CN113041210B - Colchicine external composition - Google Patents
Colchicine external composition Download PDFInfo
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- CN113041210B CN113041210B CN202110288326.9A CN202110288326A CN113041210B CN 113041210 B CN113041210 B CN 113041210B CN 202110288326 A CN202110288326 A CN 202110288326A CN 113041210 B CN113041210 B CN 113041210B
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Abstract
A colchicine composition for external use at least comprises colchicine and permeation promoter, wherein the permeation promoter is one or more of cyclodextrin, azone, oleum Menthae Dementholatum and Mentholum, and colchicine is 0.01-1.0w/v% of the whole composition for external use. The invention changes the administration route of colchicine to form a novel colchicine drug form, so that the colchicine can be put into clinical use in a novel drug form.
Description
The application is a divisional application with the application number of 2016109824148, the application date of 2016, 11 and 8, the application type of the colchicine external composition and the preparation method thereof.
Technical Field
The invention belongs to the field of medicines, in particular to the field of medicines for treating gouty arthritis. In particular, the present invention relates to colchicine external compositions for preventing or treating gouty arthritis, and a method for preparing the same.
Background
Gout is a disease caused by in vivo purine metabolic disorder, and is mainly expressed as hyperuricemia, and the crystallization of the uric acid salt in joints, kidneys and connective tissues can cause local inflammation of joints and granulocyte infiltration, resulting in gout attack. The incidence of gout worldwide increases year by year. In China, the incidence rate of the Chinese medicinal composition is increased year by year, the incidence age shows a trend of low age, and a huge burden is brought to society. According to statistics, the potential incidence of gout in China is hundreds of millions, and about 3500 tens of thousands of people are diagnosed.
Currently, drugs for treating gout clinically according to modes of action can be divided into five categories: 1. drugs that inhibit granulocyte infiltration, such as colchicine; 2. analgesic and anti-inflammatory agents, such as indomethacin, phenylbutazone, diclofenac, naproxen, sulindac, ibuprofen, and the like; 3. corticotropin or glucocorticoids, such As Corticotropin (ACTH) or prednisone; 4. uric acid excretion promoting agents such as probenecid, buprofezin, tribromouron, etc.; 5. inhibiting uric acid production, such as allopurinol.
Gout is characterized by hyperuricemia and characteristic acute arthritis, and repeated attacks can cause tophus deposition and gouty nephropathy. Acute gouty arthritis is the first symptom of gout, and most of the acute gouts are mainly manifested by red, swelling, fever, severe pain of tissues around joints, fever and plasma leukocytosis. Colchicine can be combined with microtubulin of granulocytes, so that granulocyte activity is prevented, granulocyte infiltration is inhibited, inflammatory reaction caused by leucocytes in the process of degerming movement is disturbed, and the colchicine has a specific effect on acute gouty arthritis. Colchicine is the traditional and effective clinical first choice for the prevention of acute attacks of gouty arthritis, but the main toxic and side effects of colchicine are summarized as follows: 1. adverse reactions have obvious correlation with dosage size, and the oral administration has higher safety than intravenous injection. Early adverse reactions such as abdominal pain, diarrhea, emesis and inappetence can reach 80%, and serious patients can cause dehydration, electrolyte disturbance and other manifestations. Severe hemorrhagic gastroenteritis or malabsorption syndrome can be seen after long-term administration; the adverse effects of nervous system are muscle and peripheral neuropathy including proximal muscle weakness and/or increased serum creatine kinase, and peripheral axonal polyneuropathy can appear when muscle cells are damaged, manifested as numbness, tingling and weakness. Myoneuropathy is rare, often in patients with gout prophylaxis and long-term administration and in patients with mild renal insufficiency; thrombocytopenia, drop of neutrophils, even aplastic anemia, are common to intravenous drug users and sometimes fatal risks; oliguria, hematuria, convulsion and disturbance of consciousness are frequently seen in intravenous medication and the elderly, and the mortality rate is high; other adverse reactions were phlebitis, rash, hair loss and fever. 2. Because the knowledge of the efficacy and risk of colchicine in treating wind pain and the knowledge of its toxicity severity are inconsistent, care must be taken in selecting the drug. Intravenous injection and long-term oral administration are avoided as much as possible, and intravenous and oral routes are forbidden to be used together. 3. It is forbidden for patients with low myeloproliferation, liver and kidney dysfunction, pregnant women and children under 2 years old. 4. It should be used with cautions for the elderly and those with potential impairment of liver and kidney functions. 5. Blood routine and liver and kidney function must be periodically checked. 6. The composition can cause reversible malabsorption of vitamin B12. 7. The composition can increase the efficiency of CNS inhibitor and strengthen the reactivity of sympathomimetic agent. 8. The medicine is not suitable for preventing the onset of gouty arthritis for a long time. 9. Intravenous injection is limited to fasted patients, such as gout attacks after surgery. 10. The patients with serious adverse reactions need to stop taking medicine immediately, and rescue is carried out on the symptoms.
In view of the above-mentioned toxic side effects of the medicine, its clinical application is greatly limited. In order to overcome or reduce the toxic and side effects caused by oral administration of colchicine, pharmaceutical companies have put into great effort for many years in developing and researching new dosage forms of colchicine. Yin Wei (colchicine patch for treating acute gouty arthritis, chinese J.New medicine and clinical journal, 2001, 20 (5): 373-374) for treating acute episode of gouty arthritis), the results show that the local inflammation is obviously improved and the joint edema is obviously improved; chen Qiugong et al (influence of different matrices and transdermal promoters on the external transdermal properties of colchicine gel, journal of Hua Western medicine, 2005, 20 (6): 521-523) prepared colchicine gel, studied the influence of different matrices and transdermal promoters on colchicine transdermal absorption; cao Maotang (preparation of Compound colchicine gel and clinical observations, journal of Chinese Hospital pharmacy, 2007, 27 (10): 1445-1447) and observations of its clinical effects. At present, only colchicine patches are approved to enter clinical researches and are approved to be produced, but no external preparation is marketed until now, and the clinical curative effect is still not exactly related to the low percutaneous permeability of the medicine of the external preparation. Liu Xia et al (colchicine liposome gel for anti-inflammatory effect on gout model animals, guangdong medical science, 2011, 32 (23): 3038-3040) prepared colchicine liposome gel for anti-inflammatory effect on gout model animals was observed.
The results of the above-mentioned literature studies reveal that colchicine changes the route of administration and percutaneous absorption can become a new break in the study of new dosage forms of the drug, but these studies have not yet been commercially available to serve a wide range of patients.
