WO2022105891A1 - 一种马钱子碱凝胶贴膏剂及其制备方法和用途 - Google Patents

一种马钱子碱凝胶贴膏剂及其制备方法和用途 Download PDF

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WO2022105891A1
WO2022105891A1 PCT/CN2021/131901 CN2021131901W WO2022105891A1 WO 2022105891 A1 WO2022105891 A1 WO 2022105891A1 CN 2021131901 W CN2021131901 W CN 2021131901W WO 2022105891 A1 WO2022105891 A1 WO 2022105891A1
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Prior art keywords
strychnine
cross
agent
paste
gel patch
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PCT/CN2021/131901
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English (en)
French (fr)
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胡杰
薛春美
赵倩
方秘芬
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北京盈科瑞创新医药股份有限公司
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Priority to US18/253,878 priority Critical patent/US20240100042A1/en
Priority to JP2023529039A priority patent/JP2023551417A/ja
Priority to EP21894038.5A priority patent/EP4248953A4/en
Publication of WO2022105891A1 publication Critical patent/WO2022105891A1/zh

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    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and in particular relates to a strychnine gel patch and a preparation method and application thereof.
  • Osteoarthritis is a degenerative joint disease characterized by joint pain, swelling, stiffness and other symptoms. Arthritis is the main symptom of joint swelling and pain, and the most important pathological feature of osteoarthritis is the damage of articular cartilage. Strychni is bitter in nature, warm; highly poisonous. It has the effect of clearing the collaterals and relieving pain, dissipating knots and swelling. For bruises, fractures, swelling and pain, rheumatism, numbness and paralysis. The medicinal materials of strychnids have a history of dispersing knots, reducing swelling, dredging collaterals, and relieving pain. It has been used for thousands of years in the treatment of arthritis, and it is mostly used in clinical practice.
  • strychnine is total alkaloids, which include strychnine, strychnine, strychnine, strychnine, strychnine, icariin, etc.; strychnine is The medicinal components of Chinese herbal medicine strychnids in the treatment of arthritis. Modern pharmacological studies have proved that strychnine not only has anti-inflammatory and analgesic activity, but also can promote the proliferation of chondrocytes and inhibit the early apoptosis of chondrocytes. Strychnine basically has no anti-inflammatory and analgesic effects, and strychnine is the main toxic component of strychnine.
  • strychnine-containing preparations that have been listed on the market are compound prescriptions, and because they contain strychnine, the treatment window is narrow. At present, there is no strychnine monomer-related preparation on the market.
  • the oil-water partition coefficient (logP) of strychnine is between 1 and 2, and the percutaneous absorption is good.
  • the existing technology has developed strychnine into external compound preparations, such as gels and gel patches. , the use of pressure-sensitive adhesive patches, etc., but it is necessary to add penetration enhancers such as azone with strong penetration-promoting effect in the prescription to improve the penetration effect of active ingredients.
  • Azone has a strong skin penetration promoting effect, but due to the high lipophilicity of azone, long-term use will accumulate in the skin for a long time, destroy the stratum corneum, cause irreversible skin damage, and be highly irritating.
  • the invention provides a strychnine gel patch and a preparation method thereof, which have good transdermal absorption effect without using a transdermal enhancer, are used for the treatment of osteoarthritis and rheumatoid arthritis, and can greatly improve the Improve the safety of clinical applications.
  • the purpose of the present invention is to provide a novel strychnine gel patch with excellent safety, sustained release and excellent transdermal effect, and its preparation method and application, aiming at the defects existing in the prior art.
  • the strychnine gel patch provided by the invention has good anti-inflammatory and analgesic effects according to the drug efficacy test, the preparation process is simple, the operability is strong, and industrial production can be realized.
  • a first aspect of the present invention is to provide a strychnine gel patch, calculated by weight percentage, the patch comprises 0.3%-2% strychnine, 3%-10% skeleton material, 20% strychnine -50% humectant and cosolvent, 0.1%-2% crosslinking agent and crosslinking regulator, the balance is water, and backing layer, release layer.
  • the strychnine gel patch calculated by weight percentage, comprises 0.3%-1% strychnine, 4%-8% skeleton material, 25%-40% moisturizing agent and Cosolvent, 0.3%-1% of cross-linking agent and cross-linking regulator, the balance is water, and backing layer, release layer.
  • the skeleton material is selected from carbomer, sodium alginate, gum arabic, tragacanth, gelatin, starch, xanthan gum, polyacrylic acid (sodium), polyvinyl alcohol , povidone K90, povidone K30, sodium carboxymethyl cellulose, polyvinylpyrrolidone, HPMC, alginic acid and its sodium salt, polyacrylic acid cross-linked resin, polyacrylic acid partial neutralization (NP-600, NP- 700, NP-800) in one or more combinations; preferably, the skeleton material is selected from polyacrylic acid partial neutralizers (NP-600, NP-700, NP-800), sodium polyacrylate, polyacrylic acid One or more of vitamin K90 and sodium carboxymethyl cellulose.
  • the moisturizing agent and cosolvent are selected from ethanol, urea, olive oil, polysorbate 80, polysorbate 60, propylene glycol, glycerin, DMSO, diethylene glycol monoethyl ether , a combination of one or more of polyethylene glycol 400, eucalyptus oil, cyclodextrin, sorbitol; preferably, the humectant and cosolvent are selected from glycerol, propylene glycol, DMSO, polysorbate 80, One or a combination of two or more of polyethylene glycol 400 and cyclodextrin.
  • the cross-linking agent and the cross-linking regulator are selected from aluminum hydroxide, aluminum glycerol, aluminum trichloride, aluminum sulfate, alum, composite aluminum salt, tartaric acid, citric acid A combination of one or more of , malic acid, edetic acid and its sodium salt; preferably, the cross-linking agent and the cross-linking regulator are selected from aluminum carboxylate, aluminum hydroxide, tartaric acid, citric acid, ethylene glycol A combination of one or more of teric acid and its sodium salt.
  • the backing layer is selected from materials known to those skilled in the art, such as non-woven fabrics, rayon and the like.
  • the release layer is selected from materials known to those skilled in the art, such as polypropylene embossed film, polyethylene film, release paper, plastic film, hard gauze and the like.
