CN1695622A - Sustained and controlled release semi-solid matrix preparation composition containing glipizide - Google Patents

Abstract

A slowly-or controllably-releasing semi-solid medicine for treating diabetes B is proportionally prepared from glipizide and slowly-releasing semi-solid skeleton carrier.

Description

Sustained and controlled release semi-solid matrix preparation composition containing glipizide

technical field

The invention relates to a sustained and controlled release semi-solid matrix preparation composition containing glipizide.

Background technique

Glipizide, white, odorless and tasteless, insoluble in water and ethanol, pKa is 5.9. Its English name is Glipizide, and its chemical name is 1-cyclohexyl-3-{4-[2-(5-methylpyrazine-2-amide)-ethyl]benzenesulfonyl}urea. Its structural formula is as follows:

Molecular formula: C ₂₁ H ₂₇ N ₅ O ₄ S, molecular weight: 445.54

Glipizide is a second-generation sulfonylurea oral hypoglycemic drug, which can promote the secretion of insulin by pancreatic β cells and enhance the effect of insulin on target tissues; it can also stimulate pancreatic α cells to inhibit glucagon secretion. Inhibit liver glycogen breakdown, promote muscle utilization and consumption of glucose. Clinically, it is mainly used for patients with mild to moderate non-insulin-dependent diabetes mellitus, and the oral dosage ranges from 2.5 to 30 mg per day. If the daily dose exceeds 15 mg, multiple administrations will be required, which will cause inconvenience to the patient, and cause large fluctuations in the peak and valley concentrations of the blood drug, which will easily cause toxic and side effects.

Currently, hydrophilic or hydrophobic polymers are usually mixed with other excipients to form a single uniform glipizide drug delivery system. But this drug release system has a disadvantage, this is because the release kinetics of glipizide in this system is nonlinear (first-order kinetics), after the patient takes the drug, the release of glipizide is disproportionate to time. It is released very quickly, and there is a peak of blood drug concentration in the patient's body, so that glipizide has an uneven and inconsistent release amount in the early stage of release compared with the later stage, so diabetic patients because of the sudden appearance of the drug The peak plasma concentration of Glipizide will produce various adverse reactions.

US Patent No. 5,945,125 discloses a preparation process for sustained-release tablets with a water-swellable non-crosslinked polyoxyethylene polymer with a molecular weight of 900,000 to 5,000,000 as the backbone. The purpose of selecting the water-swellable polymer here is to make the expansion rate of the polymer consistent with the dissolution rate of the expanded polymer. Although this patent mentions that glipizide can be made into a sustained-release preparation by this process, it does not specify the composition of the prescription in detail, and the absorption of glipizide in the body.

Pfizer's Ruiyining is an oral osmotic pump controlled-release formulation of glipizide, and each tablet contains 2.5-20mg of glipizide. Its release mechanism is based on osmotic pressure and hydrostatic pressure. However, a typical feature of this product is that there is a time lag of 2-3 hours from the release of the drug to the absorption into the patient's circulatory system and endocrine system. The length of the lag time depends on the volume of body fluid in the patient's gastrointestinal tract at the time of administration, because drug release from the tablet depends on hydration and osmotic pressure. In addition, in industrial production, the preparation process of osmotic pump controlled-release tablets is quite complicated, and the cost is relatively high. This process needs to make a double-layer tablet with a drug chamber and an osmotic chamber, then coat it with a semi-permeable membrane polymer, use a laser to drill holes on the side of the drug chamber, and finally wrap a layer on the outside Clothes. In addition, each step in this process requires specialized production equipment, and the cost of these equipment exceeds 1 million US dollars. Also, it takes a lot of time to ensure its precision in the process of producing Ruiyining products.

Semi-solid skeleton technology is a formulation technology developed in the 1970s. The prepared composition can be hot-melted at high temperature, or fluid under external force such as stirring state, and solid or semi-solid at room temperature. Fill hard capsules for oral administration.

