WO2019080693A1 - 一种稳定的含有非甾体抗炎药衍生物的药物组合物 - Google Patents

一种稳定的含有非甾体抗炎药衍生物的药物组合物

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Publication number
WO2019080693A1
WO2019080693A1 PCT/CN2018/108622 CN2018108622W WO2019080693A1 WO 2019080693 A1 WO2019080693 A1 WO 2019080693A1 CN 2018108622 W CN2018108622 W CN 2018108622W WO 2019080693 A1 WO2019080693 A1 WO 2019080693A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acid
pharmaceutical composition
alkyl
formula
Prior art date
Application number
PCT/CN2018/108622
Other languages
English (en)
French (fr)
Inventor
张婧
Original Assignee
浙江越甲药业有限公司
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by 浙江越甲药业有限公司 filed Critical 浙江越甲药业有限公司
Priority to EP18871568.4A priority Critical patent/EP3701937A4/en
Priority to US16/758,880 priority patent/US20200360335A1/en
Priority to JP2020523346A priority patent/JP6961817B2/ja
Priority to CN201880066950.0A priority patent/CN111565708B/zh
Priority to CN202310496340.7A priority patent/CN116350618A/zh
Publication of WO2019080693A1 publication Critical patent/WO2019080693A1/zh
Priority to US18/312,466 priority patent/US11986453B2/en

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Classifications

    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • 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
    • A61K9/08—Solutions
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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]

Definitions

  • the present invention relates to the field of chemical pharmaceuticals, and more particularly to a stable pharmaceutical composition containing a non-steroidal anti-inflammatory drug derivative.
  • Non-steroidal anti-inflammatory drugs are a class of anti-inflammatory drugs that do not contain steroid structures, including aspirin, salicylic acid, acetaminophen, indomethacin, naproxen, naproxen, diclofenac, ibuprofen, Nimesulide, rofecoxib, celecoxib, etc.
  • Non-steroidal anti-inflammatory drugs have antipyretic, analgesic, anti-inflammatory, anti-rheumatic and anti-coagulation effects, and are widely used in clinically for the relief of osteoarthritis, rheumatoid arthritis, various fevers and various pain symptoms. .
  • Non-steroidal anti-inflammatory drugs exert antipyretic, analgesic and anti-inflammatory effects by inhibiting the synthesis of prostaglandins.
  • the analgesic effect of non-steroidal anti-inflammatory drugs is mainly in the periphery, and the analgesic mechanism includes: 1) inhibition of prostaglandin synthesis; 2) inhibition of lymphocyte activity and activation of T lymphocyte differentiation, reduction of afferent nerve endings Stimulation; 3) Direct action on nociceptors to prevent the formation and release of painful substances.
  • non-steroidal anti-inflammatory drugs have an anti-inflammatory effect, inhibiting the synthesis of prostaglandins, inhibiting the aggregation of leukocytes, reducing the formation of bradykinin, inhibiting the aggregation of platelets, and the like, thereby exerting an anti-inflammatory effect.
  • Non-steroidal anti-inflammatory drugs have inhibitory effects on the occurrence, development and metastasis of tumors, and have synergistic effects with other anti-tumor drugs.
  • aspirin and ibuprofen are the most classic non-steroidal anti-inflammatory drugs.
  • Aspirin also known as acetylsalicylic acid, was first synthesized in 1853 and was used in clinical treatment in 1899. Aspirin has a variety of drug effects, which can relieve headaches by vasodilation in a short period of time, so it can be used for analgesia and antipyretic. Aspirin is the drug of choice for the treatment of rheumatic fever. After administration, it can relieve fever, reduce inflammation, improve joint symptoms and reduce erythrocyte sedimentation rate. In addition to rheumatoid arthritis, this product is also used to treat rheumatoid arthritis, which can improve symptoms and create conditions for further treatment.
  • aspirin is used for osteoarthritis, ankylosing spondylitis, juvenile arthritis and other non-rheumatic musculoskeletal disorders, and can also relieve symptoms.
  • Aspirin inhibits platelet aggregation and thus prevents thrombosis. It can be used clinically to prevent transient ischemic attack, myocardial infarction, atrial fibrillation, prosthetic heart valve or other postoperative thrombosis, and can also be used to treat unstable angina. .
  • Aspirin can also be used to reduce skin and mucous membrane syndrome (Kawasaki disease). The study also found that aspirin played a role in the prevention of colon cancer, rectal cancer, esophageal cancer and so on. Therefore, the therapeutic use of aspirin is very valuable.
  • Ibuprofen also known as ⁇ -methyl-4-(2-methylpropyl)phenylacetic acid, is the only recommended antipyretic drug for children in the World Health Organization and the US FDA. It is recognized as the preferred anti-inflammatory drug for children. Ibuprofen has anti-inflammatory, analgesic and antipyretic effects, and is suitable for the treatment of mild to moderate migraine attacks, prevention of migraine, chronic episodes of lateral headache, strenuous and menstrual headache, rheumatoid arthritis, Rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and neuritis.
  • Ibuprofen reduces the synthesis of prostaglandins by inhibiting cyclooxygenase, blocks the release of inflammatory mediators, and produces anti-inflammatory and analgesic effects, and at the same time acts as an antipyretic effect through the hypothalamic thermoregulatory center.
  • non-steroidal anti-inflammatory drugs are prone to adverse reactions in the gastrointestinal tract.
  • the main symptoms are indigestion, stomach and duodenal bleeding, stomach ulcers and gastritis. Therefore, researchers have been trying to study non-steroidal anti-inflammatory drug derivatives of other routes of administration in order to reduce or avoid the gastrointestinal side effects caused by non-steroidal anti-inflammatory drugs.
  • Chinese patents CN 101484415 B and CN 101489985 B respectively disclose a water-soluble aspirin prodrug (an acetylsalicylic acid derivative) and an ibuprofen prodrug (an ibuprofen derivative), which are treated before The drug can be administered into the body by transdermal administration, avoiding the gastrointestinal side effects of oral administration of common non-steroidal anti-inflammatory drugs.
  • the invention provides a stable pharmaceutical composition comprising a non-steroidal anti-inflammatory drug derivative.
  • the pharmaceutical composition comprises at least an isolated solid portion and a liquid portion, wherein the solid portion comprises a therapeutically effective amount of a pharmaceutically acceptable salt of a compound of Formula 1, which is pharmaceutically acceptable Solvent,
  • R 1 represents H, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl, preferably methyl or ethyl,
  • R 2 represents H, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl, preferably methyl or ethyl,
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 2.
  • the compound represented by Formula 1 is selected from the group consisting of:
  • the pharmaceutically acceptable salt of the compound represented by Formula 1 is a salt of a compound represented by Formula 1 and an inorganic or organic acid, preferably a compound represented by Formula 1 and hydrochloric acid, A salt formed from hydrobromic acid, hydrofluoric acid, hydroiodic acid, phosphoric acid, acetic acid, oxalic acid, citric acid or thiocyanate.
  • the pharmaceutically acceptable salt of the compound represented by Formula 1 is:
  • Salicylic acid-(2-diethylaminoethyl ester) hydrochloride or
  • the present invention provides a stable pharmaceutical composition comprising a non-steroidal anti-inflammatory drug derivative.
  • the pharmaceutical composition comprises at least an isolated solid portion and a liquid portion, wherein the solid portion comprises a therapeutically effective amount of a compound of Formula 2, the liquid portion being a pharmaceutically acceptable vehicle,
  • R 1 represents H, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl, preferably methyl or ethyl,
  • R 2 represents H, C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl, preferably methyl or ethyl,
  • n 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, preferably 1 or 2.
  • X - represents a monovalent anion, more preferably Cl - , Br - , F - , I - , AcO - , oxalate, dihydrogen phosphate, citrate, thiocyanate.
  • the compound represented by Formula 2 is selected from the group consisting of:
  • X - represents an anion, preferably a monovalent anion, more preferably Cl - , Br - , F - , I - , AcO - , oxalate, dihydrogen phosphate, citrate, thiocyanate.
  • the compound represented by Formula 2 is:
  • Salicylic acid-(2-diethylaminoethyl ester) hydrochloride or
  • the compound represented by Formula 2 is a pharmaceutically acceptable salt of the compound represented by Formula 1. Therefore, the reference herein to "the pharmaceutically acceptable salt of the compound represented by Formula 1" and “the compound represented by Formula 2" are used interchangeably.
  • the mass ratio of the solid portion to the liquid portion is from 0.1:100 to 40:100, more preferably from 0.5:100 to 20:100, most preferably from 1:100 to 10:100.