  • the strychnine gel patch may further comprise 0.05%-0.075% by weight of an antioxidant;
  • the antioxidant is selected from anhydrous sodium sulfite, coke A combination of one or more of sodium sulfite, sodium bisulfite, sodium thiosulfate, tert-butyl-p-hydroxyanisole, dibutyl phenol, vitamin C, vitamin C palmitate, edetic acid and its sodium salt ;
  • the strychnine gel patch can also contain 0.01%-0.3% bacteriostatic agent, preferably 0.1%-0.2% bacteriostatic agent in weight percentage; the bacteriostatic agent is selected from chlorobutanol, hydroxyl The combination of one or more of phenethyl ester, benzyl alcohol, methylparaben, butylparaben, sorbic acid and its potassium salt, menthol, benzoic acid and its sodium salt;
  • the strychnine gel patch can also contain 0.1-10% filler by weight percentage; preferably 0.1-5% filler; the filler is selected from kaolin, diatomite, bentonite, zinc oxide, A combination of one or more of titanium dioxide and micropowder silica gel; preferably, the filler is selected from a combination of one or more of kaolin, titanium dioxide, and micropowder silica gel;
  • the invention provides a preparation method of strychnine gel patch, which can be prepared by any one of methods one to three.
  • Method 1 comprising the following steps: (1) preparing a blank matrix comprising a moisturizing agent and a cosolvent, a bacteriostatic agent, a skeleton material, a cross-linking agent and a cross-linking regulator, an antioxidant and a prescription amount of water; The strychnine paste is dissolved in a cosolvent and mixed with a blank matrix to obtain a strychnine paste; (3) the strychnine paste is coated on the backing layer, and a release layer is attached to obtain a strychnine gel paste ointment.
  • Method 2 comprising the following steps: (1) preparing a strychnine organic phase, comprising a moisturizing agent and a cosolvent, strychnine, a bacteriostatic agent, a skeleton material, a cross-linking agent and a cross-linking regulator, and an antioxidant; (2) preparing an aqueous phase matrix, comprising a crosslinking agent, a crosslinking regulator and water; (3) mixing the strychnine organic phase and the aqueous phase matrix to obtain a strychnine paste; (4) strychnine paste The body is coated on the backing layer, and the release layer is attached to obtain the strychnine gel patch.
  • Method three comprising the following steps: (1) preparing an organic phase matrix, including a moisturizing agent, a bacteriostatic agent, a skeleton material, a cross-linking agent, a cross-linking regulator, and an antioxidant; (2) preparing a strychnine aqueous phase, It comprises strychnine, a cross-linking agent and a cross-linking regulator, a cosolvent and water; (3) the organic phase matrix is mixed with the strychnine aqueous phase to obtain a strychnine paste; (4) the strychnine paste The body is coated on the backing layer, and the release layer is attached to obtain the strychnine gel patch.
  • an organic phase matrix including a moisturizing agent, a bacteriostatic agent, a skeleton material, a cross-linking agent, a cross-linking regulator, and an antioxidant
  • (2) preparing a strychnine aqueous phase It comprises strychnine, a cross-linking agent and a cross-linking regulator,
  • Method 4 includes the following steps:
  • organic phase matrix comprising a moisturizing agent, a skeleton material, a crosslinking agent and a crosslinking regulator
  • organic phase matrix is mixed with strychnine aqueous phase to obtain strychnine paste
  • strychnine paste is coated on the backing layer, and the release layer is attached to obtain strychnine gel paste Ointment
  • the organic phase matrix further optionally includes bacteriostatic agents and antioxidants.
  • the invention provides the application of a strychnine gel patch in the preparation of a medicament for knee osteoarthritis.
  • blank base refers to everything except strychnine in the strychnine paste.
  • organic phase refers to the water-immiscible, organic compound-based portion.
  • aqueous phase refers to the water-based portion.
  • matrix material refers to a substance that supports the product's framework, stores the drug, creates viscosity, and retains water and moisture.
  • solvent refers to a substance that aids in the dissolution and release of the main drug.
  • humectant refers to a substance designed to retard water loss and improve product stability.
  • crosslinking agent refers to a substance that makes the product have a microscopic three-dimensional structure and improves the stability of the product.
  • crosslinking modifier refers to a substance that improves product stability and enables the drug to be in an optimal dissolution state.
  • the present invention has the following beneficial effects:
  • strychnine topical patch avoids oral toxicity, improves the bioavailability of the drug, and improves the therapeutic effect.
  • the prepared strychnine gel patch uses simple medicinal excipients and does not use highly irritating transdermal accelerators such as azone, but has excellent transdermal effect, good skin compatibility, moisturizing and breathable , non-irritating to skin and mucous membranes, large drug loading, and can be applied repeatedly.
  • the balance in the prescription is made up with water.
  • the above prescription shows that the paste obtained by replacing the partial neutralization of sodium polyacrylate with CMC-Na or gelatin is unstable, while the partial neutralization of sodium polyacrylate, cross-linking agent and cross-linking Regulators are the main ingredients, together with suitable cosolvents, moisturizing agents and other skeleton materials, a gel patch with stable properties can be obtained.
  • an appropriate preparation method can be selected according to the types of the auxiliary materials, and the gel patches obtained by the three methods have stable and good properties.
  • strychnine is dissolved in DMSO, add propylene glycol, glycerol, NP-800, CMC-Na, kaolin, disodium edetate, aluminum glycerol and mix to obtain strychnine organic phase; (2) ) Mixing and dissolving tartaric acid and water to obtain an aqueous phase solution, adding the strychnine organic phase and stirring to obtain a strychnine paste; (3) the strychnine paste is coated on the backing layer , and attach the release layer to obtain the strychnine gel patch.
  • strychnine , tartaric acid, polysorbate 80, and water are mixed and dissolved to obtain a strychnine aqueous phase solution, which is added to the organic phase matrix and stirred evenly to obtain a strychnine paste; (3) the strychnine paste is coated on On the backing layer, a release layer is attached to obtain a strychnine gel patch.
