CN113274342A - Colchicine composition for external use - Google Patents
Colchicine composition for external use Download PDFInfo
- Publication number
- CN113274342A CN113274342A CN202110531626.5A CN202110531626A CN113274342A CN 113274342 A CN113274342 A CN 113274342A CN 202110531626 A CN202110531626 A CN 202110531626A CN 113274342 A CN113274342 A CN 113274342A
- Authority
- CN
- China
- Prior art keywords
- colchicine
- polyoxyethylene
- castor oil
- glycerol
- tween
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pain & Pain Management (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Dermatology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
A colchicine composition for external use at least comprises colchicine and an emulsifier, wherein the emulsifier is one or more selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and tween. The invention changes the administration route of colchicine to form a new colchicine medicament form, so that the colchicine can be put into clinical use in the new medicament form.
Description
The application is filed with application number of 2016109824148, application date of 2016, 11, 8 and application type of patent, and is named as colchicine composition for external use and a divisional application of a preparation method thereof.
Technical Field
The invention belongs to the field of medicines, and particularly relates to the field of medicines for treating gouty arthritis. In particular, the invention relates to a colchicine external composition for preventing or treating gouty arthritis, in particular to a colchicine liniment and a preparation method thereof.
Background
Gout is a disease caused by purine metabolic disorder in vivo, which is mainly manifested as hyperuricemia, and urate is precipitated and crystallized in joints, kidneys and connective tissues, so that local inflammation and granulocyte infiltration of the joints can be caused, and gout attack is caused. The incidence of gout increases year by year worldwide. In China, the incidence rate of the disease also rises year by year, and the onset age shows a low-age trend, which brings huge burden to the society. According to statistics, the number of potential gout diseases in China reaches hundreds of millions, and about 3500 thousands of gout diseases have been diagnosed.
At present, the drugs for treating gout clinically according to the mode of action can be divided into five types: 1. an anti-granulocyte-infiltrating agent such as colchicine; 2. analgesic and anti-inflammatory agent (non-steroidal anti-inflammatory drug), such as indomethacin, phenylbutazone, diclofenac, naproxen, sulindac, ibuprofen, etc.; 3. corticotropin or glucocorticoids, such As Corticotropin (ACTH) or prednisone; 4. drugs for promoting uric acid excretion, such as probenecid, sulindac, benzbromarone, etc.; 5. uric acid production-inhibiting agents, such as allopurinol.
Gout disease is characterized by hyperuricemia and characteristic acute arthritis, and repeated attacks can cause tophus deposition and gouty nephropathy. Acute rheumatic arthritis is the first symptom of gout, and most of the symptoms are acute, and mainly manifested as red, swollen, hot and severe pain of tissues around joints, fever and plasma leukocytosis. Colchicine can bind with tubulin of granulocyte, thereby preventing granulocyte activity, inhibiting granulocyte infiltration, interfering inflammatory reaction of leukocyte in dedifferentiation movement, and has specific effect on acute gouty arthritis. Colchicine is the first choice of traditional effective clinical drugs for acute attack of gouty arthritis and prevention of acute attack of recurrent gouty arthritis, however, the main toxic and side effects of colchicine are summarized as follows: 1. adverse reaction has obvious correlation with dosage size, and oral administration has higher safety than intravenous injection. Early adverse reactions, such as abdominal pain, diarrhea, vomiting and anorexia, occur at a rate of 80%, and severe cases may cause dehydration and electrolyte disorders. Severe hemorrhagic gastroenteritis or malabsorption syndrome can be seen after long-term administration; the nervous system adverse reactions are muscle and peripheral neuropathy including proximal muscle weakness and/or serum creatine kinase increase, and peripheral nerve axonal polyneuropathy can occur while muscle cells are damaged, and the peripheral nerve axonal polyneuropathy is manifested by numbness, stabbing pain and weakness. The muscular neuropathy is not common, and is often seen in patients who take the medicine for a long time and patients with mild renal insufficiency for preventing gout; thrombocytopenia, neutropenia and even aplastic anemia are frequently seen in intravenous medication patients and sometimes cause fatal risks; oliguria, hematuria, convulsion and consciousness disorder, which are commonly seen in intravenous medicines and the elderly, have high mortality rate; other adverse reactions include phlebitis, rash, alopecia and fever. 2. Due to the inconsistent knowledge of the efficacy and risk of colchicine in treating gout and the severity of its toxicity, caution must be exercised in selecting this drug. Intravenous injection and long-term oral administration are avoided as much as possible, and intravenous and oral routes are prohibited. 3. It is forbidden for patients with myelodysplasia and hepatic and renal insufficiency, pregnant women and children under 2 years old. 4. It should be used with cautions for the elderly and those with potential damage to liver and kidney functions. 5. The blood routine and the liver and kidney functions must be regularly checked. 6. The medicine can cause reversible malabsorption of vitamin B12. 7. The composition can enhance the effect of central nervous system inhibitor and enhance the response of sympathomimetic agent. 8. The medicine is not suitable for preventing the onset of gouty arthritis for a long time. 9. Intravenous injection of this product is limited to fasting patients, such as during gout attacks following surgery. 10. Patients with serious adverse reactions need to stop taking the medicine immediately and rescue the medicine for the symptoms.
In view of the above-mentioned toxic side effects, the clinical application of the drug is greatly limited. In order to overcome or reduce the toxic and side effects caused by oral administration of colchicine, a large amount of work has been put into development and research of new formulations of colchicine by pharmacists for many years. Yi Wei Zhi (colchicine adhesive plaster for treating acute gouty arthritis, China new medicine and clinical journal, 2001, 20(5): 373) 374) prepares the colchicine adhesive plaster for treating patients with acute attack stage of the gouty arthritis, and the result shows that the local inflammation is obviously improved and the joint edema is obviously improved; the colchicine gel is prepared by the aged colchicine and the like (influence of different matrixes and transdermal enhancers on the external transdermal property of the colchicine gel, Waxi pharmacy journal, 2005, 20(6): 521-; cao Chong et al (preparation and clinical observation of Compound colchicine gel, J. Pharmacology, China, 2007, 27(10):1445-1447) prepared Compound colchicine gel and observed its clinical effect. At present, only colchicine patches are approved to enter clinical research and production, but the external preparation is not yet on the market, and the external preparation is probably lower in drug transdermal permeability and still has uncertain clinical curative effect. Liuxia et al (colchicine liposome gel for anti-inflammatory action of gout model animals, Guangdong medicine 2011, 32(23):3038-3040) prepared colchicine liposome gel for anti-inflammatory action of gout model animals.
