RU2629843C1 - Method for production of nifedipine ointment (versions) - Google Patents

Abstract

FIELD: pharmacology.

SUBSTANCE: nifedipine and polyethylene glycol with a molecular weight of 1500±1000 (PEG) are mixed at the ratio of 1.00:2.00-4.00. The mixture of nifedipine and PEG is dissolved in 95% ethanol at a mixture/ethanol ratio of 1.00:13.00-15.00 at a temperature of 25±5°C. The resulting solution is introduced into the molten mixture of PEG with a molecular weight of 400 (70.00 parts) and PEG with a molecular weight of 1500 (30.00 parts) at a temperature of 95±5°C at a solution:base ratio of 1.00:5.00-11.00. The resulting ointment is thoroughly mixed and packed in sealed packages. Version 2 is proposed. A methods for nifedipine ointment preparation, comprising dilution of the mixture of nifedipine and polyvinylpyrrolidone with a molecular weight of 10000±2000 at a ratio of 1.00:0.50-1.50 in 95% ethanol at a mixture and ethanol ratio of 1:26.00-30.00 at a temperature of 25±5°C, the resulting solution is injected into anhydrous lanolin at the solution: anhydrous lanolin ratio of 1:2.15-4.55, petroleum jelly is added, at the lanolin mixture:petroleum jelly ratio of 1:1.05-1.25. The resulting ointment is thoroughly mixed and packed in sealed packages.

EFFECT: increased bioavailability of nifedipine slightly soluble in water, providing better release by increasing the solubility and dissolution rate of the drug substance DS, reduced dose and side effects of the drug substance DS on the body, increasing the comfort of ointments application.

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Description

The invention relates to the pharmaceutical industry and relates to the production of nifedipine ointment for the treatment of inflammation of hemorrhoids and fissure of the anus.

Known medicinal composition containing vaseline as a base, as a drug that reduces spasms of smooth muscle muscles - nifedipine 0.3%, as an anesthetic - lidocaine 1.5% (Perrotti P, Dominici P, Grossi E, Cerutti R, Antropoli C, Topical nifedipine with lidocaine ointment versus active control for pain after hemorrhoidectomy: results of a multicentre, prospective, randomized, double-blind study, Can J. Surg. 2010 Feb; 53 (1): 17-24).

The disadvantage is the petroleum jelly chosen as the basis, which interferes with the penetration of medicinal substances (drugs) introduced into it into biological tissues - the smooth muscles of the anal canal. At the same time, the effect of local treatment is significantly reduced. Vaseline negatively affects the epithelium of the anal canal, clogging the pores of the tissues, the concentration of drug and its penetration rate when passing through the mucous and submucous layers are sharply reduced. In addition, on the surface of the tissues of the anal canal, the fixation of the vaseline-based drug composition is difficult and its rapid outflow from the surface of the mucosa is observed, and the effectiveness of treatment depends on the creation of the necessary concentration of drug in the muscle of the anal sphincter. As a result, a high concentration of nifedipine is used in the composition - 0.3%.

Known drug composition for the treatment of anal fissures (RU 2483721), including a base in the form of tizol gel, lidocaine, as a drug that reduces spasms of smooth muscle muscles - nifedipine or nitroglycerin. The disadvantage of the composition is the low bioavailability (DB).

A known method of producing ointment of nifedipine based on petroleum jelly (patent CN 1813766 A). This ointment is prepared according to the following technology: 0.2 g of nifedipine is mixed in a mortar with petrolatum in an amount of 99.8 g until a homogeneous mixture is obtained. This ointment is suspension. As a basis, the ointment contains petroleum jelly. However, petroleum jelly does not dissolve in water and, as a result, provides a low release and low DB of sparingly soluble drugs.

Emulsion ointment bases are of great interest due to the ability to dramatically increase the skin resorption of water-soluble drugs that make up ointments. However, a significant drawback of emulsion bases is the difficulty of introducing into their composition slightly soluble drugs in water, due to the low release and low DB of drugs.

For drugs that are poorly soluble in water, the absorption rate is often determined by the rate of their dissolution. In this regard, the problem of increasing the solubility of poorly soluble drugs, as well as optimizing the release of drugs from the dosage form (LF), which largely characterizes the pharmacological activity of the drug and is used for non-experimental prediction of its DB, remains relevant.

The objective of the invention is a method for producing ointments of nifedipine with increased pharmaceutical bioavailability of drugs.

To solve the problem of improving the solubility of nifedipine, as well as improving the degree of absorption, a method is proposed for preparing a solution of nifedipine with polymer carriers: polyethylene glycol (PEG) or polyvinylpyrrolidone (PVP). The resulting solution is introduced into an emulsion or anhydrous hydrophilic base. The concentration of drugs in the manufactured soft drugs is 0.2%. Anhydrous hydrophilic (option 1) and emulsion (option 2) bases were chosen as the optimal bases for the manufacture of soft drugs with nifedipine, all ratios are indicated in% by weight.