  • glycerin 400 Propylene Glycol 160 NP-700 100 Aluminum hydroxide 6 ethyl paraben 2 Disodium Edetate 4 tartaric acid 10 Eucalyptus Oil 40 polyvinyl alcohol 60 water 1208 backing layer non-woven fabric release layer Polypropylene Embossed Film
  • Ethyl paraben is dissolved in propylene glycol, and glycerin, oleic acid, NP-600, CMC-Na, sodium alginate, kaolin, disodium edetate, titanium dioxide, aluminum glycerol are added and mixed to obtain an organic phase matrix; (2 ) mixing strychnine, citric acid and water to obtain a strychnine aqueous phase solution, adding in the organic phase matrix and stirring to obtain a strychnine paste; (3) coating the strychnine paste On the backing layer, a release layer is attached to obtain a strychnine gel patch.
  • Test Example 1 Properties of the strychnine gel patch preparation of the present invention
  • Test Example 2 Study on the release rate of the strychnine gel patch formulation of the present invention
  • Example 1 Measure 900ml of the dissolution medium (4% sodium chloride solution) in the dissolution vessel, pre-warm to 32°C ⁇ 0.5°C, and apply Example 1, Example 2, Example 3, Example 4, Example 5, and Example 6,
  • Example 7 Example 8, Example 9, and Example 10 were fixed on the net plate, with the dissolution surface facing up, and kept as flat as possible. Then place the mesh plate horizontally at the lower part of the dissolution cup, and make the mesh plate and the rotating surface of the pulp bottom parallel, the distance between the two is 25mm ⁇ 2mm, 50 rpm, take samples regularly, absorb an appropriate amount of the dissolution liquid, and replenish the same volume in time. The temperature is 32 °C ⁇ 0.5 °C dissolution medium. The results are shown in Table 2 below:
  • Example 1 (%) 0 26.39 38.07 65.78 80.14 90.52
  • Example 2 (%) 0 40.33 56.84 86.35 96.31 100.53
  • Example 3 (%) 0 35.17 43.23 73.96 84.87 98.05
  • Example 4 (%) 0 42.11 54.49 84.87 95.97 99.78
  • Example 5 (%) 0 43.21 60.57 88.17 98.39 100.04
  • Example 6 (%) 0 42.43 55.02 86.84 95.29 99.86
  • Example 7 (%) 0 41.67 58.09 87.14 95.68 100.63
  • Example 8 (%) 0 38.07 57.78 87.02 95.54 100.02
  • Example 9 (%) 0 43.57 59.08 87.29 94.09 100.35
  • Example 10 (%) 0 25.93 37.29 68.74 82.16 93.04
  • Example 1 and Example 10 are slightly slower than other examples, there is no obvious difference in the release rate of the other examples.
  • the 8-hour cumulative release results of all the examples are greater than 90%, with good effects.
  • Test Example 3 In vitro release study of the strychnine gel patch formulation of the present invention
  • the rats were sacrificed by de-cervical vertebrae, the abdomen and surrounding hair were removed with a razor, and the dehaired part of the rat skin was peeled off with dissecting scissors. Facing the drug supply room, the inner layer of the skin was just in contact with the receiving solution, and the gel patch with the anti-adhesive layer was removed on the skin surface.
  • the temperature of the water bath in the receiving chamber was 37°C, and the rotational speed of the magnetic stirring was 500 rpm. Samples were taken at 1, 2, 4, 6, 8, and 24 h respectively, all the receiving solution was taken out, and an equal amount of fresh receiving solution was added. The results are shown in Table 3 below:
  • Example 2 ( ⁇ g) 0 0.78 2.15 6.38 10.45 14.89 76.37
  • Example 4 ( ⁇ g) 0 0.19 0.56 2.01 3.42 5.68 49.15
  • Example 5 ( ⁇ g) 0 0.21 0.78 3.52 6.89 15.25 80.02
  • Example 6 ( ⁇ g) 0 0.23 0.56 3.08 6.56 12.74 55.81
  • Example 7 ( ⁇ g) 0 0.20 0.77 3.19 6.78 14.15 70.61
  • Example 8 ( ⁇ g) 0 0.19 0.69 2.77 5.89 10.96 52.63
  • Example 9 ( ⁇ g) 0 0.10 0.63 2.98 6.32 11.05 56.62 Comparative example (commercially available indomethacin bab ointment) 0 0.27 0.74 1.98 3.48 5.33 32.36
  • the strychnine gel patch provided by the present invention does not use a skin penetration enhancer such as azone with a strong penetration promoting effect to improve the skin penetration effect of the active ingredient.
  • a skin penetration enhancer such as azone
  • the commercially available indomethacin bab ointment contains azone, and in the in vitro transdermal experiment, the test results show that the cumulative transdermal quality of the embodiment of the present invention in 24 hours is higher than that of the control group.
  • Example 2 The prescriptions in Table 3 were screened through the pre-test of the efficacy of osteoarthritis.
  • Example 2, Example 5, and Example 7 had better efficacy in the treatment of osteoarthritis. Therefore, to embodiment 2, example 5, embodiment 7 has carried out formal osteoarthritis pharmacodynamics research, concrete test method and result are as follows:
  • SD rat, SPF grade (special pathogen-free laboratory animal): body weight 210-220g, all male, purchased from Speifu (Beijing) Biotechnology Co., Ltd.;
  • Flurbiprofen gel patch manufacturer: MIKASA SEIYAKU CO.,LTD KAKEGAWA FACTORY, packaging company: Beijing Tide Pharmaceutical Co., Ltd. Lot number: 103023-01,
  • L-cysteine WXBD0897V, SIGMA
  • the modeling site was the right knee joint, and the modeling was unilateral.
  • Rats were injected with 4% papain and 0.03mol/L L-cysteine (mixed in volume 2:1) into the joint cavity to establish a model.
  • the X-ray film results showed that compared with the model group, the X-ray scores of the example group and the flurbiprofen gel patch group were significantly decreased (p ⁇ 0.001, p ⁇ 0.01, p ⁇ 0.05), and both of them could significantly reduce the severity of the model rats.
  • Degenerative diseases such as knee joint cavity stenosis, osteophyte and bone sclerosis have a significant therapeutic effect on knee osteoarthritis.
  • the pain threshold results showed that, compared with the model group, the pain threshold was significantly increased in the example group and flurbiprofen gel patch group (p ⁇ 0.001), and both were significantly analgesic.
  • the gross observation score of articular cartilage showed that compared with the model group, the gross observation score of articular cartilage in the example group and flurbiprofen gel patch group was significantly lower (p ⁇ 0.01, p ⁇ 0.05), both of which had the effect of protecting cartilage.