Experiments have shown that the bioavailability of Ruiyining in animals (beagle dogs) is lower than that of common preparations of glipizide.

Contents of the invention

The technical problem to be solved in the present invention is to disclose a slow and controlled release semi-solid matrix preparation composition containing glipizide, so as to overcome the problems in the prior art that the drug cannot be released stably for a long time in the body, the number of administrations is high, and the side effects In the case of high incidence, in order to improve the safety and compliance of patients with medication.

The composition of the invention comprises: 0.5-6 wt% of glipizide and 94-99.5 wt % of slow-release semi-solid skeleton carrier.

The sustained-release semi-solid matrix carrier includes one or more of C12-C18 high-melting fatty acid esters, vegetable oils or cellulose polymers, and the components and weight of the preferred sustained-release semi-solid matrix carrier The percentage content is:

The amount of high melting point fatty acid ester is generally 24-70wt%;

The dosage of vegetable oil is generally 20-75wt%;

The dosage of cellulose polymer is 1-10wt.

The optimum dosage range of high melting point fatty acid ester is 30-58wt%;

The optimum dosage range of vegetable oil is 40～65wt%;

The optimal amount of cellulose polymer is in the range of 2-5 wt%.

Wherein, the high melting point fatty acid ester of C12～C18 is selected from beeswax, carnauba wax, stearyl alcohol, glyceryl monostearate, polyethylene glycol stearate, glyceryl behenate, stearic acid or One or more of glyceryl palmitostearate;

Vegetable oils including lauric, palmitic, palmitoleic, stearic, oleic, linoleic, eicosapentaenoic, docosahexaenoic, as well as grain oils, cottonseed oil, herring oil, safflower One or more of oil, shark liver oil, soybean oil, olive oil, or wheat seed oil.

Cellulose includes one or more of methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose or low-substituted hydroxypropyl cellulose ether polymers.

Low-substituted hydroxypropyl cellulose ether polymers refer to hydroxypropyl cellulose ether polymers with a hydroxypropyl content of 4-10%;

The carrier material forms a network skeleton structure, and the drug is dispersed in the molecular or microcrystalline state, and slowly released from the network skeleton through the principle of erosion and diffusion, and different drug release rates can be achieved by adjusting the proportion of each component in the carrier.

The preparation method of the sustained and controlled release semi-solid matrix preparation composition containing glipizide of the present invention comprises the following steps:

The components are quantitatively mixed in proportion, heated and melted to 65-80°C, stirred to make the mixture uniform, and cooled to 50-60°C at room temperature to obtain the product.

The sustained and controlled release semi-solid matrix preparation composition containing glipizide of the present invention can be directly filled into hard capsules by a capsule liquid filling machine to obtain hard capsules, or filled with soft capsules by a rotary mode capsule machine, or through a method known in the art. The method is made into small pills, or made into drop pills with a drop pill machine.

The preparation of the sustained and controlled release semi-solid matrix preparation composition containing glipizide disclosed in the present invention is to mix glipizide and the carrier substance in the proportion of the prescription evenly, place it in a beaker and heat it to 80°C in a water bath, and heat it while heating. Stir, and after it is completely melted, cool at room temperature to about 60°C and fill it into hard capsules. Although the dose of glipizide is very small in this sustained and controlled release system, glipizide can be uniformly dispersed in the carrier skeleton. The release mechanism of the formed glipizide sustained and controlled release semi-solid matrix preparation composition in vivo is an erosion and diffusion mechanism. As the carrier matrix is slowly eroded away, glipizide is slowly released close to zero order . In addition, because the carrier contains a considerable amount of oil, this makes the whole preparation lighter than water, which can achieve the effect of gastric floating, increase the residence time of the capsule in the gastrointestinal tract, and reduce the impact of food on the gastric emptying rate. impact on the slow-release effect of the preparation; glipizide is dispersed in the semi-solid state of the skeleton, and under the action of gastrointestinal peristalsis, the capsule can adhere to the intestinal wall, thus increasing the residence time of the preparation. Enhances the sustained-release therapeutic effect of glipizide.

