CN111905097B

CN111905097B - Application of oral glycopeptide lowering in preparation of medicine for treating or preventing diabetes complicated with cardiovascular diseases

Info

Publication number: CN111905097B
Application number: CN202010853498.1A
Authority: CN
Inventors: 高向东; 田浤; 钱鹏; 姚文兵; 陆伟晟
Original assignee: China Pharmaceutical University
Current assignee: China Pharmaceutical University
Priority date: 2020-08-23
Filing date: 2020-08-23
Publication date: 2022-06-28
Anticipated expiration: 2040-08-23
Also published as: CN111905097A

Abstract

The invention relates to an application of oral hypoglycemic peptide, which is used for preparing a medicine or a medicine composition for treating or preventing diabetes and cardiovascular diseases. The oral hypoglycemic peptide is polypeptide OHP 2. The polypeptide can effectively improve myocardial hypertrophy and fibrosis damage caused by diabetes, reduce the content of related myocardial enzymes, regulate lipid metabolism level, improve myocardial cell oxidative stress and mitochondrial damage, and play a role in protecting the heart, so that the polypeptide can be used as a candidate molecule for treating or preventing cardiovascular diseases (especially diabetic cardiomyopathy) complicated by diabetes, and has a good application prospect.

Description

Application of oral glycopeptide lowering in preparation of medicine for treating or preventing diabetes complicated with cardiovascular diseases

Technical Field

The invention relates to an application of oral glycopeptide lowering in preparation of a medicament for treating or preventing diabetic cardiomyopathy, belonging to the technical field of biological medicines.

Background

Diabetes mellitus is a chronic metabolic disease characterized by hyperglycemia and insulin resistance, which is caused by relative insufficiency of insulin secretion to different degrees due to the interaction of various internal and external factors on the basis of genetic susceptibility. As many as 4.25 billion diabetic patients worldwide as 2017, and if no measures are taken, it is expected that the number of people with diabetes will rise to 6.29 billion by 2045 years, so diabetes has become an increasingly serious global health problem. Most of the diabetics die of diabetic complications, wherein the diabetic complications have high death risk which is 2-4 times higher than that of the common people and account for 65 percent of related mortality. Diabetic Cardiomyopathy (DCM) is a major cardiovascular complication, independent of cardiovascular diseases such as coronary artery disease or hypertension, and is a myocardial disease with abnormal myocardial structure and function.

The pathogenesis of diabetic cardiomyopathy is very complex and not completely elucidated, and current studies show that the pathogenesis mainly comprises glycolipid metabolic disorder, insulin resistance, inflammatory reaction, oxidative stress, endoplasmic reticulum stress, activation of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, and the like. Although researchers have studied the complex pathophysiological processes of diabetic cardiomyopathy, there are no specific strategies for guiding treatment in clinical practice. At present, the reduction of blood sugar level is still the basis of a treatment scheme of diabetic cardiomyopathy, but in the later development stage of diabetes, due to the combined action of multiple factors, the effect of simply controlling blood sugar on macrovascular complications is very limited, so blood pressure reduction treatment, lipid regulation treatment, antiplatelet treatment and the like are required to be supplemented.

Since 2008, the FDA and european medicines authorities in the united states required all new applications for hypoglycemic drugs to be marketed to be forced into cardiovascular outcome tests to evaluate their effect on the cardiovascular system. Research results show that part of hypoglycemic drugs can improve cardiovascular health and exceed the blood sugar control capability of the hypoglycemic drugs, and the hypoglycemic drugs comprise polypeptide drugs such as liraglutide and somagliptin and the like and sodium-glucose cotransporter 2 inhibitors such as engelizin and the like. Both liraglutide and somaglutide are fatty acid modified polypeptide products developed by norand, in clinical studies, liraglutide significantly reduces the risk of death from serious cardiovascular events, while treatment with somaglutide reduces the major outcomes of the combination including cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. The empagliflozin is an orally available chemical drug which achieves a hypoglycemic effect mainly by inhibiting reabsorption of glucose by renal tubules, and clinical test results show that the empagliflozin can reduce the relative risk of cardiovascular diseases and the risk of hospitalization due to heart failure compared with placebo, but the empagliflozin can increase the risk of lower limb amputation and diabetic ketoacidosis by 2 times. Compared with the preparation, the polypeptide hypoglycemic drug has less side effects and is suitable for the diabetes patients taking the drug for a long time, but the polypeptide drug has poor stability in vivo and needs frequent injection, so the learning cost of the patients is increased, the patients can be suffered from a plurality of pains due to long-term repeated injection, and the compliance of the patients is not obviously improved even if the preparation is a peri-exenatide preparation. Therefore, the development of orally administered hypoglycemic polypeptides has been a hot point of research and development.