  • the mass ratio of the pharmaceutically acceptable salt of the compound represented by Formula 1 to the liquid portion (the pharmaceutically acceptable solvent) is: 0.1: 100-40: 100, still more preferably 0.5:100-20:100, most preferably 1:100-10:100.
  • the pharmaceutically acceptable vehicle is selected from the group consisting of sterile water, decarbonated water, ethanol, aqueous sorbitol, physiological saline.
  • the solid portion is in a dosage form selected from the group consisting of powders, granules, pills, tablets, capsules.
  • the solid portion further comprises a pharmaceutically acceptable binder.
  • the pharmaceutically acceptable binder is selected from the group consisting of: hypromellose, carbomer, ethylcellulose, hydroxypropylcellulose, vinylcellulose, starch (more preferably Pregelatinized starch), polyvinylpyrrolidone.
  • the pharmaceutically acceptable salt of the compound represented by Formula 1 forms a granule with the pharmaceutically acceptable binder.
  • the mass ratio of the pharmaceutically acceptable salt of the compound represented by Formula 1 to the pharmaceutically acceptable binder is from 100:0.05 to 100:10, more preferably 100. : 1-100: 5, most preferably 100: 1-100: 2.
  • the powder or granules of the present invention have an angle of repose of no more than 40°, preferably no more than 35°, more preferably no more than 30°.
  • the granules are passed through a 10 mesh screen but are not passed through a 60 mesh screen.
  • the powder can pass through an 80 mesh screen.
  • the solid portion is stored in a closed pharmaceutically acceptable packaging material.
  • the pharmaceutically acceptable packaging material is selected from the group consisting of: a low density polyethylene film, a low density polyethylene bag, a high density polyethylene film, a low density polyethylene bottle, a high density polyethylene bottle, Polypropylene bottles, polyethylene terephthalate bottles, polyester/aluminum/polyethylene composite bags, glass bottles, or combinations thereof.
  • the pharmaceutical composition further comprises a medicinal spray device, a medicinal dropper, a medicinal soft brush or a combination thereof.
  • the pharmaceutical composition when used, mixes the solid portion with a liquid portion to form a spray, drop, or abrasive.
  • Another aspect of the present invention provides a method of preparing the particles, the method of which comprises the steps of:
  • the concentration of the binder solution formulated in the step (1) is from 0.1 w/w% to 3.0 w/w%.
  • the mass ratio of the pharmaceutically acceptable salt of the compound represented by Formula 1 in the step (2) to the dry powder of the binder is from 100:0.1 to 100:5.
  • the mass ratio of the binder solution added in the step (2) to the pharmaceutically acceptable salt of the compound represented by the formula 1 is from 1:100 to 10:100.
  • the drying temperature in the step (3) is 55-65 °C.
  • the drying time in the step (3) is 4-6 hours.
  • the beneficial effects of the present invention are that the non-steroidal anti-inflammatory drug derivative of the present invention cannot be stably present in a solvent (unstable state of solution). Therefore, the solid portion of the drug needs to be stored separately from the solvent. More preferably, the solid portion of the drug can be stored in a suitable pharmaceutical packaging material, which can significantly improve the stability of the drug.
  • the angle of repose of the granules does not exceed 30°, the fluidity is good and non-adhesive, and the granules can be quickly dissolved in the solvent to facilitate the dissolution operation of the patient during use.
  • the solid portion of the pharmaceutical composition can be administered by transdermal administration after being dissolved in a solvent, thereby avoiding gastrointestinal adverse reactions (bleeding, etc.) and systemic exposure which may be caused by oral administration.
  • the solid portion and the liquid portion are mixed to form a plurality of external pharmaceutical dosage forms, which are convenient for the patient to use.
  • the present invention provides a stable pharmaceutical composition
  • a stable pharmaceutical composition comprising a non-steroidal anti-inflammatory drug derivative, the pharmaceutical composition comprising at least an isolated solid portion and a liquid portion, wherein the solid portion comprises a therapeutically effective
  • R 1 represents H or C 1 -C 6 -alkyl, preferably C 1 -C 5 -alkyl, more preferably C 1 -C 4 -alkyl, even more preferably C 1 -C 3 -alkyl, most preferably A Base or ethyl group,
  • R 2 represents H or C 1 -C 6 -alkyl, preferably C 1 -C 5 -alkyl, more preferably C 1 -C 4 -alkyl, even more preferably C 1 -C 3 -alkyl, most preferably A Base or ethyl group,
  • n represents 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, preferably a natural number of n ⁇ 6, more preferably a natural number of n ⁇ 4, and most preferably a natural number of n ⁇ 3.
  • the term "contains at least” means that the pharmaceutical composition may also contain any other components which may be present in any amount so long as the component present at that level is acceptable to the human body. And there is no adverse effect on the activity of the active ingredient in the pharmaceutical composition of the invention.
  • the "pharmaceutically acceptable salt” preferably refers to a relatively non-toxic inorganic acid or organic acid addition salt of the compound represented by Formula 1, and an example of the pharmaceutically acceptable salt is represented by Formula 1.
  • a salt formed by a compound with an inorganic acid including but not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid, sulfuric acid, disulfuric acid, phosphoric acid or nitric acid, or a salt formed with an organic acid.
  • Organic acids include, but are not limited to, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2 -(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid , persulfate, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonate
  • C 1 -C 6 -alkyl refers to a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Examples of C 1 -C 6 -alkyl groups are: methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2 -methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2- Dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl,
  • the pharmaceutical composition of the present invention can be used for the treatment of indications for non-steroidal anti-inflammatory drugs (such as aspirin, ibuprofen) including, but not limited to, pain. , fever, inflammation, rheumatism, arthritis, blood clots, cancer, stroke, dementia, diabetes, diabetic complications, cardiovascular disease, cerebrovascular disease, etc.
  • non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen
  • non-steroidal anti-inflammatory drug derivative of the present invention For the preparation method of the non-steroidal anti-inflammatory drug derivative of the present invention, reference may be made to the Chinese patent CN 101484415 B, CN 101489985 B, US Patent 3,365,483 or other references.
  • the advantage of such prodrug derivatives is that they can be administered into the body by transdermal administration, avoiding the gastrointestinal side effects of oral administration of common non-steroidal anti-inflammatory drugs. Therefore, such drugs are preferably transdermally administered into the body in a solution dosage form.
  • the non-steroidal anti-inflammatory drug derivative does not stably exist in a solvent (solution state is unstable). Therefore, it is necessary to separate the solid portion of the drug from the solvent, and more preferably, the solid portion of the drug can be stored in a closed pharmaceutical packaging material, which can significantly improve the stability of the drug.
  • the mass ratio of the solid portion to the liquid portion is from 0.1:100 to 40:100, more preferably from 0.5:100 to 20:100, most preferably from 1:100 to 10:100.
  • the solid portion of the pharmaceutical composition is a powder, granule, pill, tablet, or capsule containing a pharmaceutically acceptable salt of the compound represented by Formula 1.
  • the solid portion of the pharmaceutical composition is a granule formed from a pharmaceutically acceptable salt of the compound represented by Formula 1 and a pharmaceutically acceptable binder.
  • pharmaceutically acceptable binder means a viscous solid powder or viscous liquid which enables aggregation of non-tacky or less viscous materials into granules or compression molding, and should be combined with the pharmaceutical composition of the present invention.
  • the active ingredient non-steroidal anti-inflammatory drug derivative (the pharmaceutically acceptable salt of the compound represented by Formula 1) is compatible, that is, it can be blended therewith without substantially lowering the therapeutic effect of the drug under normal circumstances.
  • the pharmaceutically acceptable binder is selected from the group consisting of: hypromellose, carbomer, ethylcellulose, hydroxypropylcellulose, vinylcellulose, starch (more preferably Pregelatinized starch), polyvinylpyrrolidone.
  • the solid portion of the pharmaceutical composition is a pharmaceutically acceptable salt of the compound represented by Formula 1 and a pharmaceutically acceptable binder
  • the granules are pharmaceutically acceptable (eg, sterile) Water) mixed and dissolved, applied to dry to form a film, not easy to fall off, to facilitate the adhesion and absorption of drugs on the patient's skin.
  • binders including hypromellose, carbomer, ethyl cellulose, hydroxypropyl cellulose, ethylene cellulose, starch, polyvinylpyrrolidone, and the general formula 1 of the present invention.
  • the pharmaceutically acceptable salts of the compounds are mixed, wet granulated, granulated, and the granules are separately dissolved in a pharmaceutically acceptable vehicle (e.g., sterile water).