Disclosure of Invention
The medicine must be made into proper dosage form for clinical use. If the dosage form is improperly selected, the prescription process is unreasonably designed, so that the physicochemical properties (such as appearance, dissolution rate and stability) of the product are affected, and the clinical curative effect can be reduced and the drug toxicity can be increased. Thus, a suitable dosage form is selected; a reasonable prescription process is designed; the quality of the product is improved, and the method plays a very important role in the research and development of new drugs.
The invention successfully develops a novel dosage form of colchicine based on the research of the prior art, and a percutaneous absorption colchicine external composition, in particular to colchicine liniment.
In a first aspect, the present invention provides a colchicine topical composition comprising or consisting of: colchicine, a solvent, a cosolvent, optionally a permeation enhancer, and optionally an emulsifier.
In a preferred embodiment of the invention, the vehicle is one or more of glyceryl triacetate, ethyl acetate, isopropyl alcohol, polyethylene glycol, glyceryl monoacetate, glyceryl diacetate, glyceryl triacetate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol, polyoxyethylated castor oil, benzyl acetate, diacetyl monoglyceride, diacetyl (mono-, di) glycerol, glyceryl diacetate, triethanolamine oleate, triglyceryl caprylate, triglyceryl caprate, benzyl butyrate and simethicone, preferably glyceryl triacetate or polyethylene glycol, preferably polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, polyethylene glycol-900, polyethylene glycol-1000, polyethylene glycol-1450, polyethylene glycol-3350, polyethylene glycol-4000, polyethylene glycol-4500, polyethylene glycol-6000 or polyethylene glycol-8000.
In another preferred embodiment of the invention, the co-solvent is a polyol, preferably ethylene glycol, propylene glycol or glycerol, more preferably 1, 2-propanediol.
In another preferred embodiment of the invention, the permeation enhancer is selected from one or more of cyclodextrin, azone, peppermint oil and menthol, preferably cyclodextrin and/or azone, preferably beta-cyclodextrin, alpha-cyclodextrin, gamma-cyclodextrin, hydroxy-beta-cyclodextrin (HP-beta-CD), dimethyl-beta-cyclodextrin, trimethyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin or maltotriosyl-beta-cyclodextrin.
In another preferred embodiment of the present invention, the emulsifier is selected from one or more of polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil and tween, preferably polyoxyethylated (40) castor oil, polyoxyethylated (35) castor oil, polyoxyethylated (60) castor oil, polyoxyethylated (80) castor oil, polyoxyethylated (90) castor oil, polyoxyethylated (100) castor oil, polyoxyethylated (40) hydrogenated castor oil, polyoxyethylated (30) hydrogenated castor oil, polyoxyethylated (50) hydrogenated castor oil, polyoxyethylated (60) hydrogenated castor oil, tween-20, tween-40, tween-60 or tween-80.
In another preferred embodiment of the present invention, the colchicine topical composition consists of colchicine, glyceryl triacetate, 1, 2-propanediol, hydroxypropyl- β -cyclodextrin and azone;
consists of colchicine, polyethylene glycol, 1, 2-propylene glycol, glycerol, beta-cyclodextrin and azone;
consists of colchicine, polyethylene glycol, 1, 2-propylene glycol, glycerol, dimethyl-beta-cyclodextrin and tween; or colchicine, glyceryl triacetate, polyethylene glycol, 1, 2-propylene glycol and polyoxyethylated castor oil.
In another preferred embodiment of the invention, colchicine is 0.01-1.0w/v%, more preferably 0.2w/v% of the total topical composition.
In another preferred embodiment of the present invention, the colchicine topical composition consists of the following components:
in another preferred embodiment of the present invention, the colchicine topical composition is a transdermal absorption composition, which is applied transdermally in the form of a dissolving agent, spray or liniment, preferably in the form of a liniment.
The term "dissolution agent" refers to a liquid formulation of a drug dissolved in a suitable solvent. Is suitable for oral administration or external use.
The term "aerosol" refers to a dosage form that is powered by compressed air or inert gas to spray a liquid formulation with a nonmetallic atomizer.
The term "liniment" refers to a liquid preparation for skin rubbing, as a solution, emulsion or suspension of the drug in a suitable solvent.
In a second aspect, the present invention provides a method of preparing a colchicine topical composition, comprising: adding colchicine into cosolvent, optional permeation promoter, optional emulsifier and small amount (or right amount) of solvent to dissolve colchicine completely, and adding the rest solvent to obtain colchicine topical composition.
In particular, the preparation method comprises the following steps: colchicine is added into 1, 2-propylene glycol, hydroxypropyl-beta-cyclodextrin, azone and a small amount of triacetin to dissolve colchicine completely, and then the rest of triacetin is added to obtain colchicine external composition.
The invention has the outstanding characteristics that colchicine is quickly absorbed through skin, the onset of gout arthritis in the onset period is controlled, and the systemic toxic and side effects after the original oral administration of the medicine hardly occur.
The colchicine composition for external use, especially colchicine liniment, is true solution, consists of permeation assisting system of composite solvent, is recipe optimized based on great amount of pharmacological research, has no irritation and allergy to skin and simple production process, and is suitable for industrial production. The product has stable property and controllable quality, is coated on the surface of inflammation when being used by patients, has good absorption, quick response, quick pain relief of the patients, almost no systemic toxic or side effect, convenient use for the patients, and can be used for treating acute stage attacks of gouty arthritis of gout patients and also for preventing long-term maintenance drugs of gout attacks.
Drawings
FIG. 1 is a process flow diagram of a process for preparing colchicine liniment.
Detailed Description
The invention discloses a colchicine external composition, in particular colchicine liniment, which is subjected to prescription screening and preparation process research. According to the selected prescription and preparation process, colchicine liniments of a plurality of batches are respectively prepared for quality standard research, stability research, animal irritation and sensitization research and gout treatment/prevention research.
The present invention will be described in detail below with reference to examples and drawings, but the examples should not be construed as limiting the scope of the present invention.