  • Measurement time before grouping and at the end of administration.
  • Measurement method let the rats run on a track with a length of 1 meter and a width of A4 paper, and the two hind feet are coated with ink pad. Then score according to the amount of model foot print mud covering the entire foot.
  • Scoring standard 0 points: the left and right soles have the same color
  • the left sole is 25-50% darker than the right sole;
  • the left sole is 50-75% darker than the right sole;
  • Measurement time before grouping and at the end of administration.
  • Determination method Determination by high-frequency X-ray machine. Evaluate according to the K-L grading system.
  • Scoring criteria 0 points: no change
  • JSN joint stenosis
  • labial hyperplasia Suspected joint stenosis
  • Measurement method VonFrey pain method.
  • the articular surface is rough, with small cracks and gray color

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Abstract

一种马钱子碱凝胶贴膏剂及其制备方法。所述马钱子碱凝胶贴膏剂，按重量百分比计算，包括0.3％-2％的马钱子碱，3％-10％骨架材料，20％-50％保湿剂和助溶剂，0.1％-2％的交联剂与交联调节剂，余量为水，以及背衬层，防粘层。使用简单的药用辅料，不使用透皮促进剂，皮肤相容性好，保湿透气，对皮肤和粘膜无刺激性，载药量大，可反复贴敷。该贴膏剂用于治疗或改善骨关节炎、风湿性关节炎，类风湿性关节炎等相关需要抗炎镇痛的疾病。

Description

一种马钱子碱凝胶贴膏剂及其制备方法和用途 技术领域
本发明属于药物制剂领域，具体涉及一种马钱子碱凝胶贴膏剂及其制备方法和用途。
背景技术
骨关节炎(OA)是一种关节退行性疾病，临床表现为关节疼痛、肿胀、僵硬等症状。关节炎是以关节肿痛为主要症状，骨关节炎最重要的病理学特征是关节软骨受损。马钱子性苦，温；有大毒。具有通络止痛，散结消肿的功效。用于跌打损伤，骨折肿痛，风湿顽痹，麻木瘫痪等。马钱子药材散结、消肿、通络、止痛，治疗关节炎已有上千年的历史，临床多为复方应用。马钱子的主要有效成分是总生物碱，其包括马钱子碱、士的宁、番木鳖次碱、马钱子新碱、番木鳖甙、依卡精等；马钱子碱是中药材马钱子治疗关节炎的药效成分。现代药理学研究证明，马钱子碱不仅具有抗炎镇痛活性，还能够促进软骨细胞增殖和抑制软骨细胞早期凋亡。士的宁基本无抗炎、镇痛作用，并且，士的宁是马钱子的主要毒性成分。
已上市的含马钱子碱相关制剂，全部为复方，由于含有士的宁，治疗窗口窄。目前，还没有马钱子碱单体相关制剂上市。
马钱子碱的油水分配系数(logP)在1-2之间，经皮吸收较好，目前已有现有技术将马钱子碱开发成外用复方制剂，比如凝胶剂、凝胶贴剂、使用压敏胶的贴剂等，但都需要在处方中加入具有强促渗作用的氮酮等透皮促进剂以提高活性成分的透皮效果。氮酮有极强的皮肤促渗作用，但由于氮酮具有高亲脂性，长期使用会在皮肤中长期蓄积，破坏角质层，导致不可逆的皮肤损伤，具有强刺激性。
本发明提供一种马钱子碱凝胶贴膏剂及其制备方法，不需要使用透皮促进剂就有很好的透皮吸收效果，用于骨关节炎、风湿性关节炎治疗，可以大幅度提高临床应用的安全性。
发明内容
本发明的目的就是针对现有技术存在的缺陷，提供一种安全、缓释、透皮效果优异的新型马钱子碱凝胶贴膏剂及其制备方法和用途。且本发明提供的马钱子碱凝胶贴膏剂，经药效试验表明具有良好的抗炎镇痛效果，制备工艺简单、可操作性强，可实现工业化生产。
本发明的第一个方面在于提供一种马钱子碱凝胶贴膏剂，按重量百分比计算，该贴膏剂包括0.3％-2％的马钱子碱，3％-10％骨架材料，20％-50％保湿剂和助溶剂，0.1％-2％的交联剂与交联调节剂，余量为水，以及背衬层，防粘层。
优选地，所述马钱子碱凝胶贴膏剂，按重量百分比计算，该贴膏剂包含0.3％-1％的马钱子碱，4％-8％骨架材料，25％-40％保湿剂和助溶剂，0.3％-1％的交联剂与交联调节剂，余量为水，以及背衬层，防粘层。
所述马钱子碱凝胶贴膏剂中，所述骨架材料选自卡波姆、海藻酸钠、阿拉伯胶、西黄芪胶、明胶、淀粉、黄原胶、聚丙烯酸(钠)、聚乙烯醇、聚维酮K90、聚维酮K30、羧甲基纤维素钠、聚乙烯吡咯烷酮、HPMC、海藻酸及其钠盐、聚丙烯酸交联树脂、聚丙烯酸部分中和物(NP-600、NP-700、NP-800)中的一种或多种的组合；优选地，所述骨架材料选自聚丙烯酸部分中和物(NP-600、NP-700、NP-800)、聚丙烯酸钠、聚维酮K90、羧甲基纤维素钠中的一种或多种。
所述马钱子碱凝胶贴膏剂中，所述保湿剂和助溶剂选自乙醇、尿素、橄榄油、聚山梨酯80、聚山梨酯60、丙二醇、甘油、DMSO、二乙二醇单乙醚、聚乙二醇400、桉叶油、环糊精、山梨醇中的一种或多种的组合；优选地，所述保湿剂和助溶剂选自甘油、丙二醇、DMSO、聚山梨酯80、聚乙二醇400和环糊精中的一种或两种或多种的组合。