Polypeptide hypoglycemic drugs represented by exenatide and analogues thereof are hot spots developed in recent years. Exenatide injection has been approved by the FDA in the united states for marketing in 2005 and has shown beneficial hypoglycemic and cardioprotective effects in numerous studies. Clinical studies show that exenatide has good effects of reducing blood sugar and losing weight, and can reduce the risk of heart failure recurrence; in addition, exenatide can also reduce reperfusion injury in patients with ST-elevation myocardial infarction. It has also been found in preclinical studies that exenatide can improve structural and functional abnormalities of diabetic mice by inhibiting heart lipid accumulation and lipid toxicity mediated by the ROCK/PPAR alpha pathway.

The blood sugar reducing medicines represented by the exenatide and the analogues thereof have the advantages of low risk of hypoglycemia, capability of delaying gastric emptying, weight reduction, cardiovascular and renal protection and the like, and are extremely ideal. However, this does not mean that each specific drug of such hypoglycemic drugs has a myocardial protective effect.

At present, no specific therapeutic guidelines are provided for diabetic cardiomyopathy, and medicines with blood sugar reducing and heart protecting effects represented by exenatide are widely concerned, but research shows that exenatide mutants have no obvious cardiovascular benefits, and lixisenatide is a representative medicine.

Lixisenatide is obtained by removing proline at the carboxyl terminal of exenatide and adding six lysines, and in the head-to-head research of exenatide, the Lixisenatide is equivalent to exenatide in terms of blood sugar reduction and glycosylated hemoglobin, has good blood sugar reduction effect in clinic, but is inferior to exenatide in weight reduction. While in clinical trials evaluating the cardiovascular effects of lixisenatide, lixisenatide failed to show good results, there was no significant difference in cardiovascular events or hospitalization compared to placebo. The research results show that not all exenatide mutants have the similar myocardial protection effect with exenatide, so that the development of exenatide analogues with the myocardial protection effect is urgently needed.

The inventor and the subject group have obtained some research results in the field, and have applied for chinese patent application nos. CN201310694475.0 and CN103665148B on 12/17 in 2013, CN201710810530.6 and CN109485720A on 11/09 in 2017, and CN201910747519.9 and CN110437329A on 14/08/2019. The inventors have now obtained new results in further studies.

Disclosure of Invention

The invention aims to: according to the latest research results of the inventor, the application of the oral glycopeptide lowering in the preparation of the medicine for treating or preventing the diabetes mellitus complicated by the cardiovascular disease is provided.

The technical scheme for solving the technical problems of the invention is as follows:

the application of the oral hypoglycemic peptide is characterized in that the application is used for preparing a medicine or a medicine composition for treating or preventing cardiovascular diseases complicated by diabetes;

the amino acid sequence of the oral hypoglycemic peptide is as follows:

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Ser-Gln-Met-Glu-Glu-Glu-Ala-Val-Lys-Glu-Phe-Ile-Glu-Trp-Leu-Val-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys。

preferably, the diabetic-complicated cardiovascular disease is diabetic cardiomyopathy.

Preferably, the diabetic cardiomyopathy is cardiomyopathy caused by type i or type ii diabetes.

Preferably, the medicament or the pharmaceutical composition is in a dosage form for gastrointestinal administration.

Preferably, the medicament or pharmaceutical composition comprises a carrier, which is a pharmaceutically acceptable carrier.

Preferably, the oral hypoglycemic peptide is obtained by solid phase synthesis.