  • a pharmaceutically acceptable vehicle e.g., sterile water.
  • the hydroxypropylmethylcellulose and the pharmaceutically acceptable salt of the compound represented by the above formula 1 form particles having the best solubility, can form a clear solution, and can be dried to form a transparent film, which is not easy to fall off. It facilitates the adhesion and absorption of the drug on the patient's skin.
  • the pharmaceutically acceptable binder is hypromellose.
  • the mass ratio of the pharmaceutically acceptable salt of the compound represented by Formula 1 to the pharmaceutically acceptable binder is from 100:0.05 to 100:10, more preferably 100. : 1-100: 5, most preferably 100: 1-100: 2.
  • the “rest angle” formed by the accumulation of powder or particles reflects its fluidity.
  • the term “rest angle” generally refers to the maximum angle formed by the free slope of the powder or particle buildup layer and the horizontal plane.
  • the "injection method” is used to measure the angle of repose, that is, the particulate material flows from the funnel and falls on the plane to form a cone, and the cone bottom angle is the angle of repose.
  • the powder or granule has an angle of repose of 40 or less, more preferably 35 or less, and even more preferably 30 or less.
  • the solid portion of the pharmaceutical composition of the invention is stored in a closed pharmaceutically acceptable packaging material.
  • pharmaceutically acceptable packaging material means that there is no significant interaction between the container sealing material and the contents, without causing a change in the activity and stability of the product, or a risk of toxicity, and under normal storage/use conditions, packaging Any influence between the ingredients of the material and the product will not result in unacceptable changes in product quality or packaging.
  • the pharmaceutically acceptable packaging materials include, but are not limited to, low density polyethylene film, low density polyethylene bag, high density polyethylene film, low density polyethylene bottle, high density polyethylene bottle, polypropylene bottle, poly pair Ethylene phthalate bottle, polyester/aluminum/polyethylene composite film, polyester/aluminum/polyethylene composite bag, glass bottle, or a combination thereof.
  • the pharmaceutically acceptable packaging material is a combination of a high density polyethylene bottle and a polyester/aluminum/polyethylene composite bag.
  • the liquid portion of the pharmaceutical composition of the present invention uses a pharmaceutically acceptable vehicle.
  • the pharmaceutically acceptable vehicle includes, but is not limited to, sterile water, decarbonated water, ethanol, aqueous sorbitol solution, physiological saline, and the like.
  • the pharmaceutical composition further comprises a medicinal spray device, a medicinal dropper, a medicinal soft brush, or a combination thereof.
  • the solid portion of the pharmaceutical composition is mixed with the liquid portion at the time of use to form a spray, drop, or abrasive.
  • the solid portion (granules) of the pharmaceutical composition is packaged in a high density polyethylene bottle and placed in a polyester/aluminum/polyethylene pharmaceutical packaging composite bag; the liquid portion is sterile water
  • a solvent stored in a medicinal glass bottle or a medicinal polyethylene plastic bottle
  • a medicinal spray device such as a medicinal spray pump
  • the granules and the solvent may be packaged in a corresponding ratio, for example, packaged as 5 g of granules and 50 mL of sterile water.
  • the invention also provides a method of preparing the particles, the method comprising the steps of:
  • a pharmaceutically acceptable salt of the compound represented by Formula 1 is mixed with a binder solution prepared in the step (1).
  • the inventors have found that it is difficult to obtain a desired granule by directly adding a binder (for example, hypromellose) solution to a pharmaceutically acceptable salt of the compound represented by Formula 1 of the present invention, and the obtained granule is loose and easy. Broken, easy to agglomerate. Therefore, the inventors have improved the granulation method by first mixing a pharmaceutically acceptable salt of the compound represented by Formula 1 of the present invention with a binder (for example, hypromellose) dry powder, and then adding a binder ( For example, a solution of hypromellose) is mixed to obtain the desired granules.
  • a binder for example, hypromellose
  • the present invention provides another method of preparing the particles, the method comprising the steps of:
  • the concentration of the binder solution formulated in the step (1) is from 0.1 w/w% to 3.0 w/w%.
  • the mass ratio of the pharmaceutically acceptable salt of the compound represented by Formula 1 in the step (2) to the dry powder of the binder is from 100:0.1 to 100:5.
  • the mass ratio of the binder solution added in the step (2) to the pharmaceutically acceptable salt of the compound represented by the formula 1 is from 1:100 to 10:100.
  • the drying temperature in the step (3) is 55-65 °C.
  • the drying time in the step (3) is 4-6 hours.
  • a pharmaceutically acceptable salt of the compound represented by Formula 1 may be subjected to a sieving treatment prior to the step (2) to facilitate the subsequent granulation step.
  • the method comprises the steps of:
  • the formulated hypromellose solution (the mass ratio of the compound to the binder dry powder is preferably from 100:1 to 100:5, more preferably from 100:1 to 100:2, even more preferably from 100:1.5 to 100:1.7) , uniformly mixed into a soft material, pressed through a 14 mesh sieve;
  • the drying temperature is 60 ° C; preferably, the drying time is less than 12 hours, more preferably 4-6 hours);
  • granules are selected (preferably, granules which pass through a 10-mesh sieve but cannot pass through a 60-mesh sieve) are selected.
  • the invention also provides a method of preparing the tablet, the method comprising the steps of:
  • the unit in the weight percent by volume in the present invention is well known to those skilled in the art and, for example, refers to the weight (gram) of the solute in a 100 ml solution.
  • reaction ratio of aspirin and thionyl chloride at an equivalent ratio of 1:1.1 was carried out at a reaction temperature of 50 ° C for 2 hours to form o-acetyl salicylate.
  • the isopropyl acetate phase is taken; in the salt formation process, isopropyl acetate is used as a solvent, and then the amount of hydrogen chloride is strictly controlled, so that the pH of the reaction solution is about 3.5.
  • the reaction was completed to give a crude material of 2-(diethylamino)ethyl 2-acetoxybenzoate hydrochloride.
  • the synthesized 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride crystals were characterized by nuclear magnetic resonance.
  • the instrument was a Bruker AV-500 superconducting nuclear magnetic resonance spectrometer with a test temperature of 300.0K.
  • the solvent was CDCl 3 , and the obtained characteristic data was as follows, demonstrating that the structure of the finished product was consistent with 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride.
  • Mobile phase water (15 ml of triethylamine + 3.5 ml of 10% tetrabutylammonium hydroxide plus water to 1000 ml): methanol: glacial acetic acid (63:27:10).
  • Step (3) Mixing 100 g of 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride pretreated with the step (1) with 1.5 g of hypromellose dry powder, and then adding Step (2) Prepared 9-10 g of hypromellose solution, and mix well to make a soft material. Pressed through a 14 mesh screen;
  • the obtained 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride particles are white-like, with an angle of repose of 28°, and the pH of the aqueous solution at 25 ⁇ 0.5° C. is 4.3-4.4. .
  • the 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride spray granules prepared above were packaged in high-density polyethylene bottles, sealed and placed in polyester/aluminum/poly In the composite bag for ethylene pharmaceutical packaging, samples were taken at 0 °C, 2 °C, and 60% ⁇ 10% relative humidity at 0 months, 3 months, 6 months, 9 months, and 12 months, respectively. Detection of properties, loss on drying, moisture, specific impurities (salicylic acid-(2-diethylaminoethyl ester) hydrochloride, acetylsalicylic acid, salicylic acid), related substances, main drug content.
  • reaction temperature is controlled to be 15-30 ° C, and ibuprofen and thionyl chloride are reacted in an equivalent ratio of 1:1.2.
  • reaction produces ibuprofen chloride.
  • Dichloromethane was added, 2.0 equivalents of diethylaminoethanol was added, and ibuprofen chloride was slowly added dropwise in an ice water bath. The dropping process was slightly warmed up, the stirring was continued for 2 hours, and the addition of 0.5% diluted aqueous solution of hydrochloric acid was terminated.
  • the reaction mixture was separated, and the organic phase was washed with saturated sodium hydrogen sulfate, washed with water and dried over anhydrous sodium sulfate After adding a solution of isopropyl acetate containing hydrogen chloride gas, a large amount of a white solid was precipitated and suction filtered to give 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride. The acetone was recrystallized to give 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride crystals (powder), and the powder had an angle of repose: 40°.
  • the synthesized 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride crystal was subjected to nuclear magnetic resonance characterization, and the instrument was a Bruker AV-500 superconducting nuclear magnetic resonance apparatus.