所述马钱子碱凝胶贴膏剂中，所述交联剂与交联调节剂选自氢氧化铝、甘羟铝、三氯化铝、硫酸铝、明矾、复合铝盐、酒石酸、柠檬酸、苹果酸、依地酸及其钠盐中的一种或多种的组合；优选地，所述交联剂与交联调节剂选自甘羟铝、氢氧化铝、酒石酸、柠檬酸、依地酸及其钠盐中的一种或多种的组合。
所述马钱子碱凝胶贴膏剂中，所述背衬层选自本领域人员公知的材料，如无纺布、人造棉布等。
所述马钱子碱凝胶贴膏剂中，所述防粘层选自本领域人员公知的材料，如聚丙烯压花膜、聚乙烯膜、防黏纸、塑料薄膜、硬质纱布等。
本发明第一个方面的一些实施方式中，所述马钱子碱凝胶贴膏剂按重量百分比计算还可以包含0.05％-0.075％抗氧剂；所述抗氧剂选自无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基苯酚、维生素C、维生素C棕榈酸酯、依地酸及其钠盐中的一种或多种的组合；
所述马钱子碱凝胶贴膏剂按重量百分比计算还可以包含0.01％-0.3％抑菌剂，优选0.1％-0.2％抑菌剂；所述抑菌剂选自三氯叔丁醇、羟苯乙酯、苯甲醇、羟苯甲酯、羟苯丁酯、山梨酸及其钾盐、薄荷脑、苯甲酸及其钠盐中的一种或多种的组合；
所述马钱子碱凝胶贴膏剂按重量百分比计算还可以包含0.1-10％填充剂；优选0.1-5％填充剂；所述填充剂选自高岭土、硅藻土、皂土、氧化锌、二氧化钛、微粉硅胶中的一种或多种的组合；优选地，所述填充剂选自高岭土、二氧化钛、微粉硅胶中的一种或多种的组合；
本发明提供一种马钱子碱凝胶贴膏剂的制备方法，可使用方法一至方法三中的任一种方法制备。
方法一：包括以下步骤：(1)制备空白基质包含保湿剂与助溶剂、抑菌剂、骨架材料、交联剂与交联调节剂、抗氧剂以及处方量的水；(2)将马钱子碱溶于助溶剂中与空白基质混合得到马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
方法二：包括以下步骤：(1)制备马钱子碱有机相，包含保湿剂与助溶剂、马钱子碱、抑菌剂、骨架材料、交联剂与交联调节剂、抗氧剂；(2)制备水相基质，包含交联剂与交联调节剂和水；(3)马钱子碱有机相与水相基质混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
方法三：包括以下步骤：(1)制备有机相基质，包含保湿剂、抑菌剂、骨架材料、交联剂与交联调节剂、抗氧剂；(2)制备马钱子碱水相，包含 马钱子碱、交联剂与交联调节剂、助溶剂与水；(3)有机相基质与马钱子碱水相混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
方法四：包括如下步骤：
(1)制备有机相基质，包含保湿剂、骨架材料、交联剂与交联调节剂；(2)制备马钱子碱水相，包含马钱子碱、交联调节剂与水；(3)有机相基质与马钱子碱水相混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂；步骤(1)有机相基质还任选包含抑菌剂、抗氧剂。
上述方法中所有辅料按照处方量及种类实际情况进行调整。
本发明提供一种马钱子碱凝胶贴膏剂在制备用于膝骨关节炎的药物中的应用。
本发明中，如无特别说明，其中：
术语“空白基质”是指除马钱子碱膏体中除马钱子碱以外的一切组成。
术语“有机相”是指与水不相溶的，以有机化合物为主体的部分。
术语“水相”是指水为主体的部分。
术语“骨架材料”是指有产品的骨架支撑，药物储库，产生粘性，保水保湿作用的物质。
术语“助溶剂”是指有助于主药溶解及释放的物质。
术语“保湿剂”是指在于延缓水份丢失、提高产品稳定性的物质。
术语“交联剂”是指使产品具有微观立体结构，提高产品稳定性的物质。
术语“交联调节剂”是指提高产品稳定性，使药物处于最佳溶出状态的物质。
与现有技术相比，本发明具有以下有益效果：
1、马钱子碱口服治疗关节炎毒副作用大，开发马钱子碱局部外用贴膏剂，避免了口服毒性，提高药物的生物利用度，提高治疗效果。
2、制备得到的马钱子碱凝胶贴膏剂，使用简单的药用辅料，不使用氮酮等具有强刺激性的透皮促进剂，但透皮效果优异，皮肤相容性好，保湿透气，对皮肤和粘膜无刺激性，载药量大，可反复贴敷。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。本发明发明人经过大量创造性的劳动，进行处方工艺筛选过程，获得了本发明的技术方案。
处方筛选预实验
通过大量的处方筛选及工艺研究，确定本发明的最优的处方及工艺。部分处方筛选过程见表1。
表1马钱子碱凝胶贴膏处方工艺筛选过程
Figure PCTCN2021131901-appb-000001
处方中余量以水补足，以上处方说明用CMC-Na或明胶等代替聚丙烯酸钠部分中和物所得的膏体性状不稳定，而以聚丙烯酸钠部分中和物、交联 剂与交联调节剂为主，配以适宜的助溶剂、保湿剂和其余的骨架材料可得到性状稳定的凝胶贴膏。而制备方法可根据辅料的种类选择适宜的制备方法，三种方法所得凝胶贴膏性状均稳定、良好。
实施例1
配方 用量(g)
马钱子碱 6
甘油 400
丙二醇 160
NP-700 120
甘羟铝 6
羟苯乙酯 2
依地酸二钠 4
酒石酸 6
水 1296
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇后加入甘油、NP-700、依地酸二钠、甘羟铝混匀，得到有机相基质；(2)将酒石酸、水、马钱子碱混匀溶解，得到马钱子碱水相，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例2
配方 用量(g)
马钱子碱 12
甘油 400
丙二醇 100
乙醇 100
NP-600 60
CMC-Na 60
甘羟铝 6
酒石酸 6
薄荷脑 20
依地酸二钠 4
水 1232
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将薄荷脑溶于乙醇后，加入丙二醇、甘油、NP-600、CMC-Na、依地酸二钠、甘羟铝混匀，得到有机相基质；(2)将马钱子碱、酒石酸、水混匀溶解，得到马钱子碱溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例3
配方 用量(g)
马钱子碱 12