The oral hypoglycemic peptide related by the invention is polypeptide OHP2 which is described in the specific embodiment in Chinese invention patent application with application number CN201910747519.9 and application publication number CN 110437329A. After further research on the polypeptide, the inventor of the invention finds that the polypeptide can effectively improve myocardial hypertrophy and fibrotic damage caused by diabetes, reduce the content of related myocardial enzymes, regulate lipid metabolism level, and improve myocardial cell oxidative stress and mitochondrial damage, thereby playing a role in protecting the heart, so that the polypeptide can be used as a candidate molecule for treating or preventing cardiovascular diseases (especially diabetic cardiomyopathy) complicated by diabetes, and has a good application prospect.

Drawings

Fig. 1 is a graph showing the results of monitoring blood glucose and body weight changes in example 2 of the present invention.

FIG. 2 is a graph showing the results of echocardiography examination in example 3 of the present invention.

FIG. 3 is a graph showing the results of myocardial hypertrophy detection in example 4 of the present invention.

FIG. 4 is a graph showing the results of myocardial fibrosis test in example 5 of the present invention.

FIG. 5 is a graph showing the results of measurement of serum central myopathy in example 6 of the present invention.

FIG. 6 is a graph showing the results of the measurement of cardiac lipid deposition in example 7 of the present invention.

FIG. 7 is a graph showing the results of the test of oxidative stress in the heart in example 8 of the present invention.

FIG. 8 is a graph showing the results of mitochondrial damage detection in example 9 of the present invention.

Detailed Description

The invention is described in further detail below with reference to embodiments and with reference to the drawings. The invention is not limited to the examples given. In each example, the methods used were conventional unless otherwise specified, and the reagents and materials used were commercially available unless otherwise specified.

Example 1

This example is the establishment and grouping of diabetic cardiomyopathy rat models.

The specific process is as follows:

the first step is as follows: after 56 male Wistar rats were adaptively fed for one week, 8 male Wistar rats were randomly selected as a control group and were fed with ordinary feed all over the way, and after the other rats were given high-fat diet for 4 weeks as a model group, STZ solution (prepared by dissolving streptozotocin STZ in 0.1mol/L citric acid buffer solution at pH 4.5) was intraperitoneally injected at a dose of 15mg/kg for three consecutive weeks, while the control group was given a corresponding volume of 0.1mol/L citric acid buffer solution at pH 4.5. One week later, the rats in the model group are subjected to tail breaking and blood taking, the fasting blood glucose is measured by a glucometer, the fasting blood glucose is more than 11.1mmol/L as the standard for successful model making, the unqualified rats are removed, and the qualified rats are continuously subjected to high fat diet for 4 weeks.

The second step: the model-building rats were divided into 6 groups: the soxhlet peptide group (Semaglutide), the engagliflozin group (Empagliflozin), the OHP2 high-dose group, the OHP2 medium-dose group, the OHP2 low-dose group, and the model group (vehicle), wherein the soxhlet peptide and the engagliflozin are positive control drugs. These 6 groups of rats and the first step of control group of rats were combined into 7 groups of rats.

Specifically, the somagluteptide is administrated by subcutaneous injection, the dosage is 12 mu g/kg, and the administration is carried out once a day; the engagliflozin is administrated by gastric lavage, the dose is 10mg/kg, and the administration is carried out once a day; OHP2 is administered by intragastric administration, and the high, medium and low doses are 1.48mg/kg, 0.74mg/kg and 0.37mg/kg respectively twice a day; the model group is provided with a blank solvent, and the administration period of each group is eight weeks; the control group was gavaged twice daily with PBS solution.

The OHP2 is the oral hypoglycemic peptide related by the invention, and the amino acid sequence of the oral hypoglycemic peptide is as follows:

example 2

This example is the monitoring of blood glucose and body weight changes during treatment of OHP2 in diabetic rats.

Animal groups and dosing regimens are shown in example 1. Fasting blood glucose was measured weekly during eight consecutive weeks of dosing, and changes in body weight of rats were recorded daily and statistically analyzed.

The results are shown in FIG. 1. Wherein the change in fasting plasma glucose is shown in panel A of fig. 1, and the fasting plasma glucose in the control group is lower than that in each of the other groups during the administration period; after eight weeks of administration, fasting blood glucose levels of the OHP2 high and medium dose group, the engagliflozin group, and the somaglutide group were significantly reduced compared to the vehicle model group, which indicates that OHP2 was able to effectively control fasting blood glucose levels in diabetic rats.