The present invention discloses a sustained and controlled release semi-solid matrix preparation composition of glipizide, because a high melting point fatty acid ester with a certain HLB value is used in the prescription to solve the physical availability of the glipizide sustained release preparation The problem is lower than that of ordinary films. The bioavailability of the glipizide preparation of the present invention is 1-1.5 times of the bioavailability of Ruiyining.

In terms of technology, this semi-solid filling process of glipizide has many advantages compared with other slow and controlled release processes: it can avoid cross-contamination caused by flying drug dust, improve the operating safety of workers, and benefit Labor protection; the drug is dispersed in the excipient to be isolated from air and moisture to increase the stability of the drug; the most important thing is that the preparation process is simple and economical, and the mechanical equipment occupies a small area, which is conducive to large-scale industrial production.

Description of drawings

Figure 1 is a graph comparing the in vitro release curves of the glipizide preparation of the present invention and the commercially available Ruiyining osmotic pump controlled-release tablets.

Fig. 2 is an open, double cross-controlled test diagram of glipizide of the present invention and the commercially available Ruiyining osmotic pump controlled-release tablet carried out in 6 healthy male beagle dogs.

Figure 3 is the in vitro release curve of Example 1.

Figure 4 is the in vitro release curve of Example 2.

Figure 5 is the in vitro release curve of Example 3.

Figure 6 is the in vitro release curve of Example 4.

Figure 7 is the in vitro release curve of Example 5.

Figure 8 is the in vitro release curve of Example 6.

Figure 9 is the in vitro release curve of Example 7.

Detailed ways

The comparison of in vitro release curves between the glipizide preparation of the present invention and the commercially available Ruiyining osmotic pump controlled-release tablets is shown in Figure 1. Dissolution conditions: tolerance medium: PH7.4 phosphate buffer; 500ml; basket method; speed 100 rpm.

An open-label, double-crossover controlled trial of glipizide of the present invention and commercially available Ruiyining osmotic pump controlled-release tablets was carried out in 6 healthy male beagle dogs. The result is shown in Figure 2.

The in vitro release test was carried out using the method disclosed in the Journal of China Pharmaceutical University, 1996, 27(11): 661-664, Research on the preparation of glipizide tablets and its drug release characteristics.

Example 1

329g of macrogol glyceride stearate and 141g of glyceryl behenate, heat and melt at 80°C, add 5g of glipizide, stir to mix evenly, cool to 60-70°C and fill with capsule liquid Machine filling in No. 1 capsules to make 1000 capsules. The in vitro release curve is shown in Figure 3. (Release 24H)

Example 2

Glipizide 5, Palmitic acid 200g, Glyceryl behenate 150g, Beeswax 150g Grind until fully dissolved, mix well and heat to 80°C, stir to mix evenly, cool to 60-70°C and use capsule liquid filling machine Fill in No. 1 capsules to obtain 1000 capsules. The in vitro release curve is shown in Figure 4. (Release 24H)

Example 3

103.4g of macrogol glycerol stearate, 117.5g of carnauba wax, heat and melt at 80°C, add 5g of glipizide, 4.7g of ethyl cellulose (10CP), stir to make the mixture uniform, and slowly add 239.7 g of soybean oil, after mixing, was cooled to 60-70 DEG C and filled in No. 1 capsules with a capsule liquid filling machine to obtain 1000 capsules. The in vitro release curve is shown in Figure 5. (Release 24H)

Example 4

Glipizide 5g, glyceryl palmitostearate 216.2g, oleic acid 239.7g, mix, heat and melt at 80°C, stir evenly, cool to 60-70°C and fill in No. 1 capsule liquid filling machine Capsules, 1000 capsules were prepared. The in vitro release curve is shown in Figure 6. (Release 24H)