EXAMPLE one prescription study of colchicine Liniment
1 instrument and reagents
1.1 instruments
The Agilont1260 type high performance liquid chromatograph (Agilent corporation) comprises a G131K quaternary gradient pump, a G13298 injector, a G1316A column incubator, a G1315DDAD detector, and a workstation: chemstationforLC3 ds. VV-1800 ultraviolet visible spectrophotometer (Shimadzu); KS-2500 ultrasound apparatus (Ningbokesen instruments); pH211A acidometer (HANNA, italy); BP211D one ten thousandth, a precision electronic balance (Sartorius germany); ZORBAXC18 column (150 mm. Times.4.60 mm,5 μm, agilent Co.); YB-3 clarity detector (Tianjin university precision instruments factory); DHG-9140A electrothermal constant temperature blast drying oven (Shanghai-Hengzhi Co., ltd.); SDC-II type high purity water apparatus (institute of sanitary equipment at the military medical academy of sciences); SHZ-D (III) circulating water vacuum pump (Yingyu to Hua instrument works). HWS-1.50 hygrothermograph (Ningbo Haishufu laboratory).
1.2 pharmaceutical products and reagents
Glyceryl triacetate (lot number: 141217, beijing Xingjin chemical Co.); 1, 2-propanediol (lot number: 060312, beijing chemical company, analytical grade); azone (pharmaceutical, beijing North Rily Site Biochemical Co., ltd.); hydroxypropyl-beta-cyclodextrin (HP-beta-CD), dimethyl-beta-cyclodextrin, beta-cyclodextrin (shanxi spring chemical industry limited); colchicine (lot number: 141102409008; kunming pharmaceutical Co., ltd.); tween-80 (lot number: 150108; tianjin, meta. Chemical Co., ltd.); polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600 (national pharmaceutical group chemical agent Co., ltd.).
2 methods and results
2.1 basis for dosage form selection
The selected dosage form of the invention is a liniment, which is a traditional dosage form, has simple preparation process, is convenient for industrial production and convenient for use, and can be self-administered by patients. The liniment is a solution, emulsion or suspension prepared from the medicine and a solvent, and is externally applied to the skin. The liniment of the invention is a homogeneous liquid preparation for external use. Colchicine is used for the topical treatment of gouty arthritis by transdermal administration. Therefore, the control of the concentration of the drug absorbed through the skin is key to the invention, the drug can cause toxic and side effects after being absorbed by the whole body with high concentration, and the concentration is low enough to effectively treat the gouty arthritis, so the design of the administration dosage is important.
2.2 determination of primary dose
At present, the effective concentration of colchicine is in the range of 0.01% -1.0%, and the specification of the colchicine film for external use is 0.2% according to the literature report. The invention is based on the specification, and the optimal dosage is selected as the concentration of 0.2 percent, so as to optimize the prescription and the process.
2.3 prescription screening of colchicine liniments
In order to obtain the optimal colchicine liniment prescription, the invention respectively screens and optimizes the prescription and the process from the aspects of the prescription solvent, the cosolvent, the permeation aid, the emulsifier and the like, and establishes the optimal prescription and the preparation process.
2.3.1 selection of menstruum
The choice of vehicle is critical to the invention. The solvent is selected according to the following principle: has no irritation to skin; the solubility of the main medicine is good; the physical and chemical properties are stable, and the compatibility taboo with the main medicine does not occur; and does not interfere with the determination of the principal drug; meets the medicinal standard. The drug is screened by taking the solubility and the stability of the drug as indexes. The invention mainly aims at solving the problem of solubility of the main medicine, and selects the dissolvent with stable performance as an index.
According to the physicochemical properties of colchicine, it is dissolved in water to form a hydrate, which may affect transdermal absorption, thus water is not selected as a solvent. And selecting a composite permeation-assisting solvent system of an organic solvent. And then the stability of colchicine is improved by adding other suitable stabilizers.
The solvent used in the present invention is selected from one or more of glyceryl triacetate, ethyl acetate, isopropyl alcohol, polyethylene glycol, glyceryl monoacetate, glyceryl diacetate, glyceryl triacetate, glyceryl monooleate, glyceryl dioleate, glyceryl trioleate, propylene glycol ester, polyoxyethylene castor oil, benzyl acetate, diacetyl monoglyceride, diacetyl tartaric acid (mono-, di) glycerol, glyceryl diacetate, triethanolamine oleate, glyceryl caprylate, glyceryl trinitrate, benzyl butyrate and simethicone, preferably glyceryl triacetate or polyethylene glycol, preferably polyethylene glycol-200, polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600, polyethylene glycol-900, polyethylene glycol-1000, polyethylene glycol-1450, polyethylene glycol-3350, polyethylene glycol-4000, polyethylene glycol-4500, polyethylene glycol-6000 or polyethylene glycol-8000.
Most preferably, the glyceryl triacetate is used as a main solvent for dissolving the medicament, and the glyceryl triacetate also has a certain antibacterial effect when being used locally. Is nontoxic, non-irritating to the skin, and is generally considered safe (FDA 1985). Based on this as the base solvent, the prescription is screened.
2.3.2 selection of cosolvent
The cosolvent used in the present invention is a polyhydric alcohol, preferably ethylene glycol, propylene glycol or glycerin, more preferably 1, 2-propylene glycol.
The 1, 2-Propylene Glycol (PG) is colorless clear viscous liquid, has stable property, is similar to glycerol but has low viscosity, and has effects of moisturizing, moistening and prolonging drug effect on skin. Can be mixed with glyceryl triacetate in any proportion, can dissolve a plurality of organic medicines, has the functions of dissolving medicines and uniformly mixing the components, and is therefore commonly used as a solvent, a solubilizer, a humectant, a preservative and the like. When 1, 2-propylene glycol is used as an accelerator alone in the preparation, the 1, 2-propylene glycol can permeate into the stratum corneum and form accumulation therein, so that the solubility and the partition property of the medicine in the stratum corneum are improved, and the curative effect of colchicine is better exerted.
2.3.3 selection of permeation aid
The permeation aid used in the present invention is selected from one or more of cyclodextrin, azone, peppermint oil and menthol, preferably cyclodextrin and/or azone, more preferably hydroxypropyl-beta-cyclodextrin and/or azone.
Hydroxypropyl-beta-cyclodextrin (HP-beta-CD): average molecular weight m=1384, solubility in water being greater than 50g/100ml at room temperature. HP-beta-CD can form inclusion complexes with drugs, increase solubility, and can deliver drug molecules to the skin surface. Has weak effect alone, and is often combined with fatty acid and propylene glycol. The purpose of the combination with 1, 2-propanediol is to enhance the effect of this application.
Azone (also known as laurocapram, azelastone), a nonpolar transdermal absorption enhancer, softens the stratum corneum of the skin, enhances permeability, allows the drug to penetrate the skin barrier, and increases local concentration, and is widely used in formulations as a permeation enhancer for transdermal absorption.