The weight change of the rats is shown in a graph B in a graph 1, after eight weeks of treatment, compared with a vehicle model group, the weight of the rats in an OHP2 high-dose group and a Somalutide group is obviously reduced, and the weight increase trend is inhibited in an OHP2 low-dose group, which indicates that OHP2 can effectively reduce the weight increase caused by diabetes.

Example 3

This example is the effect of OHP2 on cardiac function in diabetic rats.

Animal grouping and dosing regimens are shown in example 1. At the end of the eighth week of administration, the echocardiography is used to detect the heart function of the rat, and the specific process is as follows:

the first step is as follows: the rat is put into a sealed anesthesia box, isoflurane is inhaled for anesthesia, and the rat is fixed in a supine position.

The second step: a cotton swab is dipped in a proper amount of depilatory cream to be uniformly smeared on the chest of a rat, and the front hair of the chest is removed by a scraper.

The third step: a small amount of conductive liquid is smeared on four limbs of a rat and is fixed on an electrocardio induction module, then a proper amount of ultrasonic coupling agent is smeared on the precordial region, the position is adjusted to combine with a probe handle to find out a heart image, and the image is collected and data is processed.

The results of cardiac function tests are shown in the graph A of FIG. 2, and the cardiac function of the left ventricle of rats in the vehicle model group is abnormal, and each administration group has certain improvement.

The Left Ventricular Ejection Fraction (LVEF) measurement results are shown in the B diagram of fig. 2, compared with the control group, the left ventricular ejection fraction of the rats in the vehicle model group is obviously reduced, and after eight-week treatment, the left ventricular ejection fraction can be effectively improved by each dose group of OHP2 and the positive drug group.

Similarly, as shown in the graph C of fig. 2, the left ventricular short axis shortening score of the rats in the vehicle model group was significantly decreased compared to that in the control group, and after eight weeks of treatment, the left ventricular short axis shortening score was effectively increased in each dose group of OHP2 and the positive drug group.

The results show that OHP2 has certain improving effect on cardiac dysfunction caused by diabetes.

Example 4

This example is the effect of OHP2 on myocardial hypertrophy in diabetic rats.

Animal grouping and dosing regimens are shown in example 1.

The first step is as follows: the length of the tibia of the rat was measured with a vernier caliper after eight weeks of administration, and the left ventricular tibia ratio was calculated in combination with the results of the echocardiography analysis.

The second step is that: the rats were then sacrificed and heart tissue isolated and frozen in liquid nitrogen for subsequent qRT-PCR detection of myocardial hypertrophy associated genes.

The third step: approximately 20mg of heart tissue was removed with scissors and placed in a mortar, ground thoroughly with liquid nitrogen into a fine powder, and total RNA was extracted using a total gold RNA extraction kit and the RNA concentration was determined.

The fourth step: the RNA is reversely transcribed into cDNA by a reverse transcription kit, and qPCR detection is carried out according to a primer sequence designed in the following table, wherein beta-actin is an internal reference. Note: corresponding commercially available kits were used in this example.

Results of the rat left ventricular tibia ratio are shown in a graph a of fig. 3, and the vehicle model group has a significant improvement in the left ventricular tibia ratio compared with the control group, which proves that a myocardial hypertrophy condition has occurred; after eight weeks of treatment, the OHP2 high and medium dose group and the positive drug group both reduced the left ventricular tibiofemoral ratio and almost reached normal levels.

The results of qRT-PCR detection of cardiac hypertrophy related genes ANP and beta-MHC are shown in a B picture of figure 3, the ANP expression amount of OHP2 high dose and the OHP expression amount of a positive drug group are both reduced, and the beta-MHC expression amount of OHP2 groups and a Somarlu peptide group is reduced.

The results show that OHP2 has certain improving effect on myocardial hypertrophy caused by diabetes.

Example 5

This example shows the effect of OHP2 on myocardial fibrosis in diabetic rats.

Animal groups and dosing regimens are shown in example 1.

The first step is as follows: after eight weeks of dosing, the rats were sacrificed, heart tissue was removed, placed in physiological saline to express excess blood, and fixed in 4% neutral formaldehyde for 48 h. After the sections were embedded in paraffin, the sections were stained by the massson trichrome method and observed by an optical microscope.

The second step: qRT-PCR method for detecting myocardial fibrosis-associated genes referring to example 4, primer sequences are shown in the following table.

