CN1771918A - Granisetron cataplasm and its preparation method - Google Patents

Abstract

The present invention relates to medicine technology, and is Granisetron cataplasm as 5-HT3 receptor agonist in new form. Granisetron is applied clinically in preventing and treating nausea, vomiting, etc caused by cytotoxicity treatment, and available Granisetron preparation forms have some demerits. The present invention prepares Granisetron into cataplasm with the hydrochloride or free alkali of Granisetron as main medicine component and some supplementary materials. The Granisetron cataplasm with transdermal administration has no first pass effect, reduced and constant systemic blood medicine concentration, less side effect, raised compliance and other advantages.

Description

Granisetron cataplasm and its preparation method

Technical field:

The invention relates to the technical field of medicine, and relates to a new dosage form of Granisetron, a 5- _HT3 receptor antagonist, namely a cataplasm.

Background technique:

Granisetron is a potent, highly selective peripheral and central nervous system 5-HT ₃ receptor antagonist, used for the prevention and treatment of nausea and vomiting caused by cytotoxic therapy (anti-tumor chemotherapy and radiotherapy), and other Compared with traditional antiemetic drugs, it has the advantages of high efficiency, low toxicity, safety and reliability, and has been widely used in clinical practice. At present, the dosage forms of the drug include tablets, capsules, and injections, but the existing dosage forms are insufficient, and the injections are inconvenient to use, and professional help is required; oral administration has strong first-pass metabolism, and patients often suffer from gastric Intestinal reactions make it difficult to take the drug; cannot effectively maintain a stable blood drug level.

Invention content:

The invention provides a transdermal preparation of granisetron—cataplasma.

The transdermal drug delivery preparation can avoid the first-pass effect of oral administration to the liver, reduce the blood drug concentration of the whole body, reduce toxic and side effects, and maintain a constant effective blood drug concentration; moreover, it has the advantages of reducing the number of administrations, being convenient to use, and improving the patient's compliance Etc. Therefore, granisetron is designed as a transdermal drug delivery preparation, and through slow and continuous low-dose administration, it can not only maintain its good therapeutic effect, but also overcome the shortcomings of the previous dosage forms, and improve the convenience of drug use and patient compliance.

The granisetron cataplasm comprises three layers: a backing layer, a drug reservoir layer and an anti-adhesive layer. The drug storage layer consists of granisetron hydrochloride or its free base and a matrix. Its matrix is composed of skeleton material, cross-linking agent and moisturizing agent, and may also contain penetration enhancer, defoaming agent and cross-linking regulator. The skeleton material is selected from gelatin, sodium carboxymethylcellulose, polyvinylpyrrolidone, D-sorbitol, partially neutralized polyacrylic acid (NP-700, NP-600), kaolin or zinc oxide, and 1-6 of them can be selected at the same time a compound; the cross-linking agent is selected from one of Ca(OH) ₂ , Al(OH) ₃ , CaCl ₂ , and AlCl ₃ ; the humectant is propylene glycol and glycerin; the penetration enhancer is selected from dimethyl sulfoxide, azone , oleic acid, N-methylpyrrolidone, sodium lauryl sulfate, salicylic acid, menthol, camphor, limonene, myristate isopropyl, water-soluble azone, 1-6 of which can be selected at the same time , preferably azone; defoaming agent is selected from one of ethanol, isopropanol, n-butanol, amyl alcohol, n-octanol, oleic acid, polyethylene glycol, tributyl phosphate, polypropylene glycol; cross-linking regulation The agent is citric acid. The preferred components and proportions are: 0.2-1 parts of granisetron hydrochloride, 1-2 parts of gelatin, 2-4 parts of sodium carboxymethylcellulose, 4-6 parts of polyvinylpyrrolidone, 32-40 parts of D-sorbitol , 1-2 parts of partially neutralized polyacrylic acid (NP-700), 1-2 parts of kaolin or zinc oxide, 0.12-0.36 parts of Ca(OH) ₂ , Al(OH) ₃ , CaCl ₂ or AlCl ₃ , 2- 10 parts, 8-18 parts of propylene glycol, 60 parts of distilled water; the consumption of penetration enhancer is 0.5-10% of drug storage layer; the consumption of defoamer is 0-2% of drug storage layer; The dosage is 0-1% of the drug storage layer.

The preparation method of cataplasm of the present invention is:

1. Prepare (I) phase solution: add water to fully swell the gelatin according to the above ratio, mix granisetron hydrochloride or its free base and D-sorbitol evenly, add it to the gelatin, and stir fully to obtain (I) phase solution;

2. Prepare (II) phase solution: mix sodium carboxymethylcellulose, polyvinylpyrrolidone, partially neutralized polyacrylic acid (NP-700), humectant, penetration enhancer, kaolin or zinc oxide and crosslinking regulator evenly , to obtain (II) phase solution;

3. Mix (I) and (II) phase solutions, add a specified amount of cross-linking agent, stir evenly, spread it on a non-woven fabric, bake it at 50°C for an appropriate time, cover it with an anti-adhesive film, and cut it into a specified size of cloth agent, sealed packaging.

In the present invention, granisetron is made into a cataplasm and administered through a transdermal route, which can not only avoid the gastrointestinal stimulation of oral administration and the first-pass effect of the liver, but also reduce the blood concentration of the whole body, reduce toxic and side effects, and maintain Constant and effective blood drug concentration, and the dosage can be controlled through the adjustment of the administration area, and the administration can also be interrupted at any time. It is convenient to use, reduces the number of administrations, and improves the patient's compliance with medication. It is the clinical application of granisetron. A new dosage form is provided.

Detailed ways:

Embodiment 1 preparation-granisetron cataplasm

Components and ratio: Gelatin Carboxymethylcellulose Sodium Polyvinylpyrrolidone D-Sorbitol 2g4g6g38g NP-700Ca(OH) ₂ Propylene Glycol Kaolin 2g0.3g20g2g Distilled Water Glycerin Polyethylene Glycol-200 60g8g1g Azone Hydrochloride Granisetron 8g0.6g

The preparation method is:

1. Prepare (I) phase solution: add water to fully swell the gelatin according to the above ratio, dissolve it in a water bath at 60°C, mix D-sorbitol and granisetron hydrochloride evenly, add it to the gelatin, and stir thoroughly to obtain phase (I) solution.

2. Prepare (II) phase solution: dissolve azone in propylene glycol, mix well with sodium carboxymethylcellulose, polyvinylpyrrolidone, partially neutralized polyacrylic acid (NP-700), and kaolin to obtain phase (II) solution.

3. Mix (I) and (II) phase solutions, add glycerin, polyethylene glycol-200 (PEG-200), Ca(OH) ₂ , stir well, spread on non-woven fabric, bake at 50°C for 90 minutes , covered with an anti-adhesive film, cut into cataplasms of 4×5cm ² , and sealed and packaged to obtain the finished cataplasm, with a drug content of 10 mg per patch.

Embodiment 2 prepares granisetron cataplasm

Components and ratio: Gelatin Carmellose Sodium Polyvinylpyrrolidone D-Sorbitol Distilled Water Glycerin Isopropanol 2g4g4g32g60g10g1g NP-700Al(OH) ₃ Propylene Glycol Zinc Oxide Camphor Citric Acid (20%) Granisetron Hydrochloride 0.2g0.18g20g4g6g0.4ml0.6g

The preparation method is:

1, prepare (I) phase solution (same as embodiment 1).

2. Prepare (II) phase solution: dissolve camphor in propylene glycol, mix well with sodium carboxymethylcellulose, polyvinylpyrrolidone, partially neutralized polyacrylic acid (NP-700), zinc oxide, and citric acid to obtain (II) ) phase solution.

3. Mix (I) and (II) phase solutions, add glycerin, isopropanol, Al(OH) ₃ , stir well, spread on non-woven fabric, bake at 50°C for 60 minutes, cover with anti-adhesive film, cut into 4 × 5cm ² cataplasms, the finished cataplasms are obtained, sealed and stored, with a drug content of 10 mg per patch.

Embodiment 3 prepares granisetron cataplasm

Formula and ratio: Gelatin Sodium Carboxymethyl Cellulose Polyvinyl Pyrrolidone D-Sorbitol Distilled Water Glycerin Oleic Acid 2g3g6g36g60g10g0.5g NP-700AlCl ₃ Propylene Glycol Kaolin Azone Citrate (20%) Granisetron Free Base 0.6g0.2g20g6g8g0.4ml0.6g

The preparation method is:

1, preparation (I) phase solution: (same as embodiment 1).

2. Preparation of the (II) phase solution: uniformly mix azone, propylene glycol, sodium carboxymethylcellulose, polyvinylpyrrolidone, NP-700, kaolin, and citric acid to obtain the (II) phase solution.

3. Mix (I) and (II) phase solutions, add glycerin, oleic acid, AlCl ₃ , stir well, spread on non-woven fabric, bake at 50°C for 30 minutes, cover with anti-adhesive film, cut into 4×5cm ² The cataplasm of the obtained cataplasm is the finished cataplasm, which is sealed and preserved, and the drug content of each patch is 10 mg.

Using the modified Franz diffusion cell, the granisetron cataplasm prepared in Example 1 was subjected to an in vitro transdermal absorption test. The results of the in vitro transdermal absorption test conformed to a zero-order kinetic process, and the penetration rate was 13.909 μg cm ^-2 ·h ^-1 , 24h cumulative skin penetration is 55.08%, see Table 1. Preliminary clinical observations were made on cancer patients with severe nausea and vomiting symptoms during chemotherapy and radiotherapy. Catapults can be pasted on the arms, legs, chest or abdomen of the patients, once every two days, and the results show that more than 85% The nausea of the patients was significantly reduced, and the vomiting symptoms were controlled or eliminated. There were no allergic manifestations such as redness, swelling and itching.

Table 1 The penetration situation of granisetron cataplasm through the abdominal skin of rats time (h) Cumulative permeation per unit area (μg.cm ^-2 ) Cumulative transmittance% 12468121624 1.27±0.344.44±1.1516.24±11.7734.91±13.02656.78±17.73105.56±27.66177.39±63.41320.55±112.77 0.220.762.796.009.7618.1430.4855.08

Claims (9)

1. A granisetron cataplasm, comprising a backing layer, a drug storage layer and an anti-adhesive layer, characterized in that the drug storage layer is composed of drug granisetron hydrochloride or its free base and a matrix, and the matrix is composed of a skeleton material , cross-linking agent, moisturizing agent, the skeleton material is selected from gelatin, sodium carboxymethyl cellulose, polyvinylpyrrolidone, D-sorbitol, partially neutralized polyacrylic acid NP-700 or NP-600, kaolin or zinc oxide, can be At the same time, 1-6 kinds of compounds are selected; the crosslinking agent is selected from one of Ca(OH) ₂ , Al(OH) ₃ , CaCl ₂ , and AlCl ₃ ; the moisturizing agent is propylene glycol and glycerin; the ratio of each component It is: 0.2-1 part of drug, 40-60 parts of skeleton material, 0.1-0.4 part of cross-linking agent, 10-20 parts of moisturizing agent and 60 parts of distilled water. 2. The granisetron cataplasm according to claim 1, characterized in that the components and proportions of the drug storage layer are: 1-2 parts of gelatin, 2-4 parts of sodium carboxymethylcellulose, polyethylene 4-6 parts of pyrrolidone, 19-40 parts of D-sorbitol, 1-2 parts of partially neutralized polyacrylic acid NP-700 or NP-600, 1-2 parts of kaolin or zinc oxide, Ca(OH) ₂ , Al(OH) _3. 0.12-0.36 parts of CaCl ₂ or AlCl ₃ , 2-10 parts of glycerin, 8-18 parts of propylene glycol, 60 parts of distilled water, 0.2-1 part of granisetron hydrochloride or its free base. 3. The granisetron cataplasm according to claim 1 or 2, characterized in that the matrix also contains a penetration enhancer, and the penetration enhancer is selected from dimethyl sulfoxide, azone, oleic acid, N-methyl Pyrrolidones, sodium lauryl sulfate, salicylic acid, menthol, camphor, limonene, isopropyl myristate, and water-soluble azone, 1-6 of which can be selected at the same time, and the dosage is 0.5 of the drug reservoir layer. -10%. 4. The granisetron cataplasm as claimed in claim 1 or 2, characterized in that the matrix also contains a defoamer, and the defoamer is selected from ethanol, isopropanol, n-butanol, pentanol, n-octanol , oleic acid, polyethylene glycol, tributyl phosphate, polypropylene glycol, the dosage is 0-2% of the drug reservoir layer. 5. The granisetron cataplasm as claimed in claim 3, characterized in that the matrix also contains a defoamer, and the defoamer is selected from ethanol, isopropanol, n-butanol, amyl alcohol, n-octanol, oil One of acid, polyethylene glycol, tributyl phosphate, polypropylene glycol, the dosage is 0-2% of the drug storage layer. 6. The granisetron cataplasm according to claim 1, 2 or 5, characterized in that the matrix also contains citric acid, a cross-linking regulator, and the dosage is 0-1% of the drug storage layer. 7. The granisetron cataplasm as claimed in claim 3, characterized in that the matrix also contains citric acid, a cross-linking regulator, and the dosage is 0-1% of the drug storage layer. 8. The granisetron cataplasm as claimed in claim 4, characterized in that the matrix also contains citric acid, a cross-linking regulator, and the dosage is 0-1% of the drug storage layer. 9. The granisetron cataplasm as claimed in claim 6, characterized in that the components and proportioning ratio are as follows: Gelatin 2g NP-700 2g Sodium carboxymethylcellulose 4g Ca(OH) ₂ 0.3g Polyvinylpyrrolidone 6g Propylene glycol 20g D-Sorbitol 38g Kaolin 2g Distilled water 60g Azone 8g Glycerin 8g Granisetron Hydrochloride 0.6g Polyethylene Glycol-200 1g.