2.3.4 selection of emulsifiers
The emulsifier used in the present invention is selected from one or more of polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil and tween, preferably polyoxyethylated (40) castor oil, polyoxyethylated (35) castor oil, polyoxyethylated (60) castor oil, polyoxyethylated (80) castor oil, polyoxyethylated (90) castor oil, polyoxyethylated (100) castor oil, polyoxyethylated (40) hydrogenated castor oil, polyoxyethylated (30) hydrogenated castor oil, polyoxyethylated (50) hydrogenated castor oil, polyoxyethylated (60) hydrogenated castor oil, tween-20, tween-40, tween-60 or tween-80.
2.3.5 screening procedure of prescriptions
Considering the properties of the main drugs and combining the properties and the dosage of the above selected auxiliary materials, 6 prescription compositions are designed in total, and are shown in Table 1-1. Based on this, the solubility and stability of the main drug were examined, and formulation screening was performed.
Table 1-1 prescription composition
Note that: PG represents 1-2 propylene glycol, A represents glyceryl triacetate
2.3.5.1 screening prescriptions with solubility as an index
6 formulation solutions were prepared in 6 10ml volumetric flasks according to the prescription composition listed in Table 1-1. Respectively filling into ampoule, sealing, placing in baking oven at 40deg.C for 2 days, taking out, standing at-20deg.C for 2 days, repeating for 3 times, taking out for 6 days, cooling to room temperature, filtering, diluting by several times, and measuring content. The results are shown in tables 1-2.
TABLE 1-2 solubility results
As can be seen from tables 1-2, 6 prescriptions were clear solutions at room temperature and all frozen after standing at-20℃and allowed to re-dissolve to colorless clear solutions in room temperature environment.
2.3.5.2 screening prescriptions with stability as an index
Stability is an important aspect for evaluating the quality of medicines, is also an important basis for screening success or failure of prescriptions, and relates to selection of medicine storage conditions, establishment of effective period and the like.
Samples were prepared according to the respective formulations of Table 1-1, and the samples were placed under conditions of 60℃at an illuminance of 4500.+ -. 500Lux and a humidity of RH95% for 10 days, and sampled and tested on day 0, day 5 and day 10, respectively. The results are shown in tables 1-3.
Tables 1-3 determination of the content under different conditions
As can be seen from the data in tables 1-3, each formulation is less stable at high temperature, both high humidity and high light, and the addition of HP-beta-CD results in an increase in the stability of the formulation; with the increase of the dosage of the glyceryl triacetate in the prescription, the stability of the prescription is slightly improved.
Tables 1 to 4 determination of impurity content under different conditions
As can be seen from the data in tables 1-4, the amounts of impurities in the formulations 4, 5, 6 were significantly less than those in formulations 1, 2, 3 at high temperatures, with little change in the impurities in each formulation under the remaining conditions. According to the new medicine batch rule, the main content of the preparation is 95.0% -105.0%, and the impurity is not more than 2 times of the raw material medicine, so that the preparation which meets the requirements of both the preparation and the raw material medicine is selected. Prescription 4 is selected.
2.4 preparation Process
Adding colchicine into cosolvent, optional permeation promoter, optional emulsifier and small amount of solvent according to the prescription amount, completely dissolving colchicine, and adding the rest solvent to obtain colchicine topical composition.
Preferably, the colchicine bulk drug with the prescription amount is weighed, propylene glycol, azone, HP-beta-CD and a proper amount of glyceryl triacetate with the prescription amount are respectively added to dissolve, and finally the glyceryl triacetate is added to the volume to 1000ml, stirred evenly, filtered and split-packed in a 5ml bottle, capped and stored in a shade place. Each of the medicine has a specification of 3ml and contains colchicine as a main medicine of 0.2w/v%. See fig. 1.
2.5 prescription and determination of Process
The prescription composition of colchicine liniment is determined through the prescription screening:
2.5.1 prescription i:
| component (A) | Dosage of |
| Colchicine | 2g |
| HP-β-CD | 25g |
| 1, 2-propanediol | 200ml |
| Azone | 20ml |
| Glyceryl triacetate | The total amount is up to 1000ml |
According to the prescription composition, the colchicine bulk drug with the prescription amount is weighed, propylene glycol, azone, HP-beta-CD and a proper amount of glyceryl triacetate with the prescription amount are respectively added, the mixture is dissolved in water bath with the temperature of 50 ℃, and finally the glyceryl triacetate is added to the volume of 1000ml.
2.5.2 prescription ii:
weighing colchicine and beta-cyclodextrin with prescription amount, adding into a compound solvent of glycerin, 1, 2-propylene glycol and azone, shaking to dissolve, and adding polyethylene glycol-400-1000 ml scale.
2.5.3 prescription iii:
weighing colchicine and dimethyl-beta-cyclodextrin with the prescription amount, adding into a mixed solution of glycerol, 1, 2-propylene glycol, polyethylene glycol-400 and Tween 80, shaking to dissolve, and adding ethanol-300 to 1000ml.
2.5.4 prescription iv:
weighing colchicine and polyethylene glycol-600 with the prescription amount, adding into the mixed solution of 1, 2-propylene glycol, polyoxyethylene castor oil and polyethylene glycol 400, shaking to dissolve, and adding glycerol triacetate to 1000ml scale. 3 prescription key points
3.1 selection of a Complex vehicle System is the key to the present invention, formulation of a complex (e.g., azone, 1, 2-propanediol, and glyceryl triacetate; polyethylene glycol, 1, 2-propanediol, glycerol, and azone; polyethylene glycol, 1, 2-propanediol, glycerol, and Tween; and glyceryl triacetate, polyethylene glycol, 1, 2-propanediol, and polyoxyethylated castor oil) vehicle System optimization, performance stability; the quality is controllable; has no irritation and sensitization to skin; quick absorption and reliable clinical effect. The curative effect is obviously better than oral administration, but almost no toxic or side effect is caused by the whole body.
3.2 Cyclodextrin (for example, HP-beta-CD) can be included with colchicine as a main drug to form an inclusion compound, and the inclusion compound exists in a compound solvent, so that the solubility of the main drug is increased, and the stability of the preparation is improved; and also has certain effect of reducing skin irritation.
3.3 the main vehicle (e.g., glyceryl triacetate or polyethylene glycol) of the present invention is not only a vehicle, but more importantly, it is uric acid that permeates into inflamed tissues to dissolve and deposit in the inflamed tissues, and reduces uric acid in local inflamed tissues, thereby aiding in the control of inflammation and pain relief.
3.4 the preparation process of the product is simple and convenient, can ensure the quality of the product, has lower cost and easy operation, and is suitable for batch production.