As a result of masson staining of rat heart, as shown in the A-diagram of FIG. 4, myocardial fibrosis was evident in the rats in the vehicle model group, and interstitial collagen deposition was more abundant in the myocardium, as compared with the control group. After treatment, both OHP2 and the positive drug group were able to reduce the area of masson positive area in cardiac tissue.

Results of qRT-PCR detection of myocardial fibrosis related genes TGF beta and Collagen1 are shown in a B picture of figure 4, compared with a Control group, mRNA expression levels of TGF beta and Collagen I in a Vehicle model group are remarkably improved, and occurrence of myocardial fibrosis is proved. After treatment, only the OHP2 high dose group could reduce the expression level of TGF β, but the mRNA expression levels of OHP2 dose groups and englezin group Collagen I were reduced.

The above results indicate that OHP2 has an improvement effect on myocardial fibrosis induced by diabetes.

Example 6

This example shows the effect of OHP2 on the serum central myopathy in diabetic rats.

Animal groups and dosing regimens are shown in example 1.

The first step is as follows: at the end of the eighth week of dosing, rats were fasted overnight and the orbital venous plexus was bled the following day.

The second step: standing the blood sample at room temperature for half an hour, centrifuging at 3000rpm for 10min, and packaging the obtained serum in refrigerator at-20 deg.C.

The third step: the activities of serum centromysin LDH and CK-MB were measured separately with reference to kit instructions. Note: the corresponding commercial kit was used in this example.

The detection result of LDH in serum is shown in A picture of figure 5, compared with a vehicle model group, the activity of LDH in serum can be reduced by the high dose of OHP2 and the masculine medicine group; similarly, the results of CK-MB assay in serum are shown in B-panel of FIG. 5, and the high OHP2 dose and the somaglutide group reduced the activity of CK-MB in serum compared to the vehicle model group.

The above results show that OHP2 has certain improving effect on the increase of myocardial enzyme content caused by myocardial injury.

Example 7

This example is the effect of OHP2 on cardiac lipid deposition in diabetic rats.

Animal groups and dosing regimens are shown in example 1.

The first step is as follows: after eight weeks of dosing, the rats were sacrificed and heart tissue was removed and frozen in liquid nitrogen. Fresh frozen sections were subsequently fixed and the sections were observed with an optical microscope after staining with oil red and hematoxylin.

The second step is that: shearing off partial frozen tissues, adding normal saline according to the mass-volume ratio of 1: 9, homogenizing, centrifuging at 12000rpm for 10min, and collecting supernatant. The contents of triglyceride, total cholesterol and free fatty acid in the supernatant were determined separately according to the instructions in the kit. Note: the corresponding commercial kit was used in this example.

The results of oil red staining are shown in graph A of FIG. 6, and compared with the control group, the heart tissues of rats in the vehicle model group showed obvious neutral fat deposition, and both OHP2 and the positive drug group were improved; the results of measuring the triglyceride content in heart tissue are shown in the B diagram of FIG. 6, and both OHP2 and the positive drug somaglutide can improve the deposition of triglyceride in heart tissue; the determination result of total cholesterol is shown in a C diagram of figure 6, and compared with a vehicle model group, the OHP2 can reduce the content of the total cholesterol in heart tissues and is close to a normal level, and the effects of two positive drugs are not obvious; the measurement results of free fatty acid are shown in figure 6D, where OHP2 high and medium doses had a control effect on free fatty acid in heart tissue.

The above results indicate that OHP2 has certain advantages for regulating cardiomyocyte lipid metabolism and reducing cardiac lipid deposition.

Example 8

This example is the effect of OHP2 on cardiac oxidative stress in diabetic rats.

The first step is as follows: referring to the second step of example 7, the content of malondialdehyde, a marker of oxidative stress, in the supernatant of heart tissue homogenate, was measured according to the instructions in the kit. Note: the corresponding commercial kit was used in this example.

The second step: qRT-PCR method for detecting Heart-related antioxidant enzyme genes referring to example 4, primer sequences are shown in the following table.