Example 5

Glipizide 10g, low-substituted hydroxypropyl cellulose 28.2g, cottonseed oil 286.7g, glyceryl behenate 109.25g, macrogolglycerol stearate 47g were mixed, heated and melted at 80°C, stirred Evenly, after cooling to 60-70°C, fill it into No. 1 capsules with a capsule liquid filling machine to obtain 1000 capsules. The release curve in vitro is shown in Figure 7. (Release 24H)

Example 6

Glipizide 5g, ethyl cellulose (P, 10CP), 19.2g, soybean oil 326.4g, polyethylene glycol stearate 134.4g, glycerol monostearate 160g, mix and heat at 80°C Melt, stir evenly, cool to 60-70°C and fill in No. 0 capsules with a capsule liquid filling machine. The in vitro release curve is shown in Figure 8. (Release 24H)

Example 7

Glipizide 20g, ethyl cellulose (P, 100FP) 19.2g, soybean oil 144g, glyceryl palmitostearate 316.8g, mix, heat and melt at 80°C, stir evenly, and cool to 60-70°C Then fill the No. 1 capsule with a capsule liquid filling machine. The release curve in vitro is shown in Figure 9. (Release 24H)

Claims (9)

1. A sustained and controlled release semi-solid matrix formulation composition containing glipizide, characterized in that it comprises: 0.5-6 wt% of glipizide, and 94-99.5 wt% of a sustained-release semi-solid matrix carrier. 2. The sustained and controlled release semi-solid matrix preparation composition containing glipizide according to claim 1, wherein the sustained-release semi-solid matrix carrier comprises fatty acid esters with high melting points of C12～C18, One or more of vegetable oil or cellulose polymer. 3. The sustained and controlled release semi-solid matrix preparation composition containing glipizide according to claim 2, wherein the composition and weight percentage of the slow-release semi-solid matrix carrier are: The amount of high melting point fatty acid ester is generally 24-70wt%; The dosage of vegetable oil is generally 20-75wt%; The dosage of cellulose polymer is 1-10wt. 4. The sustained and controlled release semi-solid matrix preparation composition containing glipizide according to claim 3, wherein the composition and weight percent content of the slow-release semi-solid matrix carrier are: High melting point fatty acid ester 30～58wt%; Vegetable oil 40～65wt%; Cellulose polymer 2～5wt%. 5. The slow and controlled release semi-solid matrix preparation composition containing glipizide according to claim 2, 3 or 4, wherein the high melting point fatty acid ester of C12～C18 is selected from beeswax, carnauba wax, One or more of stearyl alcohol, glyceryl monostearate, macrogol glyceryl stearate, glyceryl behenate, stearic acid or glyceryl palmitostearate. 6. according to claim 2,3 or 4 described slow and controlled release semi-solid matrix preparation compositions containing glipizide, it is characterized in that, vegetable oil comprises lauric acid, palmitic acid, palmitoleic acid, stearic acid, oil linoleic acid, eicosapentaenoic acid, docosahexaenoic acid, and one of corn oil, cottonseed oil, herring oil, safflower oil, shark liver oil, soybean oil, olive oil, or wheat seed oil species or more than one. 7. The slow and controlled release semi-solid matrix preparation composition containing glipizide according to claim 2, 3 or 4, wherein the celluloses include methylcellulose, hydroxypropylmethylcellulose, One or more of ethyl cellulose or low-substituted hydroxypropyl cellulose ether polymers. 8. The preparation method of the sustained and controlled release semi-solid matrix preparation composition containing glipizide according to any one of claims 1 to 7, characterized in that it comprises the following steps: quantitatively mixing the components in proportion, Heat and melt to 65-80°C, stir to make the mixture uniform, and cool to 50-60°C at room temperature to obtain. 9. the preparation method of the sustained and controlled release semi-solid matrix preparation composition containing glipizide according to claim 8, is characterized in that, directly fills in hard capsule with capsule liquid filling machine, obtains hard capsule, or uses The soft capsules are loaded into the rotary capsule machine, or made into small pills by methods known in the art, or made into drop pills with a drop pill machine.

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