CN1163263C - A kind of polypeptide drug oral spray - Google Patents

Abstract

The invention discloses a composition and preparation method of a polypeptide medicine oromucosal absorption medicament. The medicament is composed of the following components: polypeptide drugs, accelerators, cosolvents, flavoring agents, bacteriostats and phosphate buffer solution with pH=6.8-7.8. The insulin oral spray of the present invention provides a safe and convenient way of administration and medicine for diabetics.

Description

A kind of polypeptide drug oral spray

The invention provides a composition and a preparation method for preparing polypeptide drugs such as insulin oral spray.

Peptide drugs are easily degraded by gastric acid and various digestive enzymes in the gastrointestinal tract, so they cannot be taken orally directly, and can only be administered by injection. For example, insulin must be injected half an hour before meals to control blood sugar, and it must be administered for a lifetime, which makes patients feel painful and inconvenient. Therefore, the study of safe, convenient and effective polypeptide drugs, especially the non-injection route of administration of insulin, will greatly facilitate disease patients. Insulin non-injection route of administration has become a hot research topic in the world's pharmaceutical circles since the 1970s, and has made great progress especially since the 1990s.

There are several alternative routes of insulin administration. For example, the method of embedding an insulin pump in the peritoneum has been proved to be safe and metabolically effective. It has been used clinically abroad, but it is expensive and not affordable for ordinary patients. There are also results showing that the method of absorbing insulin through the bronchial mucosa has attractive application prospects, but there are still some difficulties to be overcome in this method. Insulin is embedded in liposomes or polymers, and then made into oral preparations. Insulin is absorbed by small intestinal mucosal cells into the blood to lower blood sugar. However, the bioavailability of the drug is low and the drug is easily cleared from the administration site. Loss is an important obstacle to the success of oral insulin. A relatively large amount of research work is currently being carried out focusing on the route of administration through the mucous membranes of the nose, eyes, lungs, and mouth. The work in this area has made some progress after more than ten years of exploration, but there are still some problems in the clinical application of these pathways, mainly the low bioavailability.

Since peptide drugs generally have a large molecular weight, oral mucosa is difficult to absorb, so choosing an appropriate low-toxicity and high-efficiency absorption enhancer and increasing the absorption area are the keys to improving the bioavailability of peptide drugs.

The object of the present invention is to propose a novel oral mucosa absorption spray of polypeptide drugs.

Taking insulin as an example, the technical scheme of the present invention is as follows:

The components of the polypeptide drug oral spray are: insulin as the polypeptide drug; soybean lecithin as the accelerator; propylene glycol and ethanol as the solubilizer; borneol as the flavoring agent; It is phenol; as the buffer solution is a phosphate buffer solution with a pH of 6.8 to 7.8.

Its prescription is (per 1000 milliliters):

Insulin 5 000U-80 000U

Soy Lecithin 5-45g

Propylene Glycol 5-45g

Ice flakes 0-10g

Ethanol 0-15ml

                                                     

    Phosphate buffer solution (pH=6.8～7.8)   Dilute to 1000ml

Preparation of Insulin Oral Spray:

Take soybean lecithin according to the prescription, add propylene glycol and borneol in ethanol solution, and stir slowly until soybean lecithin is completely dissolved; insulin is dissolved in about 2/3 of the total amount, pH = 6.8-7.8 in phenol-containing phosphate buffer . Under constant stirring (400±100 rpm), slowly add the phosphate buffer solution of insulin into the propylene glycol solution of soybean lecithin, continue stirring for about 10-30 minutes after the addition, and then add the phosphate buffer solution to the full amount .

This medicated spray is an emulsion containing water and oil, but does not require additional surfactants. Soybean lecithin (oil), which is the mucostimulator of the drug of the present invention, also acts as a surfactant in this formulation.

Put this preparation into a packaging bottle with a metered spray pump, which can spray insulin into the mouth like a mist. Insulin is attached to the mucous membranes of the oral cavity and throat, and can quickly enter the blood circulation through the mucous membranes. A new non-injection drug delivery method that increases the absorption area of the drug, improves the absorption speed, and is convenient for patients. There is no report of similar insulin spray at home and abroad at present.

In the insulin oral spray, insulin is the main drug, but its permeability through the oral mucosa is poor. In order to improve its hypoglycemic rate, it is necessary to select a suitable absorption enhancer. The present invention uses soybean lecithin as a non-toxic, safe and effective accelerator. Due to the poor water solubility of soybean lecithin, it is necessary to choose a suitable co-solvent. The present invention takes the hypoglycemic effect as an index, and studies the solubility-promoting effect of propylene glycol. The experimental results show that propylene glycol can increase the effect of soybean lecithin to promote the absorption of insulin by oral mucosa, and their optimal ratio is determined through orthogonal experiments.