甘油 400
丙二醇 100
乙醇 100
PEG400 100
聚丙烯酸钠 140
甘羟铝 6
酒石酸 10
依地酸二钠 4
水 1128
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将马钱子碱溶于PEG400、乙醇的混合溶液，加入丙二醇、甘油、聚丙烯酸钠、依地酸二钠、甘羟铝混匀，得到马钱子碱有机相；(2)将酒石酸、水混匀溶解，得到水相溶液，加入马钱子碱有机相中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例4
配方 用量(g)
马钱子碱 20
甘油 400
丙二醇 100
DMSO 160
NP-800 60
高岭土 60
CMC-Na 60
甘羟铝 4
酒石酸 4
依地酸二钠 4
水 1128
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将马钱子碱溶于DMSO后，加入丙二醇、甘油、NP-800、CMC-Na、高岭土、依地酸二钠、甘羟铝混匀，得到马钱子碱有机相；(2)将酒石酸、水混匀溶解，得到水相溶液，加入马钱子碱有机相中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例5
配方 用量(g)
马钱子碱 12
NP-700 80
甘油 400
丙二醇 100
羟苯乙酯 1.6
聚维酮K90 50
甘羟铝 6
酒石酸 6
依地酸二钠 6
聚山梨酯80 60
水 1278.4
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇后，加入甘油、NP-700、依地酸二钠、甘羟铝、聚维酮K90混匀，得到有机相基质；(2)将马钱子碱、酒石酸、聚山梨酯80、水混匀溶解，得到马钱子水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例6
配方 用量(g)
马钱子碱 10
甘油 400
丙二醇 160
NP-700 100
氢氧化铝 6
羟苯乙酯 2
依地酸二钠 4
酒石酸 10
桉叶油 40
聚乙烯醇 60
水 1208
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇，加入甘油、桉叶油、NP-700、依地酸二钠、氢氧化铝、聚乙烯醇混匀，得到有机相基质；(2)将马钱子碱、酒石酸、水混匀溶解，得到马钱子碱水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例7
配方 用量(g)
马钱子碱 24
甘油 400
丙二醇 160
聚丙烯酸钠 80
甘羟铝 6
羟苯乙酯 2
依地酸二钠 4
酒石酸 6
HPMC 80
聚山梨酯60 100
水 1138
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇，加入甘油、聚丙烯酸钠、依地酸二钠、HPMC、甘羟铝混匀，得到得到有机相基质；(2)将马钱子碱、酒石酸、聚山梨酯60、水混匀溶解，得到马钱子碱水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防 粘层得到马钱子碱凝胶贴膏剂。
实施例8
配方 用量(g)
马钱子碱 10
甘油 400
DMSO 160
丙二醇 100
NP-800 60
甘羟铝 6
羟苯乙酯 2
依地酸二钠 4
酒石酸 6
聚维酮K90 60
高岭土 60
β-环糊精 40
水 1092
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇，加入DMSO、甘油、NP-800、聚维酮K90、高岭土、甘羟铝、依地酸二钠混匀，得到有机相基质；(2)将马钱子碱、酒石酸、β-环糊精、水混匀溶解，得到马钱子碱水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例9
配方 用量(g)
马钱子碱 16
甘油 400
丙二醇 160
NP-700 80
甘羟铝 6
羟苯乙酯 2
依地酸二钠 4
酒石酸 6
尿素 40
微粉硅胶 80
二氧化钛 2
水 1204
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
(1)将羟苯乙酯溶于丙二醇，加入甘油、NP-700、依地酸二钠、甘羟铝、微粉硅胶、二氧化钛混匀，得到有机相基质；(2)将马钱子碱、酒石酸、尿素、水混匀溶解，得到马钱子碱水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
实施例10
配方 用量(g)
马钱子碱 12
甘油 400
丙二醇 160
油酸 50
NP-600 80
甘羟铝 10
羟苯乙酯 2
依地酸二钠 4
柠檬酸 6
CMC-Na 60
海藻酸钠 100
高岭土 60
二氧化钛 2
水 1054
背衬层 无纺布
防粘层 聚丙烯压花膜
制备方法：
将羟苯乙酯溶于丙二醇，加入甘油、油酸、NP-600、CMC-Na、海藻酸钠、高岭土、依地酸二钠、二氧化钛、甘羟铝混匀，得到有机相基质；(2)将马钱子碱、柠檬酸、水混匀，得到马钱子水相溶液，加入有机相基质中搅拌均匀，制得马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂。
试验例1：本发明马钱子碱凝胶贴膏制剂的性状研究
对根据实施例1-10的凝胶贴膏制剂进行物理性状的肉眼观察，可知其外观平整光滑、均匀；成型性、初黏力以及膜残留量均符合要求。
试验例2：本发明马钱子碱凝胶贴膏制剂释放度研究
采用浆碟法，根据《中国药典》2015第四部通则0931溶出度与释放度测定法第四法浆碟法第二法，具体方法为：
分别量取溶出介质(4％氯化钠溶液)900ml于溶出杯内，预温至32℃±0.5℃，将实施例1、实施例2、实施例3、实施例4、实施例5、实施例6、
实施例7、实施例8、实施例9、实施例10固定于网碟上，溶出面朝上，尽可能使其保持平整。再将网碟水平放置于溶出杯下部，并使网碟与浆底旋转面平行，两者相距25mm±2mm，50转/分钟，定时取样，吸取溶出液适量，及时补充相同体积的温度为32℃±0.5℃的溶出介质。结果见下表2：