  • the test temperature was 300.0K
  • the solvent was CDCl 3
  • the characteristic data obtained was as follows, demonstrating the structure of the finished product and 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate salt.
  • the acid salt is consistent.
  • Fluidized bed preparation of granules 200 g of 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride pretreated by the step (1)
  • the binder prepared by the step (2) is sprayed to prepare granules, wherein the material temperature is 23-28 ° C, and the inlet air temperature is 60 ° C. , cylinder temperature: 27 ° C, spray flow rate: 0.8-2.0 r / min.
  • the obtained 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride particles obtained in Example 7 were sealed in a polyester/aluminum/polyethylene pharmaceutical package.
  • 50 mL of sterile water was used as a solvent (stored in a medicinal glass bottle or a medicinal polyethylene plastic bottle), placed in a plastic tray together with the packaged granules and a medicinal spray pump, and placed in a white cardboard box.
  • the patient can dissolve 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride granules in sterile water and form a spray with a medicinal spray pump. use.
  • the 2-(diethylamino)-ethyl-2-(4-isobutylphenyl)propionate hydrochloride granules prepared above were sealed in a polyester/aluminum/polyethylene pharmaceutical packaging bag. ), placed at 25 ° C ⁇ 2 ° C temperature and 60% ⁇ 10% relative humidity, samples were taken at 0 months, 3 months, 6 months, 9 months, 12 months, respectively, to detect traits, loss on drying, moisture , specific impurities (ibuprofen), the main drug content. Among them, the traits were visually measured, and the water was measured by volumetric titration ("Chinese Pharmacopoeia" by the Fisher's method for volumetric titration). Specific impurities and main drug content were determined by high performance liquid chromatography (area normalization). The conditions of high performance liquid chromatography were the same as in Example 6.
  • the 2-(diethylamino)-ethyl-2-acetoxybenzoate hydrochloride (31.5 g) obtained in the preparation of Example 1 was dissolved in acetonitrile (30 mL), and concentrated hydrochloric acid (10 mL) was added and stirred at room temperature. After drying for 48 hours, concentrated and evaporated to dryness, and then added with 50 mL of water to dissolve, and then added with saturated sodium hydrogen carbonate solution, stirred, extracted with isopropyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, filtered, and evaporated. Recrystallization gave salicylic acid-(2-diethylaminoethyl ester) hydrochloride (17.7 g, yield: 65%).
  • the salicylic acid-(2-diethylaminoethyl ester) hydrochloride tablet obtained by the above preparation is sealed in a high-density polyethylene bottle, and 50 mL of sterile water is used as a solvent (stored in a medicinal glass bottle or medicine).
  • a polyethylene plastic bottle put it in a plastic tray with a medicinal soft brush, and put it into a white cardboard box.
  • long-term stability studies 25 ° C ⁇ 2 ° C, 12 months
  • the tablet has good stability and fully meets the requirements of the pharmaceutical industry.
  • the patient may dissolve the salicylic acid-(2-diethylaminoethyl ester) hydrochloride tablet in sterile water and use a medicinal soft brush to form an abrasive.

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Abstract

一种稳定的含有非甾体抗炎药衍生物的药物组合物，其至少包含分离的固体部分与液体部分，其中，所述固体部分包括治疗有效量的非甾体抗炎药衍生物，所述液体部分为药学上可接受的溶媒。

Description

一种稳定的含有非甾体抗炎药衍生物的药物组合物 技术领域
本发明涉及化学制药领域，尤其涉及一种稳定的含有非甾体抗炎药衍生物的药物组合物。
背景技术
非甾体抗炎药是一类不含有甾体结构的抗炎药，包括阿司匹林、水杨酸、对乙酰氨基酚、吲哚美辛、萘普生、萘普酮、双氯芬酸、布洛芬、尼美舒利、罗非昔布、塞来昔布等。非甾体抗炎药具有解热、镇痛、消炎、抗风湿和抗凝血等作用，在临床上广泛用于骨关节炎、类风湿性关节炎、多种发热和各种疼痛症状的缓解。非甾体抗炎药通过抑制***素的合成，发挥解热、镇痛和消炎作用。非甾体抗炎药的镇痛作用部位主要在外周，其镇痛机理包括：1)抑制***素的合成；2)抑制淋巴细胞活性和活化的T淋巴细胞的分化，减少对传入神经末梢的刺激；3)直接作用于伤害性感受器，阻止致痛物质的形成和释放。大多数非甾体抗炎药具有消炎作用，通过抑制***素的合成，抑制白细胞的聚集，减少缓激肽的形成，抑制血小板的凝集等作用，从而发挥消炎作用。非甾体抗炎药对肿瘤的发生、发展与转移均有抑制作用，与其它抗肿瘤药物有协同作用。其中，阿司匹林与布洛芬是最经典的非甾体抗炎药。
阿司匹林，又名乙酰水杨酸，于1853年被首次合成，并于1899年被应用于临床治疗。阿司匹林具有多种药物功效，其通过血管扩张短期内起到缓解头痛的效果，因此可用来镇痛解热。阿司匹林为治疗风湿热的首选药物，用药后可解热、减轻炎症，使关节症状好转，血沉下降。除风湿性关节炎外，该品也用于治疗类风湿性关节炎，可改善症状，为进一步治疗创造条件。此外，阿司匹林用于骨关节炎、强直性脊椎炎、幼年型关节炎及其他非风湿性炎症的骨骼肌肉疼病，也能缓解症状。阿司匹林对血小板聚集有抑制作用，因而可阻止血栓形成，临床可用于预防暂时性脑缺血发作、心肌梗塞、心房颤动、人工心脏瓣膜或其他手术后的血栓形成，也可用于治疗不稳定型心绞痛。阿司匹林还可用来减轻皮肤粘膜淋巴 结综合症(川崎病)。研究还发现，阿司匹林在预防结肠癌、直肠癌、食道癌等方面起到了作用。因此，阿司匹林在治疗上的用途是非常有价值的。