The problem is solved in the following way.

Option 1

A method of obtaining a nifedipine ointment, which consists in the fact that a mixture of nifedipine and polyethylene glycol with a molecular weight of 1500 ± 1000 in a ratio of 1.00: 2.00-4.00 is dissolved in 95% ethyl alcohol with a mixture and ethanol ratio of 1.00: 13 00-15.00 at a temperature of 25 ± 5 ° C, the resulting solution is introduced into a mixture of polyethylene glycol with a molecular weight of 400 (70.00 parts) and polyethylene glycol with a molecular weight of 1500 (30.00 parts) at a temperature of 95 ± 5 ° C molten at the ratio of solution: base 1.00: 5.00-11.00, the resulting ointment is thoroughly mixed and Packed in airtight packaging.

The invention is illustrated by the following example.

EXAMPLE 1. Ointment of nifedipine 0.2% hydrophilic

A mixture consisting of 0.2 g of nifedipine and 0.6 g of PEG-1500 is dissolved in 11.2 ml of ethyl alcohol (9.07 g). The resulting solution is introduced into a pre-molten base consisting of 63.09 g of PEG-400 and 27.03 g of PEG-1500. The molten mixture is mixed until homogeneous, an ointment is obtained and packaged in sealed packages. The introduction of an alcoholic solution (nifedipine-PEG-1500) in the ointment increases the release of nifedipine by 3.25 times (relative to a vaseline-based ointment with a similar drug content).

Option 2

The method of obtaining ointment of nifedipine, which consists in the fact that a mixture of nifedipine and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in a ratio of 1.00: 0.50-1.50 is dissolved in 95% ethyl alcohol at a ratio of the mixture and ethanol 1: 26.00- 30.00 at a temperature of 25 ± 5 ° C, the resulting solution is introduced into anhydrous lanolin at a ratio of solution: anhydrous lanolin 1: 2.15-4.55, medical vaseline is added in the ratio mixture with lanolin: vaseline 1: 1.05-1 , 25, the resulting ointment is thoroughly mixed and Packed in sealed packages. The invention is illustrated by the following example.

EXAMPLE 2. Emulsion-based nifedipine ointment

A mixture consisting of 0.2 g of nifedipine and 0.2 g of PVP-10000 is dissolved in 11.2 ml of ethyl alcohol (9.07 g). To the resulting solution, 36.21 g of anhydrous lanolin is added in portions and emulsified until a crackle is characteristic. After that, mixed with 54.31 g of petroleum jelly until a homogeneous mass is obtained, which is packaged in sealed packages. The resulting ointment increases the release of the drug by 1.65 times (relative to the ointment based on petroleum jelly with a similar content of the drug).

In FIG. 1 shows the release profile of nifedipine from the basics of different types:

1 - hydrophilic base (nifedipine solution: PEG: ethyl alcohol);

2 - emulsion base (nifedipine solution: PVP: ethyl alcohol);

3 - suspension base (nifedipine, petrolatum).

The proposed variants of the method for producing nifedipine ointment can increase the pharmaceutical availability of water-insoluble nifedipine, providing better release due to increased solubility and dissolution rate of the drug. The consequence of this is a decrease in the dose and side effects of the drug on the body. When using emulsion and hydrophilic bases, the comfort of using ointments is increased.

Claims (2)

1. A method of obtaining an ointment of nifedipine, which consists in the fact that a mixture of nifedipine and polyethylene glycol with a molecular weight of 1500 ± 1000 in a ratio (% wt.): 1.00: 2.00-4.00 is dissolved in 95% ethyl alcohol in a mixture ratio and ethanol (% wt.); 1.00: 13.00-15.00 at a temperature of 25 ± 5 ° С, the resulting solution is introduced into a mixture of polyethylene glycol with a molecular weight of 400 (70.00 parts) and polyethylene glycol with a molecular weight of 1500 (molten at a temperature of 95 ± 5 ° С) 30.00 parts) with a ratio of solution: base (% wt.): 1.00: 5.00-11.00, the resulting ointment is thoroughly mixed and Packed in sealed packages. 2. A method of obtaining an ointment of nifedipine, which consists in the fact that a mixture of nifedipine and polyvinylpyrrolidone with a molecular weight of 10,000 ± 2,000 in the ratio (wt%): 1.00: 0.50-1.50 is dissolved in 95% ethyl alcohol at a mixture ratio and ethanol (% wt.): 1: 26.00-30.00 at a temperature of 25 ± 5 ° С, the resulting solution is introduced into anhydrous lanolin at a ratio of solution: anhydrous lanolin (% wt.): 1: 2.15-4 , 55, add medical petrolatum in the ratio of a mixture with lanolin: petroleum jelly (% wt.): 1: 1.05-1.25, the resulting ointment is thoroughly mixed and Packed in sealed packages.

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