表2马钱子碱凝胶贴膏释放度实验结果
时间(h) 0 0.5 1 3 5 8
实施例1(％) 0 26.39 38.07 65.78 80.14 90.52
实施例2(％) 0 40.33 56.84 86.35 96.31 100.53
实施例3(％) 0 35.17 43.23 73.96 84.87 98.05
实施例4(％) 0 42.11 54.49 84.87 95.97 99.78
实施例5(％) 0 43.21 60.57 88.17 98.39 100.04
实施例6(％) 0 42.43 55.02 86.84 95.29 99.86
实施例7(％) 0 41.67 58.09 87.14 95.68 100.63
实施例8(％) 0 38.07 57.78 87.02 95.54 100.02
实施例9(％) 0 43.57 59.08 87.29 94.09 100.35
实施例10(％) 0 25.93 37.29 68.74 82.16 93.04
本发明提供的马钱子碱凝胶贴膏剂，在进行体外释放度实验时，除实施例1和实施例10与其他实施例相比稍微缓慢外，其余实施例释放度无明显差异，本发明所有实施例8小时累计释放结果均大于90％，具有良好效果。
试验例3：本发明马钱子碱凝胶贴膏制剂释体外释放研究
采用Franz扩散池法，以离体大鼠腹部皮肤为屏障，试验样品为实施例2、实施例4、实施例5、实施例6、实施例7、实施例8、实施例9和对比组市售吲 哚美辛巴布膏(生产厂家：尼普洛药品株式会社，进口药品注册证号H20181060)，具体方法为：
将大鼠脱颈椎处死，将腹部及周边的毛用剃毛刀脱干净，用解剖剪将褪毛部分的大鼠皮整块剥离，清洗干净后自然固定在改良的Franz扩散池上，使皮肤表面面向供药室，皮肤里层与接受液刚好接触，将揭去防粘层的凝胶贴膏贴于皮肤表面上，接受液为37℃预热的pH＝7.4的PBS缓冲液。接受室水浴温度为37℃，磁力搅拌转速为500rpm。分别于1、2、4、6、8、24h取样，将接受液全部取出，并补加等量新鲜接受液。结果见下表3：
表3马钱子碱凝胶贴膏体外透皮实验结果
时间(h) 0 1 2 4 6 8 24
实施例2(μg) 0 0.78 2.15 6.38 10.45 14.89 76.37
实施例4(μg) 0 0.19 0.56 2.01 3.42 5.68 49.15
实施例5(μg) 0 0.21 0.78 3.52 6.89 15.25 80.02
实施例6(μg) 0 0.23 0.56 3.08 6.56 12.74 55.81
实施例7(μg) 0 0.20 0.77 3.19 6.78 14.15 70.61
实施例8(μg) 0 0.19 0.69 2.77 5.89 10.96 52.63
实施例9(μg) 0 0.10 0.63 2.98 6.32 11.05 56.62
对比例(市售吲哚美辛巴布膏) 0 0.27 0.74 1.98 3.48 5.33 32.36
本发明提供的马钱子碱凝胶贴膏剂，没有使用强促渗作用的氮酮等透皮促进剂来提高活性成分的透皮效果。而对比例市售吲哚美辛巴布膏中含有氮酮，在进行体外透皮实验时，试验结果表明本发明实施例24小时的累计透皮质量均高于对比组药物。
试验例4药效试验
通过骨关节炎药效预试验对表3处方进行了筛选研究，实施例2，实例5，实施例7具有较好的治疗骨关节药效。因此对实施例2，实例5，实施例7进行了正式骨关节炎药效学研究，具体试验方法及结果如下：
4.1实验动物与药物
4.1.1实验动物和药物
SD大鼠，SPF级(无特定病原体级实验动物)：体重210-220g，全雄，购自斯贝福(北京)生物技术有限公司；
4.1.2药物
木瓜蛋白酶：716M022，Solarbio
氟比洛芬凝胶贴膏，生产企业：MIKASA SEIYAKU CO.,LTD KAKEGAWA FACTORY，分装企业：北京泰德制药股份有限公司。批号：103023-01，
L-半胱胺酸：WXBD0897V，SIGMA
4.2实验方法
4.2.1组别设置
本试验共设6组，分别为正常对照组、模型组、氟比洛芬凝胶贴膏组(阳性药组)、实施例2，实施例5，实施例7，每组10只大鼠。正常对照组、模型组均膝关节敷贴马钱子碱凝胶贴剂制剂空白。
4.2.2给药周期
连续给药14天，每天1次。
4.2.3造模
造模部位为右侧膝关节，单侧造模。
大鼠关节腔注射4％木瓜蛋白酶、0.03mol/L L-半胱胺酸(体积2:1混合)造模。
4.3实验结果
行为学评价结果显示，与模型组比较，实施例组和氟比洛芬凝胶贴膏组行为学评分均显著降低(p<0.01、p<0.05)，均可减轻大鼠不适，从而改善大鼠走路踮脚行为。
X光片结果显示，与模型组比较，实施例组和氟比洛芬凝胶贴膏组X光评分显著降低(p<0.001、p<0.01、p<0.05)，均可显著减轻模型大鼠膝关节关节腔狭窄、骨赘及骨质硬化等退行性病变，对膝骨关节炎有显著的治疗作用。
痛阈结果显示，与模型组比较，实施例组和氟比洛芬凝胶贴膏组，痛阈显著升高(p<0.001)，均可显著镇痛。
关节软骨大体观察评分结果显示，与模型组比较，实施例组和氟比洛芬凝胶贴膏组关节软骨大体观察评分显著降低(p<0.01、p<0.05)，均有保护软骨的作用。
组织病理学镜下检查结果显示，与模型组比较，实施例组均可见明显延缓病变进展，氟比洛芬凝胶贴膏组延缓病变进展无明显变化。
实验数据结果见下表。
马钱子碱凝胶贴膏治疗大鼠膝骨关节炎药效学试验结果
Figure PCTCN2021131901-appb-000002
注：与对照组比较：###p<0.001，#p<0.05；与模型组比较：**p<0.01，*p<0.05。
行为学评分、X光片评分、痛阈以及关节软骨大体观察评分的评价标准如下：
(1)行为学评分
测定时间：分组前、给药结束。
测定方法：让大鼠在长1米，A4纸宽的跑道上跑，两个后脚丫涂印泥。然后根据模型脚丫印泥占整个脚丫的量评分。
评分标准：0分：左右脚掌印泥颜色一致；
1分：左脚掌<25％颜色深于右脚掌；
2分：左脚掌25-50％颜色深于右脚掌；