The research results of the above documents reveal that colchicine changes the administration route and can become a new breakthrough for the research of the new dosage form of the medicine through transdermal absorption, but the research still does not form a commodity to serve the majority of patients.
Disclosure of Invention
The medicine must be prepared into proper dosage forms for clinical application. If the dosage form is selected improperly, the prescription process design is not reasonable, which not only affects the physicochemical properties (such as appearance, dissolution rate and stability) of the product, but also may reduce the clinical efficacy and increase the drug toxicity. Thus, a suitable dosage form is selected; designing a reasonable prescription process; the quality of the product is improved, and the product plays an important role in the research and development of new drugs.
On the basis of the research of the prior art, the invention successfully develops a new colchicine dosage form, a colchicine external composition for transdermal absorption, in particular to a colchicine liniment.
In a first aspect, the present invention provides a colchicine topical composition comprising or consisting of: colchicine, a solvent, a cosolvent, an optional penetration enhancer and an optional emulsifier.
In a preferred embodiment of the present invention, the vehicle is one or more of glycerol triacetate, ethyl acetate, isopropanol, polyethylene glycol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, glycerol monooleate, glycerol dioleate, glycerol trioleate, propylene glycol acid ester, polyoxyethylene castor oil, benzyl acetate, diacetyl monoglyceride, diacetyl tartaric acid (mono, di) glycerol, glycerol diacetate, triethanolamine oleate, triglycerol octanoate, triglycerol decanoate, benzyl butyrate and dimethicone, preferably glycerol 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, dimethicone, and mixtures thereof, 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 penetration enhancer is selected from one or more of cyclodextrin, azone, peppermint oil and menthol, preferably cyclodextrin and/or azone, said cyclodextrin preferably being 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 polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and tween, preferably polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (100) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, tween-20, tween-40, tween-60 or tween-80.
In another preferred embodiment of the present invention, the colchicine external composition consists of colchicine, triacetin, 1, 2-propylene glycol, 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 comprises colchicine, glyceryl triacetate, polyethylene glycol, 1, 2-propylene glycol and polyoxyethylene castor oil.
In another preferred embodiment of the invention, the colchicine is present in an amount of 0.01-1.0 w/v%, more preferably 0.2 w/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 external composition is a transdermal absorption composition, and is administered transdermally in the form of a dissolving agent, a spray or a liniment, preferably transdermally in the form of a liniment.
The term "dissolution agent" refers to a liquid preparation made by dissolving a drug in a suitable solvent. For oral or external use.
The term "spray" refers to a form of spraying a liquid medicine from a nonmetallic sprayer using compressed air or inert gas as a power source.
The term "liniment" refers to a solution, emulsion or suspension of a drug in a suitable solvent, a liquid formulation for rubbing the skin.
In a second aspect, the present invention provides a method for preparing a colchicine topical composition, comprising: adding colchicine into cosolvent, optional penetration enhancer, optional emulsifier and small amount (or appropriate amount) of solvent to completely dissolve colchicine, and adding the rest solvent to obtain colchicine topical composition.
In particular, the preparation method comprises: adding colchicine into 1, 2-propylene glycol, hydroxypropyl-beta-cyclodextrin, azone and a small amount of glycerol triacetate to completely dissolve the colchicine, and adding the rest glycerol triacetate to obtain the colchicine composition for external use.
The invention has the outstanding characteristics that the colchicine is quickly absorbed through skin, the attack of the gouty arthritis in the attack period is controlled, and the toxic and side effects of the whole body after the medicine is taken orally are hardly caused.
The colchicine external composition, in particular to a colchicine liniment which is a true solution and consists of an infiltration assisting system of a composite solvent, is a prescription optimally selected on the basis of a great deal of pharmaceutical research, has no irritation and allergy to skin, has 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 a patient, has good absorption and quick response, quickly relieves the pain of the patient, has almost no toxic or side effect on the whole body, is convenient for the patient to use, can be used for treating the acute stage attack of gouty arthritis of the gout patient, and can also be used as a long-term maintenance medicament for preventing the attack of gout.
Drawings
Figure 1 is a process flow diagram for preparing colchicine liniment.
Detailed Description
The invention carries out prescription screening and preparation process research on colchicine external composition, in particular to colchicine liniment. A plurality of batches of colchicine liniments are respectively prepared according to the selected prescription and the preparation process and are used 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 I study of the prescription of colchicine liniment
1 instruments and reagents
1.1 instruments
The Agilont model 1260 high performance liquid chromatograph (Agilent corporation) comprises a G131K quaternary gradient pump, a G13298 sample injector, a G1316A column oven, a G1315DDAD detector and the work stations are as follows: chemstationfor lc3 dsystems. VV-1800 UV-Vis spectrophotometer (Shimadzu, Japan); KS-2500 ultrasound machine (Ningbo Kesheng instruments Mill); pH211A acidimeter (HANNA, italy); BP211D ten-thousandth and one hundred-thousandth precision electronic balance (Sartorius, germany); ZORBAXC18 column (150 mm. times.4.60 mm, 5 μm, Agilent Co.); a YB-3 type clarity detector (precision instruments works of Tianjin university); DHG-9140A electric heating constant temperature air-blast drying oven (shanghai-constant technology ltd); SDC-II type high purity water unit (military medical academy of sciences health equipment institute); SHZ-D (III) circulating water type vacuum pump (Ongyu of Gongyi China plant). HWS-1.50 constant temperature and humidity apparatus (Ningbo Hai Shuifu laboratory Instrument Co.).
1.2 drugs and reagents
Glycerol triacetate (batch No. 141217, Xingjin chemical plant, Beijing); 1, 2-propanediol (batch No. 060312, Beijing Chemicals, Inc., analytical purity); azone (pharmaceutical, beijing beilirice biochemistry ltd); hydroxypropyl-beta-cyclodextrin (HP-beta-CD), dimethyl-beta-cyclodextrin, beta-cyclodextrin (Shaanxi spring chemical industry Limited industries Co.); colchicine (batch No. 141102409008; Kunming pharmaceutical group, Inc.); tween-80 (batch No. 150108; Tianjin, Mao chemical reagent works); polyethylene glycol-300, polyethylene glycol-400, polyethylene glycol-600 (national pharmaceutical group chemical Co., Ltd.).
2 methods and results
2.1 basis for selection of dosage forms
The selected dosage form of the invention is liniment, which is a traditional dosage form, has simple preparation process, convenient industrial production and convenient use, and can be self-administered by patients. The liniment is a solution, emulsion or suspension prepared from the medicine and a solvent and used for external application of skin. The liniment of the invention is a homogeneous liquid preparation for external use. Colchicine is administered transdermally for the topical treatment of gouty arthritis. Therefore, the control of the drug concentration of colchicine through transdermal absorption is the key of the invention, toxic and side effects can be caused after the high concentration is absorbed by the whole body, and the low concentration cannot achieve the effective treatment of the gouty arthritis, so the design of the drug administration dose is very important.