Example two anti-inflammatory action of colchicine liniment on gout model animals
1. Materials and methods
1.1 drugs and agent colchicine liniment (i.e. prescription 4 in Table 1-1, i.e. example 1, prescription i of 2.5.1, colchicine content 0.2 w/v%), colchicine (content 99.79% in Yunnan Kunming pharmaceutical Co., ltd.), sodium uric acid (supplied by Sigma Co.), prostaglandin E2 (PGE 2) radioimmunoassay kit (supplied by Beijing Toyama immunotechnology institute), tumor necrosis factor-alpha (TNF-alpha) kit (supplied by military medical science institute).
1.2 laboratory animals SD rats, male, clean grade, weighing 200-250g, supplied by laboratory animal center at the national academy of military medical science, were tested after 3d of normal feeding in the laboratory.
1.3 method
1.3.1 construction of acute gouty arthritis model the classical method of CODERRE was followed (CoderreTJ, wallPD, anklejoi, urearthrertistenisattributetraspareridservice tools for the evaluation, pharmacological biochemistry & Behavir, 1988,29 (3): 461-466). A6-gauge needle was inserted into the medial side of the tibial portion of the test rat at a 45 degree angle on the dorsal side of the left ankle, and 10% sodium urate solution was injected into the ankle cavity at 0.2 ml/min.
1.3.2 animals were grouped and 30 rats were treated randomly into 3 groups of 10 animals each, which were normal control (no modeling), model, colchicine treatment. The normal control group was not treated at all. The model group was smeared with the blank vehicle of colchicine liniment 3 times/d for 5 days. The liniment group is coated with colchicine liniment daily, and the application method is the same as that of the model group.
1.4 observations index
1.4.1 degree of rat joint swelling each group of rats was measured for their circumferences with inelastic tape at the same site of the ankle joint to be tested, 3 hours before molding, 3 hours after molding (before administration) and 3 hours after administration, and changes in the circumferences of the ankle joint of the rats before molding and before and after treatment were observed.
1.4.2 determination of PGE2, TNF-alpha, white blood cells in the joint Chamber rats of each group were sacrificed at the end of the model treatment for 72h, the joint Chamber of the test was opened to remove joint effusion, smears were used for white blood cell count; taking down soft tissues around the joint cavity, homogenizing, and then measuring PGE2 and TNF-alpha in the tissues by adopting a radioimmunoassay method, and operating according to the instruction of the kit.
1.5 statistical method adopts SPSS12.0 statistical software, the measured normal data are all expressed by x+ -s, the bias distribution data are expressed by M (Min-Max), the group comparison adopts t test, and the multi-group mean comparison adopts variance analysis.
2 results
2.1 effects on gouty arthritic rat ankle swelling model and liniment groups were evident in joint swelling before administration after model building, and the differences compared with the normal control group were statistically significant (P < 0.01). See Table 2-1.
Table 2-1 comparison of changes in the extent of swelling in the joints of the groups
# difference: pre-drug-post-drug application; compared with the normal group, P is less than 0.01, and XX of the liniment group treatment group and the model group (blank solvent) is less than 0.05 DeltaP and less than 0.01.
2.2 effects on PGE2, TNF-alpha levels and white blood cell counts in gouty arthritis rat articular cavity tissue
The contents of PGE2 and TNF-alpha in the joint cavity tissues of the rats in the model group are obviously increased (P is less than 0.01) compared with the normal control group, and the contents of PGE2 and TNF-alpha in the joint cavity tissues of the rats in the liniment group are obviously reduced (P is less than 0.01 and P is less than 0.05) compared with the model group. Compared with the normal control group, the number of the white blood cells in the joint cavity effusion of the rats in the model group is obviously increased (P is less than 0.01), and the number of the white blood cells in the joint cavity effusion of the rats in the liniment group is obviously reduced (P is less than 0.01) compared with the model group. See Table 2-2.
TABLE 2-2 comparison of PGE2, TNF-alpha content and white blood cell count in rat articular cavity tissues of various groups
Other formulations of the invention for liniments (e.g., example one 2.5.1 formulation ii, iii, iv) also have similar therapeutic effects.
2.3 the underlying cause of acute gouty arthritis is the precipitation of local sodium urate crystals in joints caused by hyperuricemia. The gouty arthritis model caused by the local joint injection of sodium urate is considered as a classical modeling method of gouty arthritis, and can be used for evaluating the curative effect of the gouty arthritis resistant medicament.
Colchicine is used as a first-choice drug for treating acute gout in modern medicine, can inhibit phagocytosis of uric acid salt crystals by neutrophils, block release of chemotactic factors, reduce flow and adhesion of polymorphonuclear leukocytes, inhibit phosphorylation of tyrosine and generation of leukotriene B4, thereby reducing deposition of uric acid crystals, relieving inflammatory reaction, and eliminating red swelling and pain. However, as mentioned above, colchicine is orally administered according to the standard prescribed in its pharmacopoeia, 50% -80% of patients have gastrointestinal reactions before the therapeutic effect is achieved, and serious patients cause dehydration, electrolyte disorder and other manifestations, which are intolerable to most patients. In order to avoid the toxic and side effects of colchicine by oral administration, the colchicine liniment, which is an embodiment of the invention, is quickly absorbed through skin and enters into the stratum corneum of the skin, so that the medicine entering into the blood circulation is reduced, and the toxic and side effects caused by systemic distribution can be avoided.
Based on the experimental results, the colchicine liniment has reliable anti-inflammatory effect on gout model rats, and provides a basis for clinically treating acute gout arthritis.
Example III, irritation and sensitization of colchicine Liniment to skin study
Toxicological research is a key link in drug development, and determines whether drugs can enter clinic or not, and whether the drugs are safe to use or not. Chemical irritation and allergy refer to administration of a chemical agent via non-oral route such as eye, ear, nose, mouth, respiratory tract, joint cavity, skin, rectum, vagina, vein, artery, muscle, subcutaneous, intravenous and intrathecal, toxicity (e.g., irritation and allergy etc.) locally generated on administration and/or toxicity (e.g., allergy and hemolysis etc.) generated systemically. It is a component of preclinical safety evaluation.
The colchicine liniment is a novel colchicine dosage form, and the effective treatment amount of the colchicine liniment based on oral dosage of colchicine tablets is close to the systemic poisoning amount, so that the colchicine liniment has large systemic toxic and side effects in clinical application, and the colchicine liniment is absorbed transdermally to treat gouty arthritis. Colchicine liniments were examined for skin irritation and sensitization by the skin of both large ear white rabbits and guinea pigs for safety in clinical use.