3分：左脚掌50-75％颜色深于右脚掌；
4分：左脚掌>75％颜色深于右脚掌。
(2)X光片评分
测定时间：分组前、给药结束。
测定方法：采用高频X射线机测定。按K-L分级系统进行评估。
评分标准：0分：无改变；
1分：见可疑的关节腔狭窄(JSN)和唇样增生；
2分：见明确的骨赘(OP)形成及可能的JSN；
3分：见明确的JSN、骨质硬化及可能的形态改变；
4分：见较大的OP、明确的JSN、严重骨质硬化、骨畸形。
(3)机械痛值测定
测定时间：给药结束。
测定方法：VonFrey疼痛法。
(4)关节软骨的大体观察
测定时间：试验结束。
测定方法：大鼠安乐死后，观察膝关节及软骨，进行Pelletier评分。评分标准：0分：关节面光整，色泽如常；
1分：关节面粗糙，有小的裂隙且色泽灰暗；
2分：软骨缺损深达软骨中层；
3分：软骨面溃疡形成，软骨缺损深达软骨深层；
4分：软骨剥脱，软骨下骨质裸露。

Claims (10)

  1. 一种马钱子碱凝胶贴膏剂，其特征在于，按重量百分比计算，所述贴膏剂包括0.3％-2％的马钱子碱，3％-10％骨架材料，20％-50％保湿剂和助溶剂，0.1％-2％的交联剂与交联调节剂，余量为水，以及背衬层，防粘层；更优选该贴膏剂包括0.3％-1％的马钱子碱，4％-8％骨架材料，25％-40％保湿剂和助溶剂，0.3％-1％的交联剂与交联调节剂，余量为水，以及背衬层，防粘层。
  2. 根据权利要求1所述的马钱子碱凝胶贴膏剂，其特征在于，所述骨架材料选自卡波姆、海藻酸钠、阿拉伯胶、西黄芪胶、明胶、淀粉、黄原胶、聚丙烯酸、聚丙烯酸钠、聚乙烯醇、聚维酮K90、聚维酮K30、羧甲基纤维素钠、聚乙烯吡咯烷酮、HPMC、海藻酸及其钠盐、聚丙烯酸交联树脂、聚丙烯酸部分中和物中的一种或多种的组合；优选地，所述骨架材料选自聚丙烯酸部分中和物、聚丙烯酸钠、聚维酮K90、羧甲基纤维素钠中的一种或多种。
  3. 根据权利要求1所述的马钱子碱凝胶贴膏剂，其特征在于，所述保湿剂选自乙醇、丙二醇、甘油、聚乙二醇400、山梨醇中的一种或多种的组合；所述助溶剂选自乙醇、尿素、橄榄油、聚山梨酯80、聚山梨酯60、丙二醇、DMSO、二乙二醇单乙醚、聚乙二醇400、桉叶油、环糊精中的一种或多种的组合；优选地，所述保湿剂选自甘油、丙二醇、山梨醇中的一种或两种或多种的组合；所述助溶剂选自DMSO、聚山梨酯80、聚乙二醇400和环糊精中的一种或两种或多种的组合。
  4. 根据权利要求1所述的马钱子碱凝胶贴膏剂，其特征在于，所述交联剂选自氢氧化铝、甘羟铝、三氯化铝、硫酸铝、明矾、复合铝盐中的一种或多种的组合；所述交联调节剂选自酒石酸、柠檬酸、苹果酸、依地酸及其钠盐中的一种或多种的组合；优选地，所述交联剂选自甘羟铝、氢氧化铝中的一种或两种的组合；所述交联调节剂选自酒石酸、柠檬酸、依地酸及其钠盐中的一种或多种的组合。
  5. 根据权利要求1所述的马钱子碱凝胶贴膏剂，其特征在于，所述背衬层选自无纺布、人造棉布；所述防粘层选自聚丙烯压花膜、聚乙烯膜、防黏纸、塑料薄膜、硬质纱布。
  6. 根据权利要求1-5任一项所述的马钱子碱凝胶贴膏剂，其特征在于，按重量百分比计算，所述的贴膏剂还包括0.05％-0.075％抗氧剂；所述抗氧剂选自无水亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、叔丁基对羟基茴香醚、二丁基苯酚、维生素C、维生素C棕榈酸酯、依地酸及其钠盐中的一种或多种的组合。
  7. 根据权利要求1-5任一项所述的马钱子碱凝胶贴膏剂，其特征在于，按重量百分比计算，所述的贴膏剂还包括0.01％-0.3％抑菌剂，优选0.1％-0.2％抑菌剂；所述抑菌剂选自三氯叔丁醇、羟苯乙酯、苯甲醇、羟苯甲酯、羟苯丁酯、山梨酸及其钾盐、薄荷脑、苯甲酸及其钠盐中的一种或多种的组合。
  8. 根据权利要求1-5任一项所述的马钱子碱凝胶贴膏剂，其特征在于，按重量百分比计算，所述的贴膏剂还包括0.1-10％填充剂；优选0.1-5％填充剂；所述填充剂选自高岭土、硅藻土、皂土、氧化锌、二氧化钛、微粉硅胶中的一种或多种的组合；优选地，所述填充剂选自高岭土、二氧化钛、微粉硅胶中的一种或多种的组合。
  9. 一种制备权利要求1-5任一项所述的马钱子碱凝胶贴膏剂的方法，其特征在于，所述方法选自如下：
    方法一：包括如下步骤：
    (1)制备空白基质包含保湿剂与助溶剂、骨架材料、交联剂与交联调节剂以及处方量的水；(2)将马钱子碱溶于助溶剂中与空白基质混合得到马钱子碱膏体；(3)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂；步骤(1)空白基质还任选包含抑菌剂、抗氧剂；
    方法二：包括如下步骤：
    (1)制备马钱子碱有机相，包含保湿剂与助溶剂、马钱子碱、骨架材料、交联剂与交联调节剂；(2)制备水相基质，包含交联剂与交联调节剂和水；(3)马钱子碱有机相与水相基质混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂；步骤(1)有机相还任选包含抑菌剂、抗氧剂；
    方法三：包括如下步骤：
    (1)制备有机相基质，包含保湿剂、骨架材料、交联剂与交联调节剂；(2)制备马钱子碱水相，包含马钱子碱、交联剂与交联调节剂、助溶剂与水；(3)有机相基质与马钱子碱水相混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂；步骤(1)有机相基质还任选包含抑菌剂、抗氧剂；
    方法四：包括如下步骤：
    (1)制备有机相基质，包含保湿剂、骨架材料、交联剂与交联调节剂；(2)制备马钱子碱水相，包含马钱子碱、交联调节剂与水；(3)有机相基质与马钱子碱水相混合得到马钱子碱膏体；(4)马钱子碱膏体涂布于背衬层上，附上防粘层得到马钱子碱凝胶贴膏剂；步骤(1)有机相基质还任选包含抑菌剂、抗氧剂。
  10. 权利要求1-5任一项所述的马钱子碱凝胶贴膏剂在制备用于治疗或改善骨关节炎、风湿性关节炎，类风湿性关节炎等相关需要抗炎镇痛的疾病。
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