2.2 determination of the amount of Primary medicament
At present, the effective concentration of colchicine in the invention is in the range of 0.01-1.0%, and the specification of the external colchicine film agent related to the literature report is 0.2%. The invention takes the specification as the basis, selects the concentration of 0.2 percent as the optimal dosage and optimizes the prescription and the process.
2.3 prescription screening of colchicine linimentum
In order to obtain the optimal colchicine liniment prescription, the invention respectively screens and optimizes the prescription and the process from the aspects of solvent, cosolvent, penetration enhancer, emulsifier and the like of the prescription, and establishes the optimal prescription and the preparation process.
2.3.1 selection of vehicle
The choice of vehicle is critical to the invention. The selection principle of the solvent is as follows: no irritation to the skin; the dissolubility to the main medicine is good; has stable physicochemical properties, and is not incompatible with main drugs; and does not interfere with the measurement of the main medicine; meets the medical standard. The drug solubility and stability are used as indexes for screening. The invention firstly mainly uses the premise of solving the solubility of the main drug and selects the solvent by taking the performance stability as an index.
According to the physicochemical property of colchicine, the colchicine is dissolved in water to form hydrate which can affect transdermal absorption, so that water is not selected as a solvent. Selecting a composite permeation-assisting solvent system of an organic solvent. And then the stability of the colchicine is improved by adding other proper stabilizing agents.
The solvent used in the invention is selected from one or more of glycerol triacetate, ethyl acetate, isopropanol, polyethylene glycol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, glycerol monooleate, glycerol dioleate, glycerol trioleate, propylene glycol ester, polyoxyethylene castor oil, benzyl acetate, diacetyl monoglyceride, diacetyl tartaric acid (mono, di) glycerol, glycerol diacetate, triethanolamine oleate, triglycerol caprylate, triglycerol caprate, benzyl butyrate and dimethicone, preferably is glycerol triacetate or polyethylene glycol, and the polyethylene glycol is 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-1, polyethylene glycol-300, polyethylene glycol-2, polyethylene glycol-1, polyethylene glycol-2, polyethylene glycol-1, polyethylene glycol-di (A) and/or polyethylene glycol-1, Polyethylene glycol-4000, polyethylene glycol-4500, polyethylene glycol-6000 or polyethylene glycol-8000.
Most preferably, the triacetyl glycerine is used as a main solvent to dissolve the medicine, and the triacetyl glycerine also has a certain antibacterial effect when being used locally. Is non-toxic, non-irritating to the skin and generally considered safe (FDA 1985). The prescription is screened by using the solvent as a basic solvent.
2.3.2 selection of Co-solvents
The co-solvent used in the present invention is a polyol, preferably ethylene glycol, propylene glycol or glycerol, more preferably 1, 2-propanediol.
1, 2-Propylene Glycol (PG) is colorless clear viscous liquid, has stable property, is similar to glycerin but has low viscosity, and has effects of moistening skin, and prolonging drug effect. Can be mixed with glyceryl triacetate at any ratio, can dissolve many organic medicines, has the effects of dissolving medicines and uniformly mixing all components, and is commonly used as solvent, solubilizer, humectant, preservative, etc. When used alone as an accelerant in a preparation, the 1, 2-propylene glycol can penetrate into the stratum corneum and form accumulation in the stratum corneum, so that the solubility and the distribution of the drug in the stratum corneum are improved, and the colchicine therapeutic effect can be exerted more favorably.
2.3.3 selection of the permeation enhancer
The penetration enhancer used in the 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- β -cyclodextrin (HP- β -CD): the average molecular weight M is 1384, and the solubility in water is more than 50g/100ml at room temperature. HP-beta-CD can form inclusion compound with medicine, raise solubility and can transfer medicine molecule to skin surface. The single action has weaker effect, and is often combined with fatty acid and propylene glycol. The use of 1, 2-propanediol is intended here to enhance the effect of this application.
Azone (also called laurocapram, azecapram) is a nonpolar transdermal absorption enhancer, which softens the stratum corneum of the skin, enhances permeability, enables drugs to penetrate the skin barrier, increases local concentration, and is widely used in preparations as a penetration enhancer for transdermal absorption.
2.3.4 selection of emulsifiers
The emulsifier used in the present invention is selected from one or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and tween, and is preferably polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (100) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, tween-20, tween-40, tween-60 or tween-80.
2.3.5 prescription screening Process
Considering the properties of the main drug and combining the properties and the dosage of the selected various auxiliary materials, 6 prescription compositions are designed in total, and are shown in the table 1-1. On the basis of the above, the solubility and stability of the main drug are examined, and the prescription of the preparation is screened.
TABLE 1-1 prescription composition
Note: PG represents 1-2-propanediol, A represents glycerol triacetate
2.3.5.1 screening prescription using solubility as index
6 preparation solutions were prepared in 610 ml volumetric flasks according to the formulation shown in Table 1-1. Filling into ampoules, sealing, placing in 40 deg.C baking oven, standing for 2 days, taking out, standing at-20 deg.C for 2 days, repeating for 3 times, taking out, standing to room temperature for 6 days, filtering, diluting by multiple 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, the 6 prescriptions are all clear solutions at room temperature, are completely frozen after being placed at-20 ℃, and can be redissolved into colorless clear solutions in room temperature environment.
2.3.5.2 screening prescription using stability as index
The stability is an important aspect for evaluating the quality of the medicine and an important basis for screening success or failure of the prescription, and is related to the selection of medicine storage conditions, the preparation of validity period and the like.
Samples were prepared according to the respective recipes shown in Table 1-1, and the samples were placed at 60 ℃ under a light intensity of 4500. + -. 500Lux and a humidity of RH 95% for 10 days, and then sampled at day 0, day 5 and day 10, respectively, for detection. The results are shown in tables 1-3.
TABLE 1-3 determination of the content under different conditions
As can be seen from the data in tables 1-3, the formulations were less stable at high temperatures, stable at high humidity and high light, and the stability of the formulations was improved by the addition of HP- β -CD; along with the increase of the dosage of the glycerol triacetate in the prescription, the stability of the prescription is also slightly improved.