The detection result of the malondialdehyde in the heart tissue is shown in a graph A in figure 7, compared with the control group, the content of the malondialdehyde in the heart tissue of the rat in the vehicle model group is obviously increased, which indicates that the heart tissue is in a state of high oxidative stress level, and after eight weeks of treatment, the content of the malondialdehyde in the heart can be reduced by OHP2 and somaglutide; results of qRT-PCR detection on heart-related antioxidant enzyme genes SOD1, GPX1 and HO-1 are shown in a B picture of figure 7, and high doses of OHP2 and positive drugs can remarkably improve the expression quantity of GPX1 and HO-1, and have no influence on the expression quantity of SOD 1.

The above results indicate that OHP2 has a certain control effect on the oxidative stress level of heart tissue, and OHP2 may protect the heart by regulating the oxidative stress pathway.

Example 9

This example is the effect of OHP2 on mitochondrial injury in diabetic rats.

Animal groups and dosing regimens are shown in example 1.

The first step is as follows: eight weeks after the end of dosing, the rats were sacrificed and heart tissue was removed and immediately cut 1-2mm³The tissue blocks of (4) were stored in 2.5% glutaraldehyde at 4 ℃. After fixation with osmic acid, osmotic embedding and double staining with uranium and lead, images were observed and collected using a transmission electron microscope.

The second step: cutting off a small piece of heart tissue kept in liquid nitrogen, adding a lysis solution according to the mass-volume ratio of 1: 9, homogenizing, collecting supernatant, and detecting the ATP content in the supernatant according to the instructions in the kit. Note: the corresponding commercial kit was used in this example.

The results of transmission electron microscopy are shown in a graph a of fig. 8, compared with the control group, the arrangement of mitochondria in the heart tissue of the rat in the vehicle model group is disordered, the area of mitochondria is reduced, the mitochondria are divided, the arrangement of mitochondria in the heart tissue of the OHP2 and the positive drug group is regular, and the average area is increased. The results of ATP content detection in cardiac tissue are shown in the B-diagram of fig. 8, and compared with the vehicle model group, both the OHP2 high dose and the somaglutide group increased ATP content in cardiac tissue, indicating that mitochondrial function was improved.

The above results show that OHP2 has certain improving effect on the mitochondrial injury of heart tissues of diabetic rats.

From the results of the above examples, it is known that oral administration of the hypoglycemic peptide OHP2 can effectively improve myocardial hypertrophy and fibrotic damage caused by diabetes, reduce the content of relevant myozymes, regulate lipid metabolism level, improve myocardial cell oxidative stress and mitochondrial damage, and thus exert the effect of protecting heart; and oral administration of hypoglycemic peptide OHP2 can reduce fasting blood glucose value and body weight. Therefore, the oral hypoglycemic peptide OHP2 serving as a novel orally-administrable exenatide analog can be used for preparing a medicine or a pharmaceutical composition for treating or preventing diabetes-associated cardiovascular diseases, and has a good application prospect. Wherein the diabetes-complicated cardiovascular disease can be diabetic cardiomyopathy, such as cardiomyopathy caused by type I or type II diabetes; the dosage form of the medicament or the pharmaceutical composition is a gastrointestinal administration dosage form; the medicament or the pharmaceutical composition comprises a carrier, and the carrier is a pharmaceutically acceptable carrier. In addition, oral hypoglycemic peptide OHP2 can be obtained by solid phase synthesis.

In addition to the above embodiments, the present invention may have other embodiments. All technical solutions formed by adopting equivalent substitutions or equivalent transformations fall within the protection scope of the claims of the present invention.

Claims

1. The application of the oral hypoglycemic peptide is characterized in that the application is used for preparing a medicine or a medicine composition for heart protection treatment aiming at cardiomyopathy caused by type I or type II diabetes mellitus;

the cardioprotective treatment comprises: improving abnormal cardiac function, myocardial hypertrophy and fibrosis injury caused by diabetes, reducing content of myocardial enzyme, regulating myocardial cell lipid metabolism level, and improving myocardial cell oxidative stress and mitochondrial injury;

the amino acid sequence of the oral hypoglycemic peptide is as follows:

2. use according to claim 1, wherein the medicament or pharmaceutical composition is in the form of a gastrointestinal administration form.

3. The use according to claim 1, wherein the medicament or pharmaceutical composition comprises a carrier which is a pharmaceutically acceptable carrier.

4. The use of claim 1, wherein the oral hypoglycemic peptide is obtained by solid phase synthesis.