1 laboratory apparatus and reagents
Big ear white rabbits, 30, female 15, male 15, and body weight of 2-2.5kg; 55 guinea pigs, 27 females, 28 males and 250-300g; animal grade: a cleaning stage; animal origin: the Beijing department animal breeding center; test drug: colchicine liniment is self-made, namely prescription 4 in table 1-1, namely prescription i of example one 2.5.1; blank vehicle: homemade (vehicle without main drug); positive control drug for sensitization test: 2, 4-dinitrochlorobenzene (lot number 20030701, shanghai reagent works); gauze (lot number: 010708, beijing Athens Biochemical institute); transparent ventilation type adhesive tape (3M China Co., ltd.: 1527C-0 standard: 12 mm. Times.9.1M).
2 experimental methods and results
2.1 Experimental methods
2.1.1 Single skin irritation test
15 New Zealand white rabbits with a weight of 2-2.5kg are divided into three groups of 5 animals each. One group is a complete skin group (colchicine liniment is coated on one side of the back and a blank solvent is coated on the other side), the other group is a damaged skin group (colchicine liniment is coated on one side of the back and a blank solvent is coated on the other side), and the other group is a commercial control medicine group (complete skin is coated on one side of the back and damaged skin is coated on the other side).
24 hours before the test, the back hairs on the two sides are shaved by a shaver, and the depilating range is about 3X 3cm 2 . Broken skin was scored with needle # to the extent of bleeding. The test uses the self-control method of the left side and the right side of the homozygote.
Before administration, the intact skin group should be checked for damage. Two layers of gauze (2.5X2) were used for the test.5cm 2 ) Covering on one side of dehaired skin, then directly dripping 0.5ml of the tested object onto gauze, covering with preservative film, and fixing with non-irritating adhesive tape and general adhesive tape; the other side is the same. The three groups were applied for 6 hours.
After 6 hours, the test substance was removed and the administration site was cleaned with warm water, and erythema and edema of the application site were visually observed and recorded at 1, 24, 48, and 72 hours after the removal of the test substance, respectively. The scoring standard is described in the technical guidelines for the study of chemical irritation, allergy and hemolysis.
2.1.2 multiple skin irritation test
The animals tested were grouped and dosed in the same manner as in the single irritation test, and were dosed at the same time for three consecutive days. Erythema and edema, presence of pigmentation at the site of application, bleeding spots, rough or thin skin, and time to onset and resolution thereof were observed and recorded 1 hour after each drug removal and before reapplication, and scored.
After the last application for 6 hours, the drugs were removed, and the presence or absence of erythema and edema at the applied site was visually observed and recorded at 1, 24, 48, and 72 hours of the drug removal, respectively. The scoring standard is described in the technical guidelines for the study of chemical irritation, allergy and hemolysis.
Statistical analysis was performed using SPSS11.5 statistical software treatment with random sample anova and chi-square test with significance level a=0.05.
2.1.3 sensitization test
55 guinea pigs are divided into three groups. The colchicine liniment group, the blank solvent group and the sensitization positive control medicine group are respectively adopted. The grouping method is to number the male and female parts separately and group them with random number list. Wherein 25 drug groups (13 male, 12 female) were tested; blank vehicle group 15 (8 of which were male, 7 of which were female); positive control group 15 (7 male, 8 female).
Dosage of administration: colchicine liniment: 1ml of priming dose and 0.1ml of priming dose; blank vehicle: 1ml of priming dose and 0.1ml of priming dose; positive control drug: 1ml of 1%2, 4-dinitrochlorobenzene was prepared from 75% ethanol, and 1ml of 0.1%2, 4-dinitrochlorobenzene was prepared from 75% ethanol.
Sensitization phase: 24 hours prior to the test, the haircut was performed on the 3X 3cm2 area of the back of the guinea pig with a shaver. The colchicine liniment with sensitization dose is made into a closed tablet with the area of about 2.5 multiplied by 2.5cm < 2 >, the closed tablet is locally administrated, covered by a plastic film, fixed by a non-invasive adhesive tape and a common adhesive tape, after 6 hours, residual liquid is washed off by warm water, and the same method is repeated for 7d and 14 d. Blank vehicle group and positive control group were treated in the same way.
Excitation stage: the colchicine liniment with the excitation dose is applied on the side abdomen part without administration by using a sealing sheet 14 days after the last sensitization, the sealing sheet is removed after the non-invasive adhesive tape is generally fixed for 6 hours. Blank vehicle group and positive control group were treated in the same way.
Erythema and edema and other abnormal reactions were observed at 1 and 24 hours after each sensitization and 1, 24 and 48 hours after challenge, and scored according to the guidelines for chemical drug irritation, allergy and hemolysis study techniques. And weighing at the beginning of the test and at the end of the test, respectively.
2.2 experimental results
2.2.1 New Zealand white rabbits skin irritation test
The irritation of colchicine liniment to skin is evaluated by statistics of the observed fractions of the new zealand big ear white rabbits at different times after single and multiple stimulations. The test results are shown in Table 3-1 and Table 3-2.
Table 3-1 single skin irritation results (n=5)
* P < 0.05, respectively compared with the whole skin of the same test object
The stimulus data at each time point in Table 1 is the mean of the stimulus scores of different animals at the same time in each group 2 the stimulus mean is the mean of the stimulus scores of different animals at each time point in the same group
Table 3-2 skin irritation results for multiple times (n=5)
* P < 0.05, compared with colchicine liniment in damaged skin group
The stimulus data at each time point in Table 1 is the mean of the stimulus scores of different animals at the same time in each group 2 the stimulus mean is the mean of the stimulus scores of different animals at each time point in the same group
Statistical analysis results show that there is no significant difference (P > 0.05) between colchicine liniment and blank vehicle in single skin irritation test in intact skin and damaged skin group respectively; there was no significant difference in irritation (P > 0.05) between the intact skin and the broken skin groups of the same test subjects. The irritation fraction in the whole skin group is 0-0.49, and the irritation fraction in the damaged skin group is 0.5-2.99, namely, the two tested substances have no irritation to the whole skin of the white rabbits with big ears and have slight irritation to the damaged skin.
Multiple irritation tests within the intact skin group, there was no significant difference (P > 0.05) between colchicine liniment and blank vehicle; in the damaged skin group, colchicine liniment and blank solvent have no obvious difference. The same test subjects did not differ significantly between the intact skin group and the broken skin group.