Tables 1-4 determination of impurity content under different conditions
As can be seen from the data in tables 1-4, the amounts of impurities in recipes 4, 5, and 6 at high temperatures are significantly less than those in recipes 1,2, and 3, and the impurities in each recipe do not vary much for the remaining conditions. According to the new drug approval, the main content of the preparation is 95.0-105.0%, and the impurities are not more than 2 times of the raw material drugs, so the preparation with both meeting the requirements is selected. The prescription is selected as prescription 4.
2.4 preparation Process
According to the prescription amount, colchicine is added into a cosolvent, an optional penetration enhancer, an optional emulsifier and a small amount of solvent to completely dissolve the colchicine, and then the residual solvent is added to obtain the colchicine external composition.
Preferably, the colchicine raw material medicine with the prescription amount is weighed, the propylene glycol, the azone, the HP-beta-CD and the glycerol triacetate with the prescription amount are respectively added to dissolve, finally the glycerol triacetate with the constant volume of 1000ml is added to be stirred uniformly, filtered and subpackaged in 5ml bottles, the caps are sealed and covered, and the bottles are placed in a shady and cool place to be kept away from light. Each cigarette with the size of 3ml contains colchicine as main medicine 0.2 w/v%. See fig. 1.
2.5 prescription and Process determination
The prescription screening determines the prescription composition of the colchicine liniment:
2.5.1 prescription i:
| components | Dosage of |
| Colchicine | 2g |
| HP-β-CD | 25g |
| 1, 2-propanediol | 200ml |
| Azone compounds | 20ml |
| Glycerol triacetate | Adding the total amount to 1000ml |
Weighing colchicine raw material medicine according to the prescription, respectively adding propanediol, azone, HP-beta-CD and a proper amount of glycerol triacetate according to the prescription, dissolving in water bath at 50 ℃, and finally adding glycerol triacetate to reach the constant volume of 1000 ml.
2.5.2 prescription ii:
weighing colchicine and beta-cyclodextrin according to the prescription amount, adding into a composite solvent mixed by glycerol, 1, 2-propylene glycol and azone, shaking to dissolve, and supplementing polyethylene glycol-400 to 1000ml of scales to obtain the compound colchicine and beta-cyclodextrin.
2.5.3 prescription iii:
weighing colchicine and dimethyl-beta-cyclodextrin according to the prescription amount, adding into the mixed solution of glycerol, 1, 2-propylene glycol, polyethylene glycol-400 and tween 80, shaking to dissolve, and adding polyethylene glycol-300 to 1000ml scale to obtain the final product.
2.5.4 prescription iv:
weighing colchicine and polyethylene glycol-600 according to 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. Points of the prescription
3.1 selection of composite vehicle system is the key of the invention, the optimized formula of the composite vehicle system (such as azone, 1, 2-propylene glycol and glycerol triacetate; polyethylene glycol, 1, 2-propylene glycol, glycerol and azone; polyethylene glycol, 1, 2-propylene glycol, glycerol and tween; and glycerol triacetate, polyethylene glycol, 1, 2-propylene glycol and polyoxyethylene castor oil) has stable performance; the quality is controllable; no irritation and sensitization to skin; quick absorption and reliable clinical effect. The curative effect of the traditional Chinese medicine preparation is obviously better than that of oral administration, but the traditional Chinese medicine preparation almost has no systemic toxic or side effect.
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 composite 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 the irritation of the preparation to the skin.
3.3 the main solvent (for example, glycerol triacetate or polyethylene glycol) in the invention is not only the solvent, but also mainly the solvent which permeates into the inflammatory tissue to dissolve the uric acid deposited in the inflammatory tissue, and reduces the uric acid in the local inflammatory tissue, thereby assisting the control of inflammation and the reduction of pain.
3.4 the product has simple preparation process, low cost and easy operation, can ensure the product quality, and is suitable for batch production.
Example II anti-inflammatory action of colchicine linimentum on gout model animals
1. Materials and methods
1.1 drugs and reagents colchicine liniment (i.e. formula 4 in table 1-1, i.e. formula i in example one 2.5.1, colchicine content 0.2 w/v%), colchicine (99.79% in kunming pharmaceutical co., ltd. of yunnan), sodium urate (Sigma), prostaglandin E2(PGE2) radioimmunoassay kit (provided by tokyo institute of immunology and technology, beijing), tumor necrosis factor-alpha (TNF-alpha) kit (provided by institute of military medical sciences).
1.2 Experimental animals SD rat, male, clean grade, weight 200-.
1.3 methods
1.3.1 establishment of model of acute gouty arthritis according to the classical method of CODERRRE (CoderretTJ, WallPD, Anklejoy arthritis surgery administration for the evaluation of organic matters, Pharmacology biochemistry & Behavior,1988,29(3): 461-466). A6-gauge injection needle was inserted into the medial side of the tibia at an angle of 45 degrees to the dorsal side of the left ankle joint of a test rat, and a 10% sodium urate solution was injected into the cavity of the ankle joint at a rate of 0.2 ml/tube.
1.3.2 animal grouping and treatment 30 rats were randomly divided into 3 groups of 10 animals each, normal control (no molding), model group, colchicine treatment group. The normal control group was not treated at all. The model group is smeared with blank solvent of colchicine liniment every day for 3 times/day and continuously for 5 days. The liniment group is applied with colchicine liniment every day, and the application method is the same as that of the model group.
1.4 Observation index
1.4.1 degree of swelling of rat articular the circumferences of rats were measured with inelastic flexible rule at the same position of ankle joint before model building, 3h after model building (before administration) and 3h after administration, respectively, and the change of ankle joint circumference before model building and before and after treatment was observed.
1.4.2 determination of PGE2, TNF-alpha and white blood cells in articular cavity Each group of rats was killed by decapitation after 72h of model building treatment, the tested articular cavity was opened to remove joint effusion and smear, and white blood cell counting was performed; soft tissues around the joint cavity were removed, homogenized and assayed for PGE2, TNF- α in the tissues by radioimmunoassay, following the instructions of the kit.
1.5 statistical method adopts SPSS12.0 statistical software, measured normal data are all expressed by x +/-s, the skewed distribution data are expressed by M (Min-Max), the comparison among groups adopts t test, and the comparison of multiple groups of means adopts variance analysis.
2 results
2.1 influence on swelling of ankle joint of gouty arthritis rat before drug administration after model building, the swelling of joint of model group and liniment group is obvious, and the difference compared with normal control group has statistical significance (P is less than 0.01). See Table 2-1.
TABLE 2-1 comparison of the change in the degree of swelling of the joints in each group
(×±Smm)
Difference # 1: before medicine-after medicine application; compared with the normal group, P is less than 0.01, and compared with XX in a blank solvent, the liniment group and the model group (XX) are less than 0.05, delta and less than 0.01.
