydrophilic polymer with a surface adapted to contact a first tissue of the oral cavity and adhere to it when it is moistened and an opposite surface makes contact with and adheres to an adjacent layer of the medicament / enhancer containing a permeation enhancer and the glucagon-like insulinotropic peptide, the drug / adjuvant layer adapted to be in contact with and in transfer relationship of the medicament with the buccal mucosa when the adhesive layer contacts and adheres to the first fabric.
38. The method of claim 37, wherein the permeation enhancer is a bile salt comprising a steroidal detergent consisting of a member of the group comprising the natural and synthetic salts of the colanic acid and mixtures thereof.
39. The method of claim 38, wherein the hydrophilic polymer comprises at least one member selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methylethyl cellulose, hydroxyethyl cellulose, ethyl cellulose, carboxymethyl cellulose, dextran, gaur gum [sic], polyvinyl pyrrolidone, pectins, starches, gelatins, casein, acrylic acid polymers, polymers of acrylic acid esters, t? - Tv. 1 ^ m A v ^ p - • -i ^ v i? í í ^ t ^ 1 t ?. A V? f s <; *, i n -i 1 vinyol copolymers, polymers of vinyl alcohols, akoxy polymers, polyethylene oxide polymers, polyethers and mixtures thereof.
40. The method of claim 39, wherein the adhesive layer further contains 1 or more members that are selected from the group consisting of fillers, excipients for rattling, lubricants, flavors and colorants, and wherein the drug layer / flattener further contains one or [sic] members selected from the group consisting of excipients for rattling, fillers, sabotagers, taste masking agents, colorants, stabilizers, enzymatic inhibitors and lubricants.
41. The method of claim 40, wherein the biliary salt enhancer is a salt of a bile acid conjugate with taurine
42. The method of claim 40, wherein the hydrophilic polymer comprises a mixture of polyethylene oxide and polyacrylic acid.
43. The method of claim 42, wherein the first tissue is gingival tissue.
44. The method of claim 43, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
45. The method of claim 44, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
46. The method of claim 35, wherein the determined physical form device is a matrix patch
47. The method of claim 46, wherein the organic solvent is a member selected from the group consisting of an alcohol of C or Co, and diol of Co or C, DM? O, DMA, DMF, ln-dodecyl-cyclazacycloheptan-2-one, N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures thereof; the compound that disrupts the cell envelope is a member selected from the group consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol monolaurate , propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid and mixtures of these.
48. The method of claim 47, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
49. The method of claim 48, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
50. The method of claim 35, wherein the device of physical form determined is a liquid reservoir patch and wherein the composition of the medicament is contained in this reservoir.
51. The method of claim 50, wherein the organic solvent is a member selected from the group consisting of a C 1 or C alcohol and a diol of C 1 or C, DMSO, DMA, DMF, ln-dodecyl-cyclazacycle. heptane-2-one, N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidine, triacetin, propylene carbonate and dimethyl isosorbide and mixtures thereof; the compound that disrupts the cell envelope is a member selected from the member consisting of isoprcpyl myristate, methyl laurate, oleic acid, oleyl alcohol, glyceryl monoleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, glycerol, propylene glycer monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid
52. The method of claim 51, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
53. The method of claim 52, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
54. The method of claim 35, wherein the device of physical form determined is a trochus.
55. The method of claim 54, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
56. The method of claim 55, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
57. The method of claim 32, wherein the formulation is in free form for application to the buccal mucosa and is a member that is selected from the group consisting of a gel, gum, cream and ointment.
58. The method of claim 57, wherein the penetration enhancer is a member selected from the group consisting of organic solvents, compounds that disrupt the cell envelope, steroidal detergents, bile salts, chelators, surfactants, non-surfactants, fatty acids and mixtures of these.
59. The method of claim 58, wherein the organic solvent is a member selected from the group consisting of a C¿ or C¿ alcohol and a C di diol. or C4, DMSO, DMA, DMF, l-n-dodecyl-cyclazacycloheptan-2-one, N-methylpyrrolidone, N- (2-hydroxyethyl) pyrrolidone, triacetin, propylene carbonate and dimethyl isosorbide and mixtures of these; the compound that disrupts the cell envelope is a member selected from the member consisting of isopropyl myristate, methyl laurate, oleic acid, oleyl alcohol, glycerol monooleate, glycerol dioleate, glycerol trioleate, glycerol monostearate, monolaurate glycerol, propylene glycol monolaurate, sodium dodecylsulfate and sorbitan esters and mixtures thereof; and the bile salt is a steroidal detergent that is selected from the group consisting of natural and synthetic salts of the colanic acid and mixtures of these.
60. The method of claim 59, wherein the glucagon-like insulinotropic peptide is a member selected from the group consisting of GLP-1 (7-39) amide and precursors, analogs and fragments thereof.
61. The method of claim 60, wherein the glucagon-like insulinotropic peptide is GLP-1 (7-39) amide.
62. The method of claim 32, wherein the medicament composition further contains a sulfonyl urea.
63. A method of treating diabetes, which consists of releasing a glucagon-like insulinotropic peptide for trans-oral release into the buccal mucosa of an individual, the method comprising contacting the buccal mucosa with a delivery system consisting of: (a) a medicament composition containing an effective amount of an insulinotropic peptide similar to glucagon and an effective amount of a permeation enhancer, to promote the permeation of the glucagon-like insulinotropic peptide through the buccal mucosa; and (b) the means for maintaining the composition of the medicament in a transfer ratio of the medicament with the buccal mucosa, wherein the composition of the medicament and the maintenance medium are combined in a single formulation; and maintaining the delivery system in contact with said mucosa for a sufficient time to release a sufficient amount of the peptide in the individual.