2.2.2 guinea pig skin sensitization test
Skin reactions of guinea pigs were observed and scores of skin reactions were recorded at different stages, and the average of scores of the same group was used as the skin reaction score, and data at three time points of the excitation stage were comprehensively scored, and the results are shown in tables 3 to 3. The skin reactions of each group of animals in the excitation stage and the sensitization stage were observed, and the calculated occurrence rates are summarized in tables 3 to 4. The guinea pigs were weighed at the beginning and end of the test, and differences in body weight were calculated, and the results are shown in tables 3 to 5.
TABLE 3 skin sensitization results
* The P is less than 0.05, blank solvent and positive control in sensitization stage and excitation stage are compared with colchicine liniment, and two guinea pigs die in the colchicine drug group
The above data are the means of scoring different animals at the same time in each group
TABLE 3-4 incidence of skin sensitization
* P < 0.05, blank vehicle in sensitization phase and excitation phase compared with colchicine liniment
The skin sensitization rate of guinea pigs is calculated according to three observation results after excitation
TABLE 3-5 guinea pig weight
* P < 0.05, comparison of blank vehicle with colchicine liniment
Statistical analysis of tables 3-3 shows that there was no significant difference in the overall scores of colchicine liniments after three sensitization phases and after challenge in guinea pigs (P > 0.05).
Statistical analysis in tables 3-4 shows that the skin reaction incidence of the sensitized colchicine liniment group and the blank solvent group is remarkably different (P is less than 0.001), and the skin reaction incidence of the colchicine liniment group and the positive control group is not remarkably different (P is more than 0.05). The incidence of skin reaction of colchicine liniment group after excitation and blank solvent group is obviously different (P < 0.001), and the incidence of skin reaction of colchicine liniment group and positive control group is not obviously different (P > 0.05). And the sensitization phase of colchicine liniment and the incidence rate of skin reaction after excitation have no significant difference (P is more than 0.05).
As can be seen from the comprehensive tables 3-3 and 3-4, the guinea pigs were positive for skin response after three consecutive firings with colchicine liniment, the incidence of the response was about 82.6%, but the response was mild, the average value of the response was 1.70, and there was no statistical difference between the skin response score and the incidence from the first sensitization result.
As shown by the statistical analysis in tables 3-5, there is no statistical difference (P > 0.05) between the weights of three groups of guinea pigs before the test, the weights of three groups of guinea pigs after the test are statistically different (P < 0.001), the weights of the blank vehicle group and the colchicine liniment group are compared in pairs, the weights of the guinea pigs are statistically different (P < 0.001), and the weights of the colchicine liniment group animals after the test are significantly lower than those of the blank vehicle group and the positive control group. The colchicine linium animals showed less weight gain than the blank vehicle group during the trial and were statistically different. It is explained that colchicine absorption in colchicine liniment has a certain effect on the weight gain of guinea pigs.
Other formulations of the invention for liniments (e.g., example one 2.5.1 formulation ii, iii, iv) also have similar therapeutic effects.
Conclusion 3
In the irritation test, the colchicine liniment has no irritation reaction on the skin after single administration of the whole skin, and has slight reversible irritation on damaged skin; the skin is slightly irritating after multiple administrations, and the damaged skin is slightly irritating after single and multiple administrations. The average value of the irritation of the liniment to damaged skin is 0.8, which indicates that the irritation of the colchicine liniment to the skin can not be obviously increased by multiple administrations. In particular, the repeated administration provides a safety basis for the clinical application of the preparation, and the purpose and the requirement of the preparation formulation design are also met.
In the sensitization test, guinea pigs are sensitized and re-stimulated by colchicine liniment three times in succession, and skin reactions are positive in the sensitization stage and the excitation stage, but the reactions are mild, and the comprehensive score and the skin reaction incidence rate of the sensitization stage and the skin reactions after excitation are not significantly different (P is more than 0.05). Meanwhile, the blank solvent has no sensitization to the skin of guinea pigs, and the analysis shows that the skin response after sensitization is a stimulating response, and the colchicine liniment has no sensitization.
The body weight of guinea pigs in the colchicine liniment group is lower than that of the solvent group at the end of the test, and the related data also show that colchicine has hepatotoxicity, nephrotoxicity and neurotoxicity. The dosage of the preparation can cause poisoning when the dosage of the preparation reaches more than 6mg, and the dosage of the preparation is the maximum dosage for clinical use in the experimental process. Therefore, the inhibition of normal weight gain of guinea pigs and the property of death crude drugs of two guinea pigs in colchicine liniment group in the test process have little correlation with the preparation.
Fourth example, observation of clinical efficacy
1. Data and method
1.1 clinical data selection clinic and hospitalized 59 cases, randomized into two groups, 30 colchicine liniment groups, 27 men, 3 women, age 43+ -10.8 years, disease course 5.7+ -2.1 years. The colchicine oral tablet control group 29 cases, male 27 cases, female 2 cases, age 44.0+ -10.3 years, disease course 5.3 years+ -2.6 years, and the two groups of data have no statistical significance (P > 0.05) and are comparable.
1.2 diagnostic criteria reference the gouty arthritis diagnostic criteria and clinical rheumatism criteria of the American society of rheumatology 1977
1.2.1 sudden repeated attacks of red, swelling and hot pain of joints such as toes, tarsometatarsal joints, ankle joints and the like of middle-aged and old men with obesity;
1.2.2 blood uric acid 420 umol/L;
1.2.3 reddish swelling of joint X-ray film with gout arthritis, broken joint cartilage margin, irregular joint surface, narrow joint gap, and changed bone mass in insect erosion or chiseling type defect;
the curative effect judgment observes the clinical curative effect of 3 days of administration. The effect is shown: the local red swelling and pain of the joints basically disappear, and the joint moves freely; the method is effective: the local red swelling and pain of the joints are obviously relieved, and the activity is improved; invalidation: no significant improvement or exacerbation of symptoms was seen. And meanwhile, adverse drug reactions are observed.
The colchicine liniment (i.e. prescription 4 in table 1-1, i.e. prescription i in example 1, 2.5.1) is applied to the affected part, 3 times a day, the colchicine tablet control group is orally taken, the first dose is orally taken in the acute phase, 0.5mg is orally taken every 2-3 hours later until the pain is relieved, the adverse reaction should not exceed 6mg within 24 hours, if the adverse reaction should be stopped immediately, the patient is instructed to limit the protein intake during the treatment period, and the patient is drunk more, avoids tiredness, is cooled, strictly stops drinking, and avoids high purine foods (heart, liver, kidney, brain, fish, yeast and the like) and the inducing factors.