2.2 Effect on PGE2, TNF-. alpha.levels and white blood cell counts in articular cavity tissues of gouty arthritis rats
The contents of PGE2 and TNF-alpha in the rat articular cavity tissue of 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 rat articular cavity tissue of 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 rat 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 rat in the liniment group is obviously reduced (P is less than 0.01) compared with that of the model group. See Table 2-2.
TABLE 2-2 comparison of PGE2, TNF-. alpha.content and leukocyte count in articular cavity tissues of various groups of rats
(×±Smm)
Other prescriptions of the invention (e.g. prescriptions ii, iii, iv of example one 2.5.1) also have similar therapeutic effects.
2.3 results the root cause of acute gouty arthritis is the precipitation of crystals of sodium urate in the local joints caused by hyperuricemia. The model of gouty arthritis caused by local joint injection of sodium urate is considered as a classic gouty arthritis molding method and can be used for evaluating the curative effect of anti-gouty arthritis drugs.
Colchicine as the first choice medicine for modern medicine treatment of acute gout can inhibit phagocytosis of urate crystal by neutrophil, block release of chemotactic factor, reduce polymorphonuclear leukocyte flow and adhesion, inhibit tyrosine phosphorylation and leukotriene B4 production, thereby reducing deposition of urate crystal, relieving inflammation reaction, and eliminating swelling and pain. However, the toxic and side effects of colchicine are as described above, and the colchicine is orally administered according to the standard specified by the pharmacopoeia, 50-80% of patients have gastrointestinal tract reaction before the curative effect appears, and dehydration, electrolyte disorder and other manifestations are caused by severe patients, and most patients cannot tolerate the colchicine. In order to avoid the toxic and side effects of colchicine, the colchicine liniment in the embodiment of the invention can be quickly absorbed through skin and enter the cuticle of the skin, thus reducing the drug entering blood circulation and avoiding the toxic and side effects caused by systemic distribution.
The colchicine liniment has reliable anti-inflammatory effect on rats with gout models, and provides basis for clinical treatment of acute gouty arthritis.
EXAMPLE III Studies on the irritation and sensitization of colchicine linimentum to skin
Toxicological research is a key link in drug research and development, and determines whether drugs can enter clinic or not and whether the drugs are safe to use or not. The chemical irritation and allergy refer to the local toxicity (such as irritation and allergy) and/or systemic toxicity (such as irritation and hemolysis) of the chemical preparation administered by non-oral route such as eye, ear, nose, oral cavity, respiratory tract, joint cavity, skin, rectum, vagina, vein, artery, muscle, subcutaneous, intravenous and intrathecal route. It is a component of preclinical safety assessment.
The colchicine liniment is a novel colchicine dosage form, the effective treatment amount of the colchicine liniment is close to the systemic toxic amount based on the oral dosage of colchicine tablets, and the systemic toxic and side effects are large in clinical application. For the safety of clinical use, the skin irritation and sensitization of colchicine liniment were examined on the skin of two animals, white rabbits and guinea pigs.
1 laboratory instruments and reagents
30 white big-ear rabbits, 15 female rabbits and 15 male rabbits, and the weight of the rabbits is 2-2.5 kg; 55 guinea pigs, 27 females and 28 males with a weight of 250-; animal grade: a cleaning stage; animal sources: beijing Keyu animal breeding center; test drugs: a colchicine liniment, self-made, namely formula 4 in table 1-1, namely formula i in example one 2.5.1; blank solvent: self-made (solvent without main medicine); positive control drug for sensitization test: 2, 4-dinitrochlorobenzene (batch No. 20030701, Shanghai reagent one plant); gauze (batch number: 010708, Beijing Yazhi Biochemical technology institute); transparent ventilating adhesive tape (3M China Co., Ltd.; No. 1527C-0 standard: 12 mm. times.9.1M).
2 experimental methods and results
2.1 Experimental methods
2.1.1 Single skin irritation test
New Zealand big ear white rabbits 15, weight 2-2.5kg, divided into three groups of 5 animals each. One group is complete skin group (one side of back is coated with colchicine liniment, the other side is coated with blank solvent), two groups are damaged skin group (one side of back is coated with colchicine liniment, the other side is coated with blank solvent), and three groups are commercially available control groups (one side of back is complete skin, the other side is damaged skin).
24h before the test, the hair on the back of both sides is shaved by a shaver, and the hair removal range is about 3 multiplied by 3cm respectively2. The damaged skin is marked with a needle to bleed. The test uses the homeomorphic left and right self-control method.
The intact skin groups were examined for lesions prior to administration. During the test, two layers of gauze (2.5X 2.5 cm) are used2) Covering on the skin with hair removed on one side, directly dripping 0.5ml of the tested substance on gauze, covering with fresh-keeping film, and fixing with non-irritant adhesive plaster and common adhesive plaster; the other side of the method is the same. Three groups were applied for 6 hours.
After 6 hours, the test article was removed and the administration site was cleaned with warm water, and erythema, edema, and the like at the application site were visually observed and recorded at 1, 24, 48, and 72 hours after the removal of the test article, respectively. The scoring standard is detailed in guidance of research technology on irritation, allergy and hemolysis of chemical drugs.
2.1.2 multiple skin irritation tests
The grouping and administration method of the test animals are the same as that of the single irritation test, and the administration is carried out at the same time for three consecutive days. 1 hour after each removal of the drug and before reapplication, erythema and edema, whether pigmentation, bleeding spots, rough or thin skin, and the time of occurrence and time of regression were observed and recorded at the application site, and erythema and edema were scored.
After 6 hours from the last application, the drug was removed, and the presence of erythema and edema at the application site was visually observed and recorded at 1, 24, 48 and 72 hours from the removal of the drug, respectively. The scoring standard is detailed in guidance of research technology on irritation, allergy and hemolysis of chemical drugs.
Statistical analysis was performed using SPSS11.5 statistical software processing using random sample analysis of variance and chi-square test, with a significance level a of 0.05.
2.1.3 sensitization test
Guinea pigs 55 were divided into three groups. Is colchicine liniment group, blank solvent group and sensitization positive control drug group respectively. The grouping method includes numbering the male and female separately and grouping with random number list. Of these, 25 (13 males, 12 females) were tested; the blank vehicle group was 15 (8 of them were male, 7 were female); 15 positive control groups (7 males, 8 females).
Administration dose: colchicine liniment: the sensitizing dose is 1ml, and the stimulating dose is 0.1 ml; blank solvent: the sensitizing dose is 1ml, and the stimulating dose is 0.1 ml; positive control drug: 1ml of 1% 2, 4-dinitrochlorobenzene was prepared from 75% ethanol in sensitization concentration, and 1ml of 0.1% 2, 4-dinitrochlorobenzene was prepared from 75% ethanol in excitation concentration.
