CN116650397A - Colchicine cream and preparation method thereof - Google Patents

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and specifically provides a colchicine cream and a preparation method thereof, wherein the cream comprises liposomes and a cream matrix, and the liposomes are composed of phospholipids, cholesterol, antioxidants, preservatives and autumn Narcissine; the cream base contains oil phase, water phase, emulsifier, and penetration enhancer, and the colchicine cream obtained by the present invention overcomes the defects of existing colchicine oral preparations, improves curative effect, significantly reduces adverse drug reactions, and is effective Improvement of the safety of colchicine formulations.

Description

A kind of colchicine cream and preparation method thereof

technical field

The invention belongs to the technical field of medical cream preparations, and in particular relates to a preparation method of colchicine cream.

Background technique

Gout is a disease caused by a disorder of purine metabolism. The specific manifestation is increased uric acid, urate deposits in joints, connective tissues, kidneys, etc., and precipitates sodium urate crystals. Sodium urate crystals can cause granulocyte infiltration, and granulocytes phagocytize sodium urate to produce an inflammatory response. During the inflammatory process, the production of lactic acid increases, which reduces the local pH value, which in turn promotes the further deposition of uric acid, causing damage to these parts over time.

At present, there are not many kinds of anti-gout drugs. The main clinical treatments are colchicine, non-steroidal anti-inflammatory drugs, hormones, drugs that promote uric acid excretion (such as probenecid, sulfinpyrazone, and benzbromarone) and drugs that inhibit uric acid synthesis. (Allopurinol)-based.

As early as the 18th century, colchicine has been used to treat acute gout, because it can inhibit granulocyte infiltration and lactic acid production, play an anti-inflammatory and analgesic role, and has a specific effect on acute gouty arthritic arthritis. The symptoms of redness, swelling, pain and heat in the joints will disappear.

The chemical name of colchicine is N-[(7S)-1,2,3,10-tetramethoxy-9-oxo-6,7-dihydro-5H-benzo[a]heptene-7 -yl]acetamide, its molecular formula is: C ₂₂ H ₂₅ NO ₆ , its molecular weight is 399.437, and its structural formula is:

At present, colchicine is used for the acute attack of gouty arthritis and the traditional effective clinical first choice drug for preventing the acute attack of recurrent painful arthritis. However, colchicine has relatively large toxic and side effects, and its toxicity and dosage The size has obvious correlation, and oral administration is safer than intravenous injection, and toxicity is embodied in the following aspects: (1) Gastrointestinal symptoms: abdominal pain, diarrhea, vomiting and loss of appetite are common early adverse reactions, and the incidence rate can vary. Up to 80%, severe cases can cause dehydration and electrolyte imbalance and other performance. Severe hemorrhagic gastroenteritis or malabsorption syndrome may occur in long-term users; (2) Muscle and peripheral neuropathy: proximal muscle weakness and/or increased serum creatine phosphokinase. Peripheral nerve axonal polyneuropathy may occur when muscle cells are damaged, manifested as numbness, tingling and weakness; muscle neuropathy is rare, and it is often used for long-term prevention of gout and patients with mild renal insufficiency (3) thrombocytopenia, neutropenia, and even aplastic anemia, sometimes life-threatening; (4) shock: manifested as oliguria, hematuria, convulsions and disturbance of consciousness, high mortality rate, more common in the elderly .

Contents of the invention

The invention prepares a cream formulation containing colchicine, which can be directly used for lesions, and the medicine seldom enters the blood circulation, thereby reducing the serious toxic and side effects caused by using the common formulation. In addition, liposomes are biodegradable, non-toxic and non-irritating to the skin, making them ideal carriers for topical drug delivery to the skin.