The statistical treatment dosage data are expressed as (X+/-S), and the total effective rate of the liniment treatment group is better than that of the oral control group (P < 0.05 or 0.01).
2. Results
2.1A comparison of the two groups of curative effects is shown in Table 4-1, and the results show that the total effective rate of the linimentum treatment group is superior to that of the oral administration control group (P < 0.05 or 0.01).
Table 4-1 results of comparison of two clinical efficacy sets
The significant difference P is less than 0.01 in the 3-day treatment effect 23/30 (76.7%) of the random linimentum treatment group and the 3-day treatment effect 12/29 (41.3%) of the oral administration group; the total effective rate is 100% and 86.2%, respectively, and the difference is obvious (P is less than 0.05).
Other formulations of the invention for liniments (e.g., example one 2.5.1 formulation ii, iii, iv) also have similar therapeutic effects.
2.2 adverse effects colchicine tablet oral treatment 8 (27.6%) patients showed gastrointestinal reactions such as nausea, vomiting, diarrhea. The colchicine liniment treatment group has no adverse reaction report, high safety and good patient compliance.
In a word, the invention utilizes the new thought of percutaneous absorption of medicine, selects colchicine as a model medicine, and optimizes and selects the prescription through a great deal of pharmacological study; the basis of selecting the liniment is proved through drug effect and safety evaluation, and through clinical evaluation and observation, the obvious efficiency is obviously better than that of oral administration, especially the toxic and side effects of the oral administration are reduced, the innovation of the formulation design of the medicine is realized, the animal drug effect and safety are scientifically and the clinical evaluation of patients are scientifically realized, and the clinical application of colchicine is brought with breakthrough advantages. The success of the invention can make positive contribution to relieving pains of vast gout patients and improving the domestic gout treatment level.
Claims (6)
1. A colchicine topical composition, which consists of the following components: colchicine, a solvent, a cosolvent, a permeation aid and an optional emulsifier, wherein the solvent is selected from one or more of glyceryl triacetate, polyethylene glycol 300, polyethylene glycol 400 or polyethylene glycol 600;
wherein the cosolvent is a polyol;
the permeation assisting agent is cyclodextrin, and colchicine is 0.01-1.0w/v% of the whole external composition;
the external composition is a homogeneous liquid preparation for external use.
2. The colchicine topical composition of claim 1, wherein colchicine is 0.2w/v% of the total composition.
3. The colchicine topical composition of claim 2, wherein the permeation enhancer is hydroxypropyl-beta-cyclodextrin.
4. The colchicine composition for external use according to claim 1, wherein the cyclodextrin is β -cyclodextrin, α -cyclodextrin, γ -cyclodextrin, hydroxy- β -cyclodextrin, dimethyl- β -cyclodextrin, trimethyl- β -cyclodextrin, glucosyl- β -cyclodextrin or maltotriosyl- β -cyclodextrin.
5. The colchicine external composition of claim 1, further comprising an emulsifier selected from one or more of polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil, and tween.
6. A method of preparing a colchicine topical composition according to claim 1, comprising: completely dissolving colchicine into cosolvent, permeation promoter, optional emulsifier and small amount of solvent, and adding the rest solvent to obtain colchicine topical composition.
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| CN113274343B (en) * | 2016-11-08 | 2023-08-04 | 北京天衡军威医药技术开发有限公司 | Use of polyols as co-solvents in colchicine topical compositions |
| GB2572226A (en) * | 2018-03-24 | 2019-09-25 | Aan Medical Ltd | Gout treatment |
| EP4041211A4 (en) * | 2019-10-11 | 2023-09-06 | Zenvision Pharma LLP | Improved topical composition of colchicine |
| CN113133991B (en) * | 2020-01-19 | 2023-06-13 | 南京大学 | Colchicine soluble microneedle patch and preparation method thereof |
| WO2024067722A1 (en) * | 2022-09-30 | 2024-04-04 | 北京德默高科医药技术有限公司 | Patch comprising colchicine and preparation method therefor and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03148218A (en) * | 1989-11-02 | 1991-06-25 | Nissan Chem Ind Ltd | Colchicine-containing external preparation |
| CN1568951A (en) * | 2004-04-27 | 2005-01-26 | 陈明元 | Pharmaceutical for preventing and curing acute gout, tumor and hepatic/pulmonary fibrosis and preparation method thereof |
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| JP2761542B2 (en) * | 1989-03-31 | 1998-06-04 | テイカ製薬株式会社 | Topical formulation containing colchicine |
| ITBO20060313A1 (en) * | 2006-04-26 | 2007-10-27 | Alma Mater Studiorum Uni Di Bologna | PHARMACEUTICAL FORMULATIONS FOR TRANSDERMAL USE |
| CN101062022B (en) * | 2007-05-31 | 2010-11-24 | 天津市中宝制药有限公司 | Colchicine patch absorbing from skin for treating acute goute arthritis and the preparing method thereof |
| CN101375845B (en) * | 2007-08-30 | 2012-07-04 | 北京人福军威医药技术开发有限公司 | Podophyllotoxin external-use formulation prescription for treating pointed condyloma and herpes genitalis, dosage form series and preparation method |
| CN102366403A (en) * | 2011-10-10 | 2012-03-07 | 薛巍 | Colchicine microemulsion transdermal agent, preparation method thereof and application thereof |
| CN103251550B (en) * | 2012-02-20 | 2016-04-20 | 上海市计划生育科学研究所 | Transdermal administration unguentum containing colchicine and preparation method thereof |
| CN103142477B (en) * | 2013-04-08 | 2015-09-30 | 薛巍 | A kind of preparation method containing nano-carrier microemulsion formulation of sustained-release colchicine micro emulsion |
| CN113274343B (en) * | 2016-11-08 | 2023-08-04 | 北京天衡军威医药技术开发有限公司 | Use of polyols as co-solvents in colchicine topical compositions |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH03148218A (en) * | 1989-11-02 | 1991-06-25 | Nissan Chem Ind Ltd | Colchicine-containing external preparation |
| CN1568951A (en) * | 2004-04-27 | 2005-01-26 | 陈明元 | Pharmaceutical for preventing and curing acute gout, tumor and hepatic/pulmonary fibrosis and preparation method thereof |
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| CN113274343B (en) | 2023-08-04 |
| CN113274342B (en) | 2023-06-02 |
| CN113041210A (en) | 2021-06-29 |
| CN108057018B (en) | 2021-06-08 |
| CN113274342A (en) | 2021-08-20 |
| CN113274343A (en) | 2021-08-20 |
| CN108057018A (en) | 2018-05-22 |
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