布洛芬，又名α-甲基-4-(2-甲基丙基)苯乙酸，是世界卫生组织、美国FDA唯一共同推荐的儿童退烧药，是公认的儿童首选抗炎药。布洛芬具有抗炎、镇痛、解热作用，适用于治疗轻到中度的偏头痛发作、偏头痛的预防、慢性发作性偏侧头痛、奋力性和月经性头痛、风湿性关节炎、类风湿性关节炎、骨关节炎、强直性脊椎炎和神经炎等。布洛芬通过抑制环氧化酶减少***素的合成，阻断炎症介质的释放，而产生抗炎镇痛作用，同时通过下丘脑体温调节中枢而起解热作用。
然而，口服非甾体抗炎药易产生胃肠道的不良反应。最主要的有消化不良、胃与十二指肠出血、胃溃疡和胃炎等症状。因此，研究人员一直在尝试研究其它给药途径的非甾体抗炎药衍生物，以求减轻或避免服用非甾体抗炎药所产生的胃肠道不良反应。中国专利CN 101484415 B与CN 101489985 B分别公开了一种水溶性阿司匹林前药(一种乙酰水杨酸衍生物)与布洛芬前药(一种布洛芬衍生物)，治疗中，这些前药可通过透皮给药进入体内，避免了普通非甾体抗炎药口服产生的胃肠道不良反应。
针对这些化合物获得稳定的化药制剂是制药工业必须解决的问题。
发明内容
本发明一方面提供一种稳定的含有非甾体抗炎药衍生物的药物组合物。所述药物组合物至少包含分离的固体部分与液体部分，其中，所述固体部分包括治疗有效量的通式1表示的化合物的药学上可接受的盐，所述液体部分为药学上可接受的溶媒，
Figure PCTCN2018108622-appb-000001
通式1
其中，
Ar-代表
Figure PCTCN2018108622-appb-000002
R 1代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
R 2代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
n代表1、2、3、4、5、6、7、8、9或10，优选1或2。
在一个优选的实施方案中，所述通式1表示的化合物选自：
Figure PCTCN2018108622-appb-000003
在一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐是通式1表示的化合物与无机酸或有机酸形成的盐，优选通式1表示的化合物与盐酸、氢溴酸、氢氟酸、氢碘酸、磷酸、乙酸、草酸、枸橼酸或硫氰酸形成的盐。
在一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐为：
2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐，
水杨酸-(2-二乙基氨基乙基酯)盐酸盐，或
2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐。
或者，本发明提供一种稳定的含有非甾体抗炎药衍生物的药物组合物。所述药物组合物至少包含分离的固体部分与液体部分，其中，所述固体部分包括治疗有效量的通式2表示的化合物，所述液体部分为药学上可接受的溶媒，
Figure PCTCN2018108622-appb-000004
通式2
其中，
Ar-代表
Figure PCTCN2018108622-appb-000005
R 1代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
R 2代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
X -代表负离子，
n代表1、2、3、4、5、6、7、8、9或10，优选1或2。
在一个优选的实施方案中，X -代表一价负离子，更优选Cl -、Br -、F -、I -、AcO -、草酸根、磷酸二氢根、枸橼酸根、硫氰酸根。
在一个优选的实施方案中，所述通式2表示的化合物选自：
Figure PCTCN2018108622-appb-000006
其中，
X -代表负离子，优选一价负离子，更优选Cl -、Br -、F -、I -、AcO -、草酸根、磷酸二氢根、枸橼酸根、硫氰酸根。
在一个优选的实施方案中，所述通式2表示的化合物为：
2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐，
水杨酸-(2-二乙基氨基乙基酯)盐酸盐，或
2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐。
需要说明的是，所述通式2表示的化合物即一种所述通式1表示的化合物的药学上可接受的盐。因此，本文中提及“通式1表示的化合物的药学上可接受的盐”与“通式2表示的化合物”可互换使用。
在一个优选的实施方案中，所述固体部分与所述液体部分的质量比为：0.1:100-40:100，再优选0.5:100-20:100，最优选1:100-10:100。在另一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐与所述液体部分(所述药学上可接受的溶媒)的质量比为：0.1:100-40:100，再优选0.5:100-20:100，最优选1:100-10:100。
在一个优选的实施方案中，所述药学上可接受的溶媒选自：无菌水、脱二氧化碳水、乙醇、山梨醇水溶液、生理盐水。
在一个优选的实施方案中，所述固体部分的剂型选自：粉末、颗粒、丸剂、片剂、胶囊。
在一个优选的实施方案中，所述固体部分还包括药学上可接受的粘合剂。
在一个优选的实施方案中，所述药学上可接受的粘合剂选自：羟丙甲纤维素、卡波姆、乙基纤维素、羟丙基纤维素、乙烯纤维素、淀粉(更优选预胶化淀粉)、聚乙烯吡咯烷酮。
在一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的粘合剂形成颗粒。
在一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的粘合剂的质量比为：100:0.05-100:10，更优选100:1-100:5，最优选100:1-100:2。
在一个优选的实施方案中，本发明所述粉末或者颗粒的休止角不超过40°，优选不超过35°，更优选不超过30°。
在一个优选的实施方案中，所述颗粒能通过10目筛但不能通过60目筛。在另一个优选的实施方案中，所述粉末能通过80目筛。在一个优选的实施方案中，所述固体部分储存于密闭的药学上可接受的包装材料中。
在一个优选的实施方案中，所述药学上可接受的包装材料选自：低密度聚乙烯膜、低密度聚乙烯袋、高密度聚乙烯膜、低密度聚乙烯瓶、高密度聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、聚酯/铝/聚乙烯复合袋、玻璃瓶，或其组合。
在一个优选的实施方案中，所述药物组合物还包括药用喷雾装置、药用滴管、药用软毛刷或其组合。
在一个优选的实施方案中，所述药物组合物在使用时，将所述固体部分与液体部分相混合，形成喷雾剂、滴剂、或涂擦剂。
本发明另一方面提供一种制备所述颗粒的方法，其制备方法包括如下步骤：
(1)配制粘合剂溶液；
(2)将通式1表示的化合物的药学上可接受的盐与粘合剂干粉按一定比例混合，再加入步骤(1)配制的粘合剂溶液混合均匀，制成软材；
(3)软材干燥；
(4)整粒，选择能通过10目筛但不能通过60目筛的颗粒。
在一个优选的实施方案中，所述步骤(1)中配制的粘合剂溶液的浓度为0.1 w/w％-3.0w/w％。
在一个优选的实施方案中，所述步骤(2)中通式1表示的化合物的药学上可接受的盐与粘合剂干粉的质量比为100:0.1-100:5。
在一个优选的实施方案中，所述步骤(2)中加入的粘合剂溶液与通式1表示的化合物的药学上可接受的盐的质量比为1:100-10:100。
在一个优选的实施方案中，所述步骤(3)中的干燥温度为55-65℃。
在一个优选的实施方案中，所述步骤(3)中的干燥时间为4-6小时。
本发明的有益效果在于：本发明所述的非甾体抗炎药衍生物在溶媒中无法稳定存在(溶液状态不稳定)。因此，需将药物固体部分与溶媒分开保存，更优地，可将药物固体部分贮存在合适的药用包装材料中，可以显著提高药物的稳定性。所述药物组合物的固体部分为颗粒时，颗粒的休止角不超过30°，流动性好不粘连，能够迅速溶解于溶媒中，方便患者使用时的溶解操作。将所述药物组合物的固体部分溶于溶媒中后可通过透皮给药方式给药，避免了口服药物可能造成的肠胃不良反应(出血等)和***暴露。此外，固体部分与液体部分混合后可形成多种外用药物剂型，方便患者使用。
具体实施方式
具体而言，本发明提供了一种稳定的含有非甾体抗炎药衍生物的药物组合物，所述药物组合物至少包含分离的固体部分与液体部分，其中，所述固体部分包括治疗有效量的通式1表示的化合物的药学上可接受的盐，所述液体部分为药学上可接受的溶媒，
Figure PCTCN2018108622-appb-000007
通式1
其中，
Ar-代表
Figure PCTCN2018108622-appb-000008
R 1代表H或C 1-C 6-烷基，优选C 1-C 5-烷基，更优选C 1-C 4-烷基，甚至更优选 C 1-C 3-烷基，最优选甲基或乙基，
R 2代表H或C 1-C 6-烷基，优选C 1-C 5-烷基，更优选C 1-C 4-烷基，甚至更优选C 1-C 3-烷基，最优选甲基或乙基，
n代表1、2、3、4、5、6、7、8、9或10，优选n≤6的自然数，更优选n≤4的自然数，最优选n≤3的自然数。
在本文中，术语“至少包含……”指的是所述药物组合物中还可以含有任何其它组分，这些组分可以以任何含量存在，只要以该含量存在的该组分是人体可接受的，并对于本发明药物组合物中活性成分的活性没有负面影响即可。