And (3) sensitization stage: 24h before the test, the guinea pig was depilated with a razor in an area of 3X 3cm2 on the back. Preparing a sealing patch with an area of about 2.5 × 2.5cm2 with colchicine liniment at sensitizing dose, topically administering, covering with plastic film, fixing with noninvasive adhesive plaster and common adhesive plaster, washing off residual liquid with warm water after 6 hr, and repeating the same method for 7d and 14 d. The blank solvent group and the positive control group are treated by the same method.
And (3) an excitation stage: 14 days after the last sensitization, the colchicine liniment with exciting dose is pasted on the non-administration flank by a sealing sheet, covered by a plastic film and fixed by a non-invasive adhesive plaster, and the sealing sheet is removed after 6 hours. The blank solvent group and the positive control group are treated by the same method.
Erythema edema and other abnormal reactions were observed at 1 and 24 hours after each sensitization and at 1, 24 and 48 hours after challenge and erythema and edema were scored according to the guidelines for the study of chemical irritation, hypersensitivity and hemolysis. And weighed at the beginning and end of the test, respectively.
2.2 results of the experiment
2.2.1 New Zealand big ear white Rabbit skin irritation test
The irritation of colchicine liniment to the skin was evaluated by statistics of the observed scores of new zealand white rabbits at different times after single and multiple stimulations. The test results are shown in tables 3-1 and 3-2.
Table 3-1 single skin irritation results (n ═ 5)
P < 0.05, compared to intact skin of the same test substance
1 the stimulation data at each time point in the table are the mean of the stimulation scores of different animals at the same time in each group 2 the mean of the stimulation scores at each time point of different animals in the same group
Table 3-2 multiple skin irritation results (n ═ 5)
P is less than 0.05, and the damaged skin group is compared with colchicine liniment
1 the stimulation data at each time point in the table are the mean of the stimulation scores of different animals at the same time in each group 2 the mean of the stimulation scores at each time point of different animals in the same group
The results of statistical analysis show that the single skin irritation test has no significant difference (P >0.05) between the colchicine liniment and the blank solvent in the intact skin and the damaged skin groups respectively; compared with the whole skin and the damaged skin of the same test object, the irritation of the test object is not obviously different (P > 0.05). The irritation scores in the intact skin group are both 0-0.49, and the irritation scores in the damaged skin group are both 0.5-2.99, i.e. both of the two test substances have no irritation to the intact skin of the white rabbit with big ear, and have slight irritation to the damaged skin.
Multiple irritation tests showed no significant difference between colchicine liniment and vehicle blank (P >0.05) in intact skin group; in the damaged skin group, the colchicine liniment has no significant difference with the blank solvent. The same subjects showed no significant difference between the intact skin group and the damaged skin group.
2.2.2 Guinea pig skin sensitization test
The skin reactions of guinea pigs were observed at different stages and the scores of the skin reactions were recorded, the average of the scores of the same group was used as the skin reaction score, and the data of the three time points of the challenge stage were scored comprehensively, and the results are shown in tables 3 to 3. The skin reactions of the animals in the challenge and sensitization phases were observed and the calculated incidence rates are summarized in tables 3-4. The weight difference was calculated by weighing the guinea pigs at the beginning and end of the test, and the results are shown in tables 3-5.
Tables 3-3 skin sensitization results
P is less than 0.05, blank solvents and positive control in sensitization stage and excitation stage are respectively compared with colchicine liniment, and two guinea pigs in colchicine drug group die in test
The data are the mean scores of different animals at the same time in each group
TABLE 3-4 incidence of skin sensitization
P is less than 0.05, and blank solvents in the sensitization stage and the excitation stage are compared with colchicine liniment
The skin sensitization rate of the guinea pig is calculated according to three observations after excitation
TABLE 3-5 weight of guinea pigs
P is less than 0.05, and the blank solvent is compared with colchicine liniment
Statistical analysis in tables 3-3 showed that there was no significant difference in the combined skin response scores (P >0.05) between the three sensitized colchicine liniment groups during the guinea pig sensitization phase and after challenge.
The statistical analysis in tables 3-4 shows that the skin reaction rate of the sensitized colchicine liniment group and the blank solvent group has significant difference (P is less than 0.001), and the skin reaction rate of the colchicine liniment group and the positive control group has no significant difference (P is more than 0.05). The skin reaction rate of the colchicine liniment group and the blank solvent group has significant difference (P is less than 0.001), and the skin reaction rate of the colchicine liniment group and the positive control group has no significant difference (P is more than 0.05). And the occurrence rate of the skin reaction of the colchicine liniment in the sensitization stage and after excitation has no significant difference (P is more than 0.05).
It can be seen from tables 3-3 and 3-4 that the guinea pigs showed positive skin reactions after three consecutive stimulations with colchicine liniment, the reaction incidence was about 82.6% higher, but the reactions were all slight, the average reaction value was 1.70, and there was no statistical difference between the skin reaction values and the incidence from the first sensitization results.
The statistical analysis in tables 3-5 shows that the weights of the guinea pigs in the three groups before the test are not statistically different (P >0.05), the weights of the guinea pigs in the three groups after the test are statistically different (P <0.001), the weights of the guinea pigs in the blank solvent group and the colchicine liniment group are statistically different (P <0.001), and the weights of the animals in the colchicine liniment group after the test are obviously lower than those in the blank solvent group and the positive control group. The colchicine liniment group animals showed a lower weight gain than the blank vehicle group during the test period and were statistically different. It is shown that the absorption of colchicine in colchicine liniment has a certain effect on the weight gain of guinea pigs.
Other prescriptions of the invention (e.g. prescriptions ii, iii, iv of example one 2.5.1) also have similar therapeutic effects.
3 conclusion
In an irritation test, the colchicine liniment has no irritation reaction to the skin after single administration on the intact skin and has slight reversible irritation to the damaged skin; multiple administrations of skin are slightly irritating, and both single and multiple administrations of damaged skin are slightly irritating. The mean irritation value of the liniment to damaged skin is 0.8, which shows that the colchicine liniment does not obviously increase the irritation of the skin after being used for many times. Especially, the repeated medication provides a safety basis for the clinical application of the preparation, and also achieves the aim and the requirement of the design of the preparation formulation.