The insulin oral spray of the invention is safe and nontoxic. Long-term toxicity test of local administration of insulin oral spray in rats, the dosage groups were 4.5, 9.0, 18.0 U·kg ^-1 , as well as the normal saline control group and the vehicle control group. After 6 months, the local and overall conditions of the animals in each administration group were compared with those of the normal saline control group, and no obvious abnormalities were found.

The insulin oral spray of the present invention has higher bioavailability. The invention takes normal rabbits as models, uses ELISA to measure the insulin content in the body, studies the pharmacokinetics of the insulin oral spray and calculates the pharmacokinetic parameters. The results showed that after administration to the oral mucosa of normal rabbits (1.5U/kg body weight), the serum insulin concentration increased rapidly, the peak time was 64 minutes, and the peak concentration was 141.6±6.4μU/ml, which gradually decreased after 4 hours to the pre-medication baseline level. Compared with the vehicle group, the serum insulin concentration of rabbits in the insulin oral mucosa administration group and the insulin subcutaneous injection control group had significant differences within 30-120 minutes (P<0.05). At this dose, compared with the insulin subcutaneous injection control group (0.5U·kg ^-1 ), the peak concentration and peak time of serum insulin were basically the same without significant difference (P>0.1), and the average insulin oral spray The bioavailability is 29.2%.

Insulin oral spray has the characteristics of large contact area with oral mucosa, fast absorption, high hypoglycemic rate, and safe use. Therefore, the invention of insulin oral spray will bring convenience to diabetic patients and reduce the pain of injection administration. The invention has great social and economic benefits.

The insulin oral spray prepared according to the above technical scheme has good hypoglycemic effect. For example, using chemical reagent-induced hyperglycemic animals and normal animals (rats and rabbits) and other models, the main pharmacodynamics of insulin oral spray is studied with the hypoglycemic rate of insulin oral spray as the main index. In the animal experiment, the animal was anesthetized with pentobarbital sodium, and the esophagus was ligated until 10 minutes after the administration: after the administration of the oral mucosa, the blood glucose of the animal was measured with an electronic induction blood glucose meter and an electronic induction test strip every 30 minutes, and the measurement was continued. 4 to 6 hours. At the same time, insulin subcutaneous injection (positive control) group and normal saline (negative control) group were set up. The results showed that: ①The oral doses of streptozotocin-induced diabetic rats were 1, 3, and 9 U·kg ^-1 , and the hypoglycemic rates were 21.6%, 46.3%, and 54 4%, respectively. ② Orally administered doses of 0.5, 1.5, 4.5 U·kg ^-1 to diabetic rabbits induced by alloxan, the hypoglycemic rates were 26.2%, 50.8%, 55.8%, respectively. ③ When oral administration doses of 1, 3, and 9 U·kg ^-1 were given to normal rats, the hypoglycemic rates were 30.7%, 51.6%, and 584%. ④ The oral doses of normal rabbits were 0.5, 1.5, 4.5 U·kg ^-1 , and the hypoglycemic rates were 31.2%, 54.8%, and 59.1%, respectively. ⑤Glucose tolerance test in normal rats, administered at a dose of 3U/kg, the hypoglycemic rate was 48.3%.

Claims (2)

1. A polypeptide drug oromucosal spray, which is formulated from polypeptide drugs, accelerators, solubilizers, flavoring agents, bacteriostats and buffer solutions, and is characterized in that the composition of the medicament is as a polypeptide in every 1000ml The insulin-like drug is 5,000U-80,000U, the accelerator is soybean lecithin 5-45g, the co-solvent is propylene glycol 5-45g, ethanol 0-15ml, and the flavoring agent is borneol 0-10g. The antibacterial agent is phenol 0-8g, and the buffer solution is a phosphate buffer solution with pH=6.8-7.8. 2. The preparation method of the polypeptide drug oral mucosa spray according to claim 1: it is formulated by polypeptide drugs, accelerators, pottery aids, flavoring agents, bacteriostats and buffer solutions, and soybean lecithin is obtained according to the prescription , add the ethanol solution of propylene glycol and borneol, and stir slowly until the soybean lecithin is completely dissolved; the insulin is dissolved in 2/3 of the total amount, pH=6.8～7.8 in a phenol-containing phosphate buffer solution; under constant stirring (400±100 rpm /min), slowly add the phosphate buffer solution of insulin into the propylene glycol solution of soybean lecithin, continue stirring for 10-30 minutes after the addition, and then add the phosphate buffer solution to the full amount.