In order to overcome the defects of the existing colchicine oral preparations, improve the curative effect, and reduce adverse reactions, the present invention optimizes the prescription according to the physical and chemical properties of colchicine, screens out more suitable auxiliary materials during the experiment, and makes the preparation process simpler. The raw material is less, and the transdermal absorption performance of the colchicine cream is improved. The present invention adopts liposome as carrier, and colchicine is encapsulated in liposome, can make medicine have greater skin permeability and stability, specifically adopt the following technical scheme:

A kind of colchicine emulsifiable agent, comprises colchicine liposome and cream base, wherein liposome comprises phospholipid, cholesterol, antioxidant, preservative and colchicine; Cream base comprises oil phase, water phase, Emulsifier, penetration aid.

Further preferably, the antioxidant is one or more of vitamin E, sodium thiosulfate, and sodium sulfite; the preservative includes benzalkonium bromide, chlorhexidine acetate, sodium benzoate, methyl p-hydroxybenzoate One or more of esters, ethyl p-hydroxybenzoate and propyl p-hydroxybenzoate.

Further preferably, the oil phase is one or more of stearic acid, triethylglyceride, liquid paraffin, white petrolatum, glyceryl monostearate and lanolin; the water phase is polyethylene glycol , glycerol, propylene glycol, glycerin or poloxamer; the emulsifier is polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate and Tween One or more; the penetration aid is one or more of cyclodextrin, menthol, methyl salicylate, azone, and N-methylpyrrolidone.

Further preferably, described colchicine liposome is in weight percentage, and prescription is as follows:

Further preferably, the cream base is calculated in weight percentage, and the prescription is as follows:

The invention also discloses a preparation method of colchicine cream, the specific preparation method is:

(2) Prepare liposomes by thin film-ultrasonic method;

(2) Mix the oil phase, water tank, emulsifier and penetration aid uniformly, heat up and emulsify to obtain a cream base;

(3) Add the liposome obtained in step (1) into the cream base obtained in step (2) at 50° C. to 70° C., stir, mix, and cool to obtain colchicine liposome cream.

Further preferably, the liposome is filtered through a 0.45 μm microporous membrane.

Further preferably, the liposomes are prepared by using a thin film dispersion method combined with an ultrasonic method.

The beneficial effects of the present invention are:

(1) The present invention adopts thin film dispersion method and ultrasonic method to prepare liposomes, and the excipients used are optimized, the preparation method is simple, and the production quality is stable.

(2) The dosage form obtained in the present invention has the advantages of stable drug efficacy, easy and uniform coating on the skin surface, good adhesion, non-irritating, easy to be absorbed by the skin, and convenient use.

(3) Compared with the existing preparation formulations, the colchicine cream overcomes the defects of the existing colchicine oral preparations, improves the curative effect, reduces adverse reactions, and effectively improves the safety of this variety of preparations.

Detailed ways

The present invention is further described below in conjunction with the examples, and the advantages and characteristics of the present invention are more fully shown. It is worth noting that the examples are only for the purpose of illustration, and do not limit the scope of the present invention. Various basic detail changes and modifications made on the basis of the present invention are also included within the protection scope of the present invention.

The adjuvant materials selected in the present invention all meet the requirements for medicinal use, wherein colchicine and other pharmaceutical adjuvant materials are all provided by Shandong New Times Pharmaceutical Co., Ltd.

Embodiment 1: colchicine cream

colchicine liposome

Raw materials prescription Colchicine 1.0g cholesterol 34g Phospholipids 50g Vitamin E 12g Ethyl p-hydroxybenzoate 3g

cream base

Raw materials prescription Stearic Acid and Glyceryl Monostearate 50g Propylene Glycol 42.5g polyoxyethylene castor oil 3g Azone 4.5g

Colchicine cream preparation method

(1) Adopt film-ultrasonic method to prepare colchicine liposome: take by weighing lecithin, cholesterol, colchicine, vitamin E and ethyl p-hydroxybenzoate of recipe quantity, add appropriate amount of ethanol, stir to make each composition dissolve and Mix evenly, put the solution in a pear-shaped bottle, and volatilize the solvent through a rotary evaporator under reduced pressure. The rotating speed of the rotary evaporator is 50, and the temperature is 40°C. Finally, a layer of uniform film is formed on the inner wall of the container, and the bottle is dried. Inner solvent, add 15ml phosphate buffer (pH5.0), hydrate to get a suspension, oscillate to transfer all the lipid film from the bottle wall into the water phase, fully swell the water, ultrasonic 10min, filter through 0.45 micron microporous Membrane filtration to obtain liposome solution.