在本文中，“药学上可接受的盐”优选是指通式1表示的化合物的相对无毒的无机酸或有机酸加成盐，所述药学上可接受的盐的实例有通式1表示的化合物与无机酸形成的盐，所述无机酸包括但不限于：盐酸、氢溴酸、氢氟酸、氢碘酸、硫酸、二硫酸、磷酸或硝酸，或与有机酸形成的盐，所述有机酸包括但不限于：甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、双葡糖酸、3-羟基-2-萘甲酸、烟酸、双羟萘酸、果胶酸、过硫酸、3-苯丙酸、苦味酸、新戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、枸橼酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸，优选通式1表示的化合物与盐酸、氢溴酸、氢氟酸、氢碘酸、磷酸、乙酸、草酸、枸橼酸或硫氰酸形成的盐。
术语“C 1-C 6-烷基”是指具有1、2、3、4、5或6个碳原子的直链或支链饱和单价烃基。C 1-C 6-烷基的实例有：甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，优选甲基、乙基、丙基、异丙基、丁基、仲丁基或叔丁基，更优选甲基或乙基。
根据中国专利CN 101484415 B、CN 101489985 B公开的内容可知，本发明所 述的药物组合物可用于治疗非甾体抗炎药(如阿司匹林、布洛芬)的适应症，包括但不限于，疼痛、发热、炎症、风湿、关节炎、血栓、癌症、中风、痴呆、糖尿病、糖尿病并发症、心血管疾病、脑血管疾病等。
本发明所述的非甾体抗炎药衍生物的制备方法，可参考中国专利CN 101484415 B、CN 101489985 B、美国专利3,365,483或其他参考文献。这类前药衍生物的优势在于：其可通过透皮给药进入体内，避免了普通非甾体抗炎药口服产生的胃肠道不良反应。因此，该类药物较佳地是采用溶液剂型透皮进入体内。然而，发明人发现所述非甾体抗炎药衍生物在溶媒中无法稳定存在(溶液状态不稳定)。因此，需将药物固体部分与溶媒分开保存，更优选地，可将药物固体部分贮存在密闭的药用包装材料中，可以显著提高药物的稳定性。
在一个优选的实施方案中，所述固体部分与所述液体部分的质量比为：0.1:100-40:100，再优选0.5:100-20:100，最优选1:100-10:100。
在一个优选的实施方案中，药物组合物的固体部分为含有所述通式1表示的化合物的药学上可接受的盐的粉末、颗粒、丸剂、片剂、或胶囊。
在一个优选的实施方案中，药物组合物的固体部分为所述通式1表示的化合物的药学上可接受的盐与药学上可接受的粘合剂形成的颗粒。
术语“药学上可接受的粘合剂”是指能使无粘性或粘性较小的物料聚集粘结成颗粒或压缩成型的具粘性的固体粉末或粘稠液体，且应当与本发明药物组合物中的活性成分非甾体抗炎药衍生物(通式1表示的化合物的药学上可接受的盐)相容，即能与其共混而不会在通常情况下大幅度降低药物的疗效。
在一个优选的实施方案中，所述药学上可接受的粘合剂选自：羟丙甲纤维素、卡波姆、乙基纤维素、羟丙基纤维素、乙烯纤维素、淀粉(更优选预胶化淀粉)、聚乙烯吡咯烷酮。当所述药物组合物的固体部分为所述通式1表示的化合物的药学上可接受的盐与药学上可接受的粘合剂形成颗粒时，颗粒与药学上可接受的溶媒(例如无菌水)混合溶解，涂抹晾干后形成薄膜，不易脱落，方便药物在患者皮肤上的附着与吸收。
发明人将常用的粘合剂，包括羟丙甲纤维素、卡波姆、乙基纤维素、羟丙基纤维素、乙烯纤维素、淀粉、聚乙烯吡咯烷酮分别与本发明所述通式1表示的化合物的药学上可接受的盐混合，湿法制粒，形成颗粒，再分别将颗粒与药学上可 接受的溶媒(例如无菌水)混合溶解。结果显示，羟丙甲纤维素与所述通式1表示的化合物的药学上可接受的盐形成的颗粒溶解性最佳，可以形成澄明的溶液，并且涂抹晾干后形成透明的薄膜，不易脱落，方便药物在患者皮肤上的附着与吸收。因此，在一个最佳的实施方案中，所述药学上可接受的粘合剂为羟丙甲纤维素。
在一个优选的实施方案中，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的粘合剂的质量比为：100:0.05-100:10，更优选100:1-100:5，最优选100:1-100:2。
粉末或颗粒堆积时形成的“休止角”反映了其流动性。术语“休止角”通常是指粉末或颗粒堆积层的自由斜面与水平面所形成的最大角。休止角越小，说明粉末或颗粒之间摩擦力越小，流动性越好，更方便溶解使用。测量休止角的方法是本领域技术人员所熟知的。本文实施例中采用了“注入法”测量休止角，即微粒物料由漏斗流出落于平面上形成圆锥体，锥底角即为休止角。
在一个优选的实施方案中，所述粉末或颗粒的休止角小于等于40°，更优选小于等于35°，甚至更优选小于等于30°。
在一个优选的实施方案中，本发明所述药物组合物固体部分储存于密闭的药学上可接受的包装材料中。
术语“药学上可接受的包装材料”指容器密封材料和内容物之间没有严重的相互影响，没有导致产品活性和稳定性发生改变，或者产生毒性风险，且在正常贮存/使用条件下，包装材料成分与产品之间产生的任何影响均不会导致产品质量或包装发生不可接受变化的包装材料。
所述药学上可接受的包装材料包括但不限于：低密度聚乙烯膜、低密度聚乙烯袋、高密度聚乙烯膜、低密度聚乙烯瓶、高密度聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、聚酯/铝/聚乙烯复合膜、聚酯/铝/聚乙烯复合袋、玻璃瓶，或者它们的组合。
在一个优选的实施方案中，所述药学上可接受的包装材料是高密度聚乙烯瓶与聚酯/铝/聚乙烯复合袋的组合。
在一个优选的实施方案中，本发明所述药物组合物液体部分使用药学上可接受的溶媒。
所述药学上可接受的溶媒包括但不限于：无菌水、脱二氧化碳水、乙醇、山梨醇水溶液、生理盐水等。
在一个优选的实施方案中，所述药物组合物还包含药用喷雾装置、药用滴管、药用软毛刷，或其组合。
在一个优选的实施方案中，在使用时将药物组合物固体部分与液体部分相混合，形成喷雾剂、滴剂、或涂擦剂。
在一个优选的实施方案中，所述药物组合物的固体部分(颗粒)采用高密度聚乙烯瓶包装，再置于聚酯/铝/聚乙烯药品包装用复合袋中；液体部分为无菌水作为溶媒(存放于药用玻璃瓶或药用聚乙烯塑料瓶中)，与药用喷雾装置(例如药用喷雾泵)一同置于塑料托盒后，装入白色卡纸盒中。需要说明的是，为了方便患者使用，可以预先将颗粒与溶媒按照相应比例包装，例如包装为5g颗粒和50mL无菌水。患者使用时，将颗粒5g全部溶解在无菌水50mL中，配制成10％的水溶液，再配合药用喷雾泵形成喷雾剂使用(在规定的时间内使用，例如1-2周)。
本发明还提供了一种制备所述颗粒的方法，所述方法包括如下步骤：
(1)配制粘合剂溶液；
(2)将通式1表示的化合物的药学上可接受的盐与步骤(1)配制的粘合剂溶液混合。
发明人发现，直接向本发明所述通式1表示的化合物的药学上可接受的盐中加入粘合剂(例如羟丙甲纤维素)溶液难以制得理想的颗粒，获得的颗粒松散、易碎、易结块。因此，发明人改进了制粒方法，先将本发明所述通式1表示的化合物的药学上可接受的盐与粘合剂(例如羟丙甲纤维素)干粉混合，再加入粘合剂(例如羟丙甲纤维素)溶液混合，可获得理想的颗粒。
具体而言，本发明提供另一种制备所述颗粒的方法，所述方法包括如下步骤：
(1)配制粘合剂溶液；
(2)将通式1表示的化合物的药学上可接受的盐与粘合剂干粉按一定比例混合，再加入步骤(1)配制的粘合剂溶液混合均匀，制成软材；
(3)软材干燥；
(4)整粒，选择能通过10目筛但不能通过60目筛的颗粒。
在一个优选的实施方案中，所述步骤(1)中配制的粘合剂溶液的浓度为0.1 w/w％-3.0w/w％。
在一个优选的实施方案中，所述步骤(2)中通式1表示的化合物的药学上可接受的盐与粘合剂干粉的质量比为100:0.1-100:5。
在一个优选的实施方案中，所述步骤(2)中加入的粘合剂溶液与通式1表示的化合物的药学上可接受的盐的质量比为1:100-10:100。
在一个优选的实施方案中，所述步骤(3)中的干燥温度为55-65℃。
在一个优选的实施方案中，所述步骤(3)中的干燥时间为4-6小时。
在本文中，术语“包括如下步骤……”是指除了所列出的步骤外，所述方法还可以包括任何其它的帮助或促进所述方法完成的步骤。例如，可以在所述步骤(2)之前，对通式1表示的化合物的药学上可接受的盐进行过筛处理，方便后续的制粒步骤。
在一个优选的实施方案中，所述方法包括如下步骤：
(1)用80目筛对本发明通式1表示的化合物的药学上可接受的盐进行过筛处理；
(2)配制一定浓度(优选1-3w/w％，更优选1.5w/w％)的羟丙甲纤维素溶液，室温下静置过夜，备用；
(3)将经步骤(1)预处理后的本发明通式1表示的化合物的药学上可接受的盐与羟丙甲纤维素干粉混合(优选质量比100:1.5)，再加入步骤(2)配制的羟丙甲纤维素溶液(化合物与粘合剂干粉的质量比优选为100:1-100:5，更优选100:1-100:2，甚至更优选100:1.5-100:1.7)，混合均匀制成软材，按压过14目筛；
(4)干燥软材(优选地，干燥温度为60℃；优选地，干燥时间小于12小时，更优选4-6小时)；
(5)整粒，选择颗粒(优选地，选择能通过10目筛但不能通过60目筛的颗粒)。
本发明还提供了一种制备所述片剂的方法，所述方法包括如下步骤：
(1)配制粘合剂溶液；
(2)将通式1表示的化合物的药学上可接受的盐与助流剂(如滑石粉)混合，再加入步骤(1)配制的粘合剂溶液混合均匀，制成软材；
(3)软材干燥；
(4)压片。
需要说明的是，本发明所述的技术方案可做任意组合。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。
本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量(克)。
除非另行定义，文中所使用的所有专业与科学用语与本领域技术人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明中。文中所述的优选实施方案与材料仅作示范之用。