In the sensitization test, the guinea pigs are sensitized and re-excited by colchicine liniment for three times, the skin reactions are positive in the sensitization stage and the excitation stage, but the reactions are slight, and the comprehensive scores of the skin reactions and the incidence rates of the skin reactions after the sensitization stage and the excitation stage have no significant difference (P is more than 0.05). Meanwhile, the blank solvent has no sensitization to the guinea pig skin, and the skin reaction after sensitization is considered as an irritant reaction in analysis, so that the colchicine liniment has no sensitization.
The weight of guinea pigs in the colchicine liniment group was lower than that in the vehicle group at the end of the test, and the related data also showed that colchicine had hepatotoxicity, nephrotoxicity, neurotoxicity. The human medicine dose can cause poisoning when reaching more than 6mg, and the dose of the preparation in the experimental process is the maximum dose in clinical use. Therefore, the drug property of the death genus bulk drug of two guinea pigs in the guinea pig normal weight gain inhibition and colchicine liniment group during the test is not greatly related to the preparation.
EXAMPLE four clinical observations of efficacy
1. Data and method
1.1 clinical data 59 out-patient and in-patient patients were selected and randomly divided into two groups, 30 colchicine liniment groups, wherein 27 male patients and 3 female patients are aged 43 + -10.8 years and the course of disease is 5.7 + -2.1 years. The data of 29 colchicine oral tablets in a control group, 27 male patients and 2 female patients are comparable in the age of 44.0 +/-10.3 years and the course of disease of 5.3 +/-2.6 years, and the data difference between the two groups has no statistical significance (P is more than 0.05).
1.2 diagnostic criteria reference is made to the American Association for rheumatological arthritis 1977 diagnostic criteria and the clinical rheumatological criteria
1.2.1 red, swollen and hot pain of joints such as toes, tarsometatarss and ankles which are suddenly and repeatedly attacked by middle-aged and old male obese people;
1.2.2 blood uric acid over 420 umol/L;
1.2.3 the X-ray film of the red and swollen joint has the manifestations of gouty arthritis, damaged articular cartilage margin, irregular articular surface, narrow joint gap and change of bone in worm-eating or chisel-hole defect;
the curative effect judgment observes the clinical curative effect of the medicine for 3 days. The effect is shown: the local red swelling and hot pain of the joint basically disappears and the joint moves freely; the method has the following advantages: the local inflammation and heat pain of the joint are obviously relieved, and the activity is improved; and (4) invalidation: the symptoms are not improved or aggravated obviously. And adverse drug reactions were observed.
The treatment method comprises applying colchicine liniment (formula 4 in Table 1-1, namely formula i in example one 2.5.1) to affected part, taking colchicine tablet as control group orally 3 times per day, taking first dose orally 1mg in acute stage, taking 0.5mg orally every 2-3 hr, stopping taking medicine immediately in 24h, limiting protein intake, drinking more water, avoiding fatigue, cooling, strictly giving up alcohol, and avoiding high purine food (heart, liver, kidney, brain, fish, yeast, etc.) to avoid inducing factors.
The statistical treatment dosage data are expressed as (X +/-S), and the total effective rate of the liniment treatment group is superior to that of the oral control group (P is less than 0.05 or 0.01).
2. Results
2.1 the results of the comparison of the two groups of curative effects are shown in the table 4-1, and the results show that the total effective rate of the liniment treatment group is superior to that of the oral control group (P is less than 0.05 or 0.01).
TABLE 4-1 comparison of clinical efficacy of two groups
The significant effect 23/30 (76.7%) of the random liniment treatment group after 3 days of treatment, and the significant difference P of the significant effect 12/29 (41.3%) of the oral administration group after 3 days of treatment is less than 0.01; the total effective rate is 100 percent and 86.2 percent respectively, and the difference is obvious (P is less than 0.05).
Other prescriptions of the invention (e.g. prescriptions ii, iii, iv of example one 2.5.1) also have similar therapeutic effects.
2.2 adverse reactions in the colchicine tablet oral treatment group, gastrointestinal reactions such as nausea, vomiting and diarrhea occurred in 8 patients (27.6%). And 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 transdermal drug absorption, selects the model drug colchicine, and optimizes and selects the prescription through a large amount of pharmacological research; the medicine effect and safety evaluation prove the basis for selecting the liniment, the obvious efficiency of the liniment is obviously superior to that of oral administration through clinical evaluation and observation, particularly the toxic and side effect of the oral administration is reduced, the innovation of the formulation design is realized, the medicine effect and safety of animals are scientifically improved, the clinical evaluation of patients is realized, and the breakthrough advantage is brought to the clinical application of colchicine. The success of the invention can make positive contribution to relieving the pain of the majority of gout patients and improving the level of treating gout in China.
Claims (10)
1. A colchicine composition for external use at least comprises colchicine and an emulsifier, wherein the emulsifier is one or more selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and tween.
2. The colchicine topical composition of claim 1, wherein colchicine is 0.2 w/v% of the total composition.
3. The colchicine composition for external use according to claim 1, wherein the polyoxyethylene castor oil is preferably polyoxyethylene (40) castor oil, polyoxyethylene (35) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (90) castor oil, polyoxyethylene (100) castor oil.
4. The colchicine external composition according to claim 3, wherein the polyoxyethylene hydrogenated castor oil is preferably polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (30) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil.
5. The colchicine topical composition of claim 4, wherein the tween is preferably tween-20, tween-40, tween-60 or tween-80.
6. The colchicine topical composition of claim 5, which consists of colchicine, glycerol 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
Comprises colchicine, glyceryl triacetate, polyethylene glycol, 1, 2-propylene glycol and polyoxyethylene castor oil.
7. A colchicine topical composition as claimed in claim 6, further comprising a vehicle selected from one or more of glycerol triacetate, ethyl acetate, isopropanol, polyethylene glycol, glycerol monoacetate, glycerol diacetate, glycerol triacetate, glycerol monooleate, glycerol dioleate, glycerol trioleate, propylene glycol acid esters, polyoxyethylene castor oil, benzyl acetate, diacetyl monoglyceride, diacetyl tartaric acid (mono, di) glycerol, glycerol diacetate, triethanolamine oleate, triglyceride caprylate, triglyceride caprate, benzyl butyrate and dimethicone.
8. The colchicine topical composition of claim 7, wherein the vehicle is glycerol triacetate.
9. Use of an emulsifier selected from one or more of cremophor oil, cremophor oil and tween for the preparation of a colchicine topical composition.