(2) Add cyclodextrin, azone, and glycerin to preheated (preheating temperature: 70°C) stearic acid and glycerol monostearate, and stir evenly; after heating propylene glycol to about 60°C, add the above In the solution, stir while adding, continue to stir at a high speed, and after the emulsification is complete, the cream base is obtained.

(3) Add the liposome solution preferably prepared in step (1) to the cream base at about 60°C in step (2), stir while adding, mix well and then cool to obtain colchicine lipid body cream.

Embodiment 2: colchicine cream

colchicine liposome

Raw materials prescription Colchicine 0.03g cholesterol 15g Phospholipids 65g Vitamin E 15g Ethyl p-hydroxybenzoate 4g

cream base

Raw materials prescription Stearic Acid and Glyceryl Monostearate 60g Propylene Glycol 32g polyoxyethylene castor oil 2g Cyclodextrin 6g

Cream preparation method is the same as embodiment 1

Embodiment 3: colchicine cream

colchicine liposome

Raw materials prescription Colchicine 0.02g cholesterol 15g Phospholipids 65g Sodium thiosulfate 15g sodium benzoate 4g

cream base

Raw materials prescription Triethyl Glyceride 60g Poloxamer 32g Polyoxyethylene Hydrogenated Castor Oil 2g Methyl salicylate 6g

Cream preparation method is the same as embodiment 1

Comparative example 1: colchicine cream

colchicine liposome

cream base

Raw materials prescription Stearic Acid and Glyceryl Monostearate 50g Propylene Glycol 50g polyoxyethylene castor oil 3g Azone 4.5g

Colchicine cream preparation method

(1) Preparation of cream base by ethanol injection method: Weigh the prescribed amount of cholesterol, phospholipids, vitamin E and ethyl p-hydroxybenzoate and dissolve them in ethanol, ultrasonically oscillate for 5 minutes, fully stir and mix evenly; put the prescribed amount of colchicum Dissolve the alkali in water, slowly drop it into the above solution under stirring at room temperature, evaporate the ethanol under reduced pressure at 40°C, and pass the remaining suspension through a 0.45 micron microporous membrane to obtain a colchicine liposome solution. (2) Add cyclodextrin, azone, and glycerin to preheated (preheating temperature: 70°C) stearic acid and glycerol monostearate, and stir evenly; after heating propylene glycol to about 60°C, add the above In the solution, stir while adding, continue to stir at a high speed, and after the emulsification is complete, the cream base is obtained.

(3) Add the liposome solution preferably prepared in step (1) to the cream base at about 60°C in step (2), stir while adding, mix well and then cool to obtain colchicine lipid body cream.

Comparative example 2: colchicine cream

Colchicine cream preparation method

(1) Polyethylene glycol and liquid paraffin are heated to 60°C to melt;

(2) heating the purified water to 55 degrees Celsius, and adding phenoxyethanol to the heated purified water;

(3) Mix the solution of step (1) and step (2) under stirring, and fully stir;

(4) Colchicine is added to the mixed solution of step (3) under stirring, and sodium hydroxide is added to adjust the pH value to 5.0-5.8;

(5) filling to obtain colchicine emulsifiable paste.

Comparative example 3: colchicine cream

colchicine liposome

Raw materials prescription Colchicine 1.0g cholesterol 34g Phospholipids 50g p-phenylenediamine 12g Potassium sorbate 3g

cream base

Raw materials prescription silicone oil 50g Methanol 42.5g N-Dodecyldimethylamine 3g Ethoxydiglycol 4.5g

Concrete preparation method is with embodiment 1

The liposome solution that above-mentioned method is made carries out entrapment efficiency determination

(1) Preparation of the standard curve: Accurately weigh 20 mg of colchicine standard substance, add phosphate buffer (pH 5.0) to dissolve and dilute to 50 ml. Measure 1.0, 1.5, 2.0, 2.5, 3.0ml respectively in 5ml measuring flasks, dilute to the mark with phosphate buffer, measure absorbance at λ414nm with phosphate buffer as blank. The obtained regression equation is A=0.0019C+0.0014, r=0.9997 (n=6), and the measured colchicine is linear in the range of 120-200 μg/ml.

(2) The mensuration of sample encapsulation efficiency: precise measure 4ml liposome suspension, add methanol ultrasonic destruction, measure its absorbance, get W _total after calculating concentration conversion; Another precise measure 4ml liposome suspension is used Ultracentrifuge at 20,000rpm for 30min, take the supernatant to measure its absorbance, and calculate the concentration to get W _swimming . The encapsulation efficiency was calculated according to ER﹪=( _Wtotal - _Wtotal )/ _Wtotal ×100%, where _Wtotal and _Wtotal represented the amount of drug administered and the amount of free drug that was not encapsulated, respectively. Another appropriate amount of liposome suspension was taken for microscopic examination.

In order to improve the quality of the preparation, in the liposome preparation process, the thin film dispersion method and the ultrasonic method are used comprehensively to prepare liposomes. The obtained liposomes have uniform particle size, uniform dispersion, small particle size, and most of them are single chambers. High rate.

The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. within the discussion and principles of the present invention shall be included in the within the protection scope of the present invention.

Claims (8)

1. A colchicine cream characterized in that: the cream comprises colchicine liposome and cream matrix, wherein the liposome consists of phospholipid, cholesterol, antioxidant, preservative and colchicine; the cream matrix comprises an oil phase, a water phase, an emulsifying agent and a permeation assisting agent.

2. Colchicine cream according to claim 1, wherein the antioxidant is one or more of vitamin E, sodium thiosulfate and sodium sulfite; the preservative comprises one or more of benzalkonium bromide, chlorhexidine acetate, sodium benzoate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate and propyl parahydroxybenzoate.

3. Colchicine cream according to claim 1, wherein the oil phase is one or more of stearic acid, triethyl glycerol, liquid paraffin, white vaseline, glyceryl monostearate and lanolin; the water phase is one or more of polyethylene glycol, glycerol, propylene glycol, glycerin or poloxamer; the emulsifier is one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, sodium dodecyl sulfate and tween; the permeation assisting agent is one or more of cyclodextrin, menthol, methyl salicylate, azone and N-methyl pyrrolidone.

4. Colchicine cream according to claim 1, characterized in that the colchicine liposomes are formulated in weight percentages as follows:

5. colchicine cream according to claim 1, characterized in that: the cream base is prepared by the following formula in percentage by weight:

6. the preparation method of colchicine cream according to claim 1, characterized in that the preparation method comprises the specific steps of:

(1) Preparing liposome by adopting a film-ultrasonic method;

(2) Uniformly mixing the oil phase, the water tank, the emulsifying agent and the permeation assisting agent, and heating to emulsify to obtain a cream matrix;

(3) Adding the liposome obtained in the step (1) into the cream matrix obtained in the step (2) at 50-70 ℃, stirring, uniformly mixing and cooling to obtain colchicine liposome cream.

7. The method for preparing colchicine cream according to claim 6, wherein the thin film-ultrasonic method of step (1) specifically comprises the following steps: adding lecithin, cholesterol, colchicine, vitamin E and ethyl p-hydroxybenzoate into organic solvent, stirring, evaporating to remove solvent to obtain film, mixing film with phosphate buffer solution to obtain suspension, and ultrasonic treating and filtering to obtain liposome solution.

8. The method of claim 6, wherein the liposomes are filtered through a 0.45 μm microfiltration membrane.