实施例
实施例1. 2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐的制备
以甲苯为溶剂，N,N-二甲基甲酰胺为催化剂，在反应温度50℃下，使阿司匹林与氯化亚砜以当量比1:1.1进行反应，反应2小时，反应生成邻乙酰水杨酰氯；接着，二乙氨基乙醇和酰化产物邻乙酰水杨酰氯以当量比1:1进行反应，反应温度为25℃，时间为4小时，反应生成2-(二乙氨基)-乙基2-乙酰氧基苯甲酸酯；甲基叔丁基醚萃取水相，取水相冰浴，加碳酸氢钠调pH值至7-8，再使用乙酸异丙酯为萃取剂，萃取水相，取乙酸异丙酯相；成盐过程中以乙酸异丙酯为溶剂，随后严格控制通入氯化氢气的量，使反应液pH为3.5左右。反应结束得到2-(二乙氨基)乙基2-乙酰氧基苯甲酸酯盐酸盐粗品原料。
在加热回流下，向2-(二乙氨基)乙基2-乙酰氧基苯甲酸酯盐酸盐粗品原料中连续加入无水乙腈搅拌混合，直至2-(二乙氨基)乙基2-乙酰氧基苯甲酸酯盐酸盐完全溶解。其中，2-(二乙氨基)乙基2-乙酰氧基苯甲酸酯盐酸盐粗品原料与无水乙腈的最终质量体积比为1:4。缓慢冷却至25℃，析出白色晶体，抽滤后进行固体真空旋干。
合成所得2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐晶体的理化性质如表1所示。
表1
Figure PCTCN2018108622-appb-000009
取合成所得2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐晶体进行核磁共振表征，使用仪器为Bruker AV-500超导核磁共振仪，测试温度为300.0K，溶剂为CDCl 3，得到的特征数据如下所示，证明成品的结构与2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐一致。
13C NMR(400MHz，CDCl 3)：δ8.49，20.92，47.17，49.74，58.80，122.03，123.73，126.05，131.15，134.45，150.73，163.52，169.45。
1H NMR(400MHz，CDCl 3)：δ1.42(t，6H，J＝7.5Hz)，2.35(s，3H)，3.23(m，4H)，3.42(m，2H)，4.85(t，2H，J＝5.5Hz)，7.14(d，1H，J＝8.0Hz)，7.34(dd，1H，J＝8.0Hz)，7.61(dd，1H，J＝7.5Hz)，8.00(d，1H，J＝8.0Hz)，12.54(s，1H)。
实施例2. 2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐水溶液的稳定性
取实施例1制备获得的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐5g，溶于无菌用水50mL中，于2-8℃下放置，分别于第0天、0.5个月、1个月、2个月和3个月取样，分别检测主药含量、特定杂质(水杨酸-(2-二乙基氨基乙基酯)盐酸盐、乙酰水杨酸、水杨酸)和有关物质，其中主药含量和特定杂质采用高 效液相色谱(外标法)检测，有关物质采用高效液相色谱(不加校正因子的主成分自身对照法)检测。高效液相色谱的条件如下：
色谱柱：Inertsil ODS-3(250×4.6mm，5μm)或相当的色谱柱
流速：1.0ml/min
柱温：33℃
波长：276nm、303nm
进样量：10μl
流动相：水(15ml三乙胺+3.5ml 10％四丁基氢氧化铵加水至1000ml):甲醇:冰醋酸(63:27:10)。
稳定性研究的结果显示，2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐的水溶液在2-8℃下放置3个月，主药含量已降低至86％左右，杂质水杨酸-(2-二乙基氨基乙基酯)盐酸盐上升至超过13％。这样的结果已不符合对于化学药品稳定性的一般要求。具体数据如表2所示。
表2
Figure PCTCN2018108622-appb-000010
实施例3. 2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐颗粒的制备
(1)用80目筛将实施例1制备获得的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐进行过筛处理；
(2)配制1.5％的羟丙甲纤维素溶液：将1.5g羟丙甲纤维素溶于100g热水中，搅拌均匀，室温下静置过夜，备用；
(3)将经步骤(1)预处理后的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐100g与羟丙甲纤维素干粉1.5g混合，再加入步骤(2)配制的羟丙甲纤维素溶液9-10g，混合均匀，制成软材。按压过14目筛；
(4)在60℃下干燥软材4-6小时；
(5)整粒，选择能通过10目筛但不能通过60目筛的颗粒。
获得的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐颗粒为类白色，休止角为28°，水溶液在25±0.5℃下的pH值为4.3-4.4。
实施例4. 2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐喷雾用颗粒剂的制备及其稳定性研究
取实施例3制备获得的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐颗粒5g，用高密度聚乙烯瓶包装，密封后置于聚酯/铝/聚乙烯药品包装用复合袋中。将无菌水50mL作为溶媒(存放于药用玻璃瓶或药用聚乙烯塑料瓶中)，与包装后的颗粒以及药用喷雾泵一起置于塑料托盒后，装入白色卡纸盒中。在使用时，患者可以将2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐颗粒溶解于无菌水中，配合药用喷雾泵形成喷雾剂使用。
取上述制备得到的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐喷雾用颗粒(用高密度聚乙烯瓶包装，密封后置于聚酯/铝/聚乙烯药品包装用复合袋中)，置于25℃±2℃温度和60％±10％相对湿度下，分别于0个月、3个月、6个月、9个月、12个月取样，检测性状、干燥失重、水分、特定杂质(水杨酸-(2-二乙基氨基乙基酯)盐酸盐、乙酰水杨酸、水杨酸)、有关物质、主药含量。其中，性状采用目测法，水分采用容量滴定法检测(《中国药典》费休氏法之容量滴定法)，特定杂质和主药含量采用高效液相色谱(外标法)检测，有关物质采用高效液相色谱(不加校正因子的主成分自身对照法)检测。高效液相色谱的条件同实施例2。
稳定性研究的结果显示，该喷雾用颗粒在25℃±2℃下放置12个月，其稳定性非常好，各项物理化学参数基本保持不变。具体数据如表3所示。
表3
Figure PCTCN2018108622-appb-000011
实施例5. 2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐的合成
以二氯甲烷为溶剂，N,N-二甲基甲酰胺为催化剂，控制反应温度为15-30℃，使布洛芬与氯化亚砜以当量比1:1.2进行反应，反应2-4小时，反应生成布洛芬酰氯。加入二氯甲烷，加入2.0当量的二乙胺基乙醇，冰水浴下慢慢滴加布洛芬酰氯，滴加过程有少许升温，滴加完毕继续搅拌2小时，加入0.5％稀盐酸的水溶液终止反应，分层，有机相用饱和碳酸氢钠洗，水洗，无水硫酸钠干燥，移出溶剂，得到布洛芬胺的粗产物。加入含有氯化氢气体的乙酸异丙酯溶液后，大量白色固体析出，抽滤得到2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐。丙酮重结晶得到2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐晶体(粉末)，粉末的休止角为：40°。
取合成所得2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐晶体进行核磁共振表征，使用仪器为Bruker AV-500超导核磁共振仪，测试温度为300.0K，溶剂为CDCl 3，得到的特征数据如下所示，证明成品的结构与2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐一致。
13C NMR(500MHz，CDCl 3)：δ8.42，8.51,17.92，22.18，30.00，44.78，44.83,46.91,46.97,49.40,58.49,127.04，129.41，136.89，140.87，173.66。
1H NMR(500MHz，CDCl 3)：δ0.90(t，6H，J＝7.0Hz)，1.26(m，6H),1.50(m,3H),1.86(d，J＝7.0Hz,1H)，2.44(m,2H),2.85(d，J＝7.0Hz,1H),2.95(m,3H),3.25(m，2H)，4.10(m，2H)，4.45(m,2H)，6.88(d，1H，J＝7.5Hz)，7.17(d，1H，J＝8.0Hz)，7.55(d，1H，J＝7.5Hz)，7.88(d，1H，J＝8.0Hz)，12.31(s，1H)。
实施例6. 2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐水溶液的稳定性
取实施例5制备获得的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐10g，溶于无菌用水50mL中，于25℃±2℃下放置，分别于第0天、1周、2周、3周和4周取样，分别检测主药含量、特定杂质(布洛芬)，其中主药含量和特定杂质采用高效液相色谱(面积归一法)检测。高效液相色谱的条件如下：
色谱柱：Inertsil ODS-3(250×4.6mm，5μm)或相当的色谱柱
流速：1.0ml/min
柱温：33℃
波长：264nm
进样量：10μl
流动相：(3.065g乙酸钠+150ml乙酸+375ml水):乙腈(35:65)。
稳定性研究的结果显示，2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐的水溶液在25℃±2℃下放置4周，主药含量已降低至89％左右，杂质布洛芬超过10％。这样的结果已不符合对于化学药品稳定性的一般要求。具体数据如表4所示。
表4
Figure PCTCN2018108622-appb-000012
Figure PCTCN2018108622-appb-000013
实施例7. 2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐颗粒的制备
(1)用80目筛将实施例5制备获得的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐进行过筛处理；
(2)配制0.5％的卡波姆粘合剂：1.0g卡波姆溶解于200ml水中，静置待用；
(3)流化床制备颗粒：将经步骤(1)预处理后的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐200g放入流化床(FLZB-3，创志机电科技发展有限公司)中，喷入步骤(2)配制的粘合剂，制备得到颗粒，其中，物料温度：23-28℃，进风温度：60℃，缸体温度：27℃，喷料流速：0.8-2.0r/min。
获得的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐颗粒为类白色，休止角为29°。
实施例8. 2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐喷雾用颗粒剂的制备及其稳定性研究
取实施例7制备获得的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐颗粒10g，密封于聚酯/铝/聚乙烯药品包装用复合袋中。将无菌水50mL作为溶媒(存放于药用玻璃瓶或药用聚乙烯塑料瓶中)，与包装后的颗粒以及药用喷雾泵一起置于塑料托盒后，装入白色卡纸盒中。在使用时，患者可以将2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐颗粒溶解于无菌水中，配合药用喷雾泵形成喷雾剂使用。
取上述制备得到的2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐颗粒(密封于聚酯/铝/聚乙烯药品包装用复合袋中)，置于25℃±2℃温度和60％±10％相对湿度下，分别于0个月、3个月、6个月、9个月、12个月取样，检测性状、干燥失重、水分、特定杂质(布洛芬)、主药含量。其中，性状采用目测法，水分采用容量滴定法检测(《中国药典》费休氏法之容量滴定法)，特定杂质和主药含 量采用高效液相色谱(面积归一法)检测。高效液相色谱的条件同实施例6。
稳定性研究的结果显示，该颗粒在25℃±2℃下放置12个月，其稳定性非常好，各项物理化学参数基本保持不变。具体数据如表5所示。
表5
Figure PCTCN2018108622-appb-000014
实施例9.水杨酸-(2-二乙基氨基乙基酯)盐酸盐的合成及其片剂的制备
1、化合物的合成
取实施例1制备获得的2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐(31.5g)溶于乙腈(30mL)，加入浓盐酸(10mL)，室温搅拌48小时，浓缩蒸干，加入50mL水溶解，加入饱和碳酸氢钠溶液，搅拌，乙酸异丙酯萃取，饱和食盐水洗涤，无水硫酸钠干燥，过滤，通入HCl气，析出白色固体，乙醇重结晶，得到水杨酸-(2-二乙基氨基乙基酯)盐酸盐(17.7g，收率：65％)。
HNMR(CDCl3)δ(ppm)：11.31(br，1H)，10.47(s，1H)，7.87(dd，J＝8.0，1.5Hz，1H)，7.52-7.49(m，1H)，7.03(d，J＝8.0Hz，1H)，6.95-6.92(m，1H)，4.69(t，J＝5.0Hz，2H)，3.52(q，J＝4.5Hz，2H)，3.24-3.17(m，4H)，1.30-1.25(m，6H)。
2、片剂的制备
(1)用80目筛将水杨酸-(2-二乙基氨基乙基酯)盐酸盐进行过筛处理；
(2)配制1.0％的乙基纤维素溶液：将1.0g乙基纤维素溶于100g乙醇中， 搅拌均匀，室温下静置过夜，备用；
(3)将经步骤(1)预处理后的水杨酸-(2-二乙基氨基乙基酯)盐酸盐100g与滑石粉5.0g混合，再加入步骤(2)配制的乙基纤维素溶液6-8g，混合均匀，制成软材，按压过3目筛；
(4)在60℃下干燥软材8小时；
(5)压片，得到片剂。
取上述制备获得的水杨酸-(2-二乙基氨基乙基酯)盐酸盐片剂密封于高密度聚乙烯瓶中，将无菌水50mL作为溶媒(存放于药用玻璃瓶或药用聚乙烯塑料瓶中)，配合药用软毛刷一起置于塑料托盒后，装入白色卡纸盒中。经长期稳定性研究(25℃±2℃，12个月)，该片剂的稳定性良好，完全符合制药行业的要求。
在使用时，患者可以将水杨酸-(2-二乙基氨基乙基酯)盐酸盐片剂溶解于无菌水中，配合药用软毛刷形成涂擦剂使用。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容广义地定义于权利要求范围中，任何他人完成的技术实体或方法，若是与权利要求范围所定义的完全相同，亦或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。

Claims (9)

  1. 一种稳定的含有非甾体抗炎药衍生物的药物组合物，其特征在于，所述药物组合物至少包含分离的固体部分与液体部分，其中，所述固体部分包括治疗有效量的通式1表示的化合物的药学上可接受的盐，所述液体部分为药学上可接受的溶媒，
    Figure PCTCN2018108622-appb-100001
    其中，
    Ar-代表
    Figure PCTCN2018108622-appb-100002
    R 1代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
    R 2代表H、C1的烷基、C2的烷基、C3的烷基、C4的烷基、C5的烷基或C6的烷基，优选甲基或乙基，
    n代表1、2、3、4、5、6、7、8、9或10，优选1或2；
    优选地，所述通式1表示的化合物选自：
    Figure PCTCN2018108622-appb-100003
    优选地，所述通式1表示的化合物的药学上可接受的盐是通式1表示的化合物与无机酸或有机酸形成的盐，优选通式1表示的化合物与盐酸、氢溴酸、氢氟酸、氢碘酸、磷酸、乙酸、草酸、枸橼酸或硫氰酸形成的盐；
    优选地，所述通式1表示的化合物的药学上可接受的盐为：
    2-(二乙氨基)-乙基-2-乙酰氧基苯甲酸酯盐酸盐，
    水杨酸-(2-二乙基氨基乙基酯)盐酸盐，或
    2-(二乙氨基)-乙基-2-(4-异丁基苯基)丙酸酯盐酸盐；
    优选地，所述固体部分与所述液体部分的质量比为：0.1:100-40:100，再优选0.5:100-20:100，最优选1:100-10:100。
    优选地，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的溶媒的质量比为：0.1:100-40:100，再优选0.5:100-20:100，最优选1:100-10:100。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述药学上可接受的溶媒选自：无菌水、脱二氧化碳水、乙醇、山梨醇水溶液、生理盐水。
  3. 根据权利要求1所述的药物组合物，其特征在于，所述固体部分的剂型选自：粉末、颗粒、丸剂、片剂、胶囊。
  4. 根据权利要求1所述的药物组合物，其特征在于，所述固体部分还包括药学上可接受的粘合剂；优选地，所述药学上可接受的粘合剂选自：羟丙甲纤维素、卡波姆、乙基纤维素、羟丙基纤维素、乙烯纤维素、淀粉、预胶化淀粉、聚乙烯吡咯烷酮；更优选地，所述药学上可接受的粘合剂是羟丙甲纤维素。
  5. 根据权利要求4所述的药物组合物，其特征在于，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的粘合剂形成颗粒；优选地，所述通式1表示的化合物的药学上可接受的盐与所述药学上可接受的粘合剂的质量比为：100:0.05-100:10，更优选100:1-100:5，最优选100:1-100:2。
  6. 根据权利要求3或5所述的药物组合物，其特征在于，所述粉末或者颗粒的休止角不超过40°，优选不超过35°，更优选不超过30°。
  7. 根据权利要求1所述的药物组合物，其特征在于，所述固体部分储存于密闭的药学上可接受的包装材料中；优选地，所述药学上可接受的包装材料选自：低密度聚乙烯膜、低密度聚乙烯袋、高密度聚乙烯膜、低密度聚乙烯瓶、高密度 聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、聚酯/铝/聚乙烯复合袋、玻璃瓶，或其组合；更优选地，所述药学上可接受的包装材料是高密度聚乙烯瓶与聚酯/铝/聚乙烯复合袋的组合。
  8. 根据权利要求1所述的药物组合物，其特征在于，所述药物组合物还包括药用喷雾装置、药用滴管、药用软毛刷或其组合。
  9. 根据权利要求1或8所述的药物组合物，其特征在于，所述药物组合物在使用时，将所述固体部分与液体部分相混合，形成喷雾剂、滴剂、或涂擦剂。
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