10. A process for the preparation of the colchicine topical composition of claim 1, which comprises: and completely dissolving the colchicine in the emulsifier and the solvent to obtain the colchicine composition for external use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110531626.5A CN113274342B (en) | 2016-11-08 | 2016-11-08 | Colchicine external composition |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110531626.5A CN113274342B (en) | 2016-11-08 | 2016-11-08 | Colchicine external composition |
| CN201610982414.8A CN108057018B (en) | 2016-11-08 | 2016-11-08 | Colchicine composition for external use and preparation method thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610982414.8A Division CN108057018B (en) | 2016-11-08 | 2016-11-08 | Colchicine composition for external use and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113274342A true CN113274342A (en) | 2021-08-20 |
| CN113274342B CN113274342B (en) | 2023-06-02 |
Family
ID=62137876
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110531626.5A Active CN113274342B (en) | 2016-11-08 | 2016-11-08 | Colchicine external composition |
| CN201610982414.8A Active CN108057018B (en) | 2016-11-08 | 2016-11-08 | Colchicine composition for external use and preparation method thereof |
| CN202110531686.7A Active CN113274343B (en) | 2016-11-08 | 2016-11-08 | Use of polyols as co-solvents in colchicine topical compositions |
| CN202110288326.9A Active CN113041210B (en) | 2016-11-08 | 2016-11-08 | Colchicine external composition |
Family Applications After (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610982414.8A Active CN108057018B (en) | 2016-11-08 | 2016-11-08 | Colchicine composition for external use and preparation method thereof |
| CN202110531686.7A Active CN113274343B (en) | 2016-11-08 | 2016-11-08 | Use of polyols as co-solvents in colchicine topical compositions |
| CN202110288326.9A Active CN113041210B (en) | 2016-11-08 | 2016-11-08 | Colchicine external composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (4) | CN113274342B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113274342B (en) * | 2016-11-08 | 2023-06-02 | 北京天衡军威医药技术开发有限公司 | Colchicine external composition |
| GB2572226A (en) * | 2018-03-24 | 2019-09-25 | Aan Medical Ltd | Gout treatment |
| WO2021070066A1 (en) * | 2019-10-11 | 2021-04-15 | 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 |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02258720A (en) * | 1989-03-31 | 1990-10-19 | Teika Seiyaku Kk | Colchicine-containing pharmaceutical for external use |
| 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 |
| CN103142477A (en) * | 2013-04-08 | 2013-06-12 | 薛巍 | Preparation method of sustained-release colchicine micro emulsion preparation containing nanometer-carrier |
| CN103251550A (en) * | 2012-02-20 | 2013-08-21 | 上海市计划生育科学研究所 | Transdermal delivery ointment containing colchicine, and preparation method thereof |
| CN108057018A (en) * | 2016-11-08 | 2018-05-22 | 北京人福军威医药技术开发有限公司 | Colchicin topical composition and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2838297B2 (en) * | 1989-11-02 | 1998-12-16 | 日産化学工業株式会社 | Topical 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 |
-
2016
- 2016-11-08 CN CN202110531626.5A patent/CN113274342B/en active Active
- 2016-11-08 CN CN201610982414.8A patent/CN108057018B/en active Active
- 2016-11-08 CN CN202110531686.7A patent/CN113274343B/en active Active
- 2016-11-08 CN CN202110288326.9A patent/CN113041210B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02258720A (en) * | 1989-03-31 | 1990-10-19 | Teika Seiyaku Kk | Colchicine-containing pharmaceutical for external use |
| 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 |
| CN103251550A (en) * | 2012-02-20 | 2013-08-21 | 上海市计划生育科学研究所 | Transdermal delivery ointment containing colchicine, and preparation method thereof |
| CN103142477A (en) * | 2013-04-08 | 2013-06-12 | 薛巍 | Preparation method of sustained-release colchicine micro emulsion preparation containing nanometer-carrier |
| CN108057018A (en) * | 2016-11-08 | 2018-05-22 | 北京人福军威医药技术开发有限公司 | Colchicin topical composition and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113041210B (en) | 2023-06-02 |
| CN113274343B (en) | 2023-08-04 |
| CN113274343A (en) | 2021-08-20 |
| CN108057018A (en) | 2018-05-22 |
| CN113274342B (en) | 2023-06-02 |
| CN108057018B (en) | 2021-06-08 |
| CN113041210A (en) | 2021-06-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108057018B (en) | Colchicine composition for external use and preparation method thereof | |
| Mundada et al. | Formulation and evaluation of ciprofloxacin hydrochloride soluble ocular drug insert | |
| US20210401793A1 (en) | Treatment of cutaneous disorders | |
| US20100130568A1 (en) | Topical compositions comprising telmesteine for treating dermatological disorders | |
| WO2021023099A1 (en) | Brucine gel formulation and preparation method therefor | |
| WO2014118040A1 (en) | Extract from indigo tinctoria for the topical treatment and prophylaxis of skin disorders | |
| WO2020093956A1 (en) | External preparation containing vitamin k1 and preparation method therefor | |
| JP2021121617A (en) | Isotretinoin formulations, and uses and methods thereof | |
| BR112019017049A2 (en) | cannabinoid formulations for the treatment of acne | |
| WO2024041083A1 (en) | Antifungal solution, preparation method therefor, and use thereof | |
| JPH03204815A (en) | Therapeutic composition for treating dermatological disease carried by mast cell | |
| WO2017173442A1 (en) | Topical compositions for neuropathic pain | |
| EP2468270A1 (en) | (R)-2-(3-fluoro-4-phenylphenyl)propionic acid for use in the treatment of skin diseases | |
| WO2023187116A1 (en) | Mirabegron formulation | |
| Öztürk et al. | Pharmacological and pharmaceutical technological overview for seborrheic dermatitis: A review about topical application and new approaches | |
| WO2023016583A1 (en) | Ruxolitinib composition and use thereof | |
| CN112006987B (en) | Cold compress gel for treating rhinitis and preparation method thereof | |
| WO2010122452A1 (en) | A medicinal antifungal and steroid cream incorporating a biopolymer and a process to make it | |
| RU2440108C2 (en) | Pharmaceutical composition for allergic and inflammatory skin diseases | |
| HAMDAN et al. | Formulation and evaluation in vitro a matrix type of ketotifen fumarate transdermal patches for allergic diseases | |
| Nankervis et al. | Emollients and other topical treatments | |
| Wang et al. | Preparing a novel baicalin-loaded microemulsion-based gel for transdermal delivery and testing its anti-gout effect | |
| CN115624520A (en) | Diosmin cream and application thereof | |
| Purohit et al. | COMPARATIVE CLINICAL EFFICACY OF ARK TAILA AND ARK CREAM APPLICATION IN THE MANAGEMENT OF VICHARCHIKA-AN OPEN LABELLED, RANDOMISED CONTROLLED CLINICAL TRIAL | |
| CN116650408A (en) | Local use Keli boron Luo Ningjiao |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |