CN113648297B - Pharmaceutical composition and patch containing flurbiprofen - Google Patents

Pharmaceutical composition and patch containing flurbiprofen Download PDF

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CN113648297B
CN113648297B CN202110938206.9A CN202110938206A CN113648297B CN 113648297 B CN113648297 B CN 113648297B CN 202110938206 A CN202110938206 A CN 202110938206A CN 113648297 B CN113648297 B CN 113648297B
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flurbiprofen
patch
weight
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pharmaceutical composition
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CN113648297A (en
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顾丹辉
李冬智
尹威
赵拓
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Leming Pharmaceutical Suzhou Co ltd
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7076—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising ingredients of undetermined constitution or reaction products thereof, e.g. rosin or other plant resins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The invention discloses a pharmaceutical composition containing flurbiprofen and a pharmaceutical composition of a patch. The pharmaceutical composition contains flurbiprofen as an active ingredient and pharmaceutically acceptable auxiliary materials which are pharmaceutically acceptable, wherein the pharmaceutically acceptable auxiliary materials at least comprise a stabilizer; the weight ratio of the flurbiprofen to the stabilizer is 1 (0.5-2). In the pharmaceutical composition, flurbiprofen is dispersed in an amorphous form, the components are matched with each other, and the hot-melt pressure-sensitive adhesive transdermal preparation containing the composition has the characteristics of good stability of active ingredients and excellent transdermal absorption performance.

Description

Pharmaceutical composition and patch containing flurbiprofen
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical composition and a patch containing flurbiprofen.
Background
Flurbiprofen is a propionic acid non-steroidal anti-inflammatory drug (NSAIDs) which plays a role in treatment mainly by inhibiting prostaglandin synthetase, has better analgesic and anti-inflammatory effects, is clinically used for symptomatic treatment of inflammation, fever and mild-moderate pain, and can be used for treating patients with ineffective or intolerance of aspirin.
The products containing flurbiprofen which are currently sold in the market comprise tablets, granules, injections, external preparations and the like. The flurbiprofen oral preparation is rapid to absorb, but has a short biological half-life in vivo, which is only 3-5 hours, and frequent administration is needed in the long-term rheumatoid arthritis treatment process, so that the aim of long-term treatment cannot be fulfilled. Secondly, oral flurbiprofen is prone to gastrointestinal adverse reactions, such as peptic ulcer and hemorrhage, which cause that part of patients cannot use the oral flurbiprofen.
Compared with flurbiprofen oral preparation, the transdermal administration can effectively avoid adverse reactions of gastrointestinal tracts, prolong the acting time of the medicine, reduce the administration times and improve the compliance of patients. Transdermal administration is therefore the preferred mode of flurbiprofen. For example, patent document CN104546803a discloses a preparation method of flurbiprofen hydrogel plaster, in which clomiphene is used as a solubilizer, and the drug is dispersed in a hydrophilic polymer material matrix. Similarly, patent CN1443532a disperses flurbiprofen in a hydrophilic cataplasm matrix by an emulsifier, and patent CN106822065A stabilizes the drug in a hydrophilic matrix material by adding an additional oil phase such as glyceryl decanoate or the like. However, flurbiprofen is poorly soluble in water and is often added to the hydrophilic matrix in the form of an oil-in-water emulsion mixed with a surfactant and water. Therefore, the gel patch preparation using the water-soluble polymer matrix often has the problems of slow absorption speed and unstable release of the active substance, and needs to be continuously improved. In addition, the preparation process of the water-soluble gel plaster is complex, and the pH value of the matrix is required to be strictly controlled (U.S. Pat. No. 5,807,568), so that inconvenience is caused to the production of the preparation.
Numerous attempts have been made in the prior art to make transdermal formulations of other types of matrices, such as CN103211799a which discloses a transdermal formulation employing polyisobutylene and silicone as matrix materials; CN105232496a discloses a preparation method of a coating agent containing flurbiprofen, which adopts chitosan, carbomer, glycerol and the like as matrix materials; CN103079552A uses diethylene glycol monomethyl ether
Figure BDA0003213691120000021
And caprylic capric polyethylene glycol glyceride->
Figure BDA0003213691120000022
Permeation therapy with flurbiprofen is performed by forming a pharmaceutical composition. However, the solvent-based pressure-sensitive adhesive is easy to cause the problems of environmental pollution and high energy consumption due to the use of an organic solvent in the preparation process. Emulsion type pressure-sensitive adhesives are also limited to a certain extent due to the slow drying speed, and the migration of the emulsifier. Hot Melt Pressure Sensitive Adhesives (HMPSA) are prepared by using thermoplastic polymer as matrix, coating in molten state, and cooling at normal temperatureHardening, no organic solvent is used in the preparation process, and the automation degree is high, so that the method is widely applied to the fields of medical treatment and health and the like.
Based on this, several patents report the preparation method of flurbiprofen hot-melt pressure-sensitive adhesive transdermal formulations. Japanese patent laid-open No. 8-319234 discloses a patch composed of a rubber component, a tackifying resin and a softener. However, the release is poor because several binder components do not dissolve flurbiprofen and flurbiprofen is in a crystalline state in the formulation. In order to improve the state of the drug in the matrix, WO93/04677 discloses a method of using L-menthol as a flurbiprofen dissolution agent, however, there is still a possibility of crystallization of flurbiprofen with volatilization of L-menthol. Japanese patent laid-open No. 7-309749 discloses the use of lactate as a dissolving agent, but destroys the cohesive force of the adhesive matrix, and further causes pasty residue on the skin, causing skin irritation. Patent document CN102028673a stabilizes the drug by adjusting the proportion of the tackifying resin in the matrix, thereby inhibiting crystallization of flurbiprofen into the adhesive layer, but the tackifying resin has poor compatibility with the drug, can only prolong the patch stability to about 3 months, has poor patch carrying capacity, can only maintain effective release of the drug for about 8 hours, requires clinical administration three times a day, and is excessively frequent in administration frequency.
Disclosure of Invention
In order to improve the problems existing in the prior art, the present invention provides a pharmaceutical composition comprising flurbiprofen as an active ingredient, and pharmaceutically acceptable excipients, which at least comprise a stabilizer;
the weight ratio of flurbiprofen to the stabilizer is 1 (0.5-2), for example 1 (0.7-1.5), and the weight ratio is 1:0.5, 1:0.75, 1:1, 1:1.2, 1:1.5 or any weight ratio in the range formed by combining any two of the above proportions.
According to an embodiment of the invention, the flurbiprofen is dispersed in the pharmaceutical composition in an amorphous form.
According to the implementation of the inventionThe stabilizer is a polymer nonionic surfactant, such as polyoxyethylene polyoxypropylene block copolymer (poloxamer; such as
Figure BDA0003213691120000031
) One, two or more of polyvinyl alcohol (PVA) and polyvinylpyrrolidone (PVP), preferably poloxamer or polyvinylpyrrolidone, illustratively poloxamer F68 or polyvinylpyrrolidone K-90. According to an embodiment of the present invention, the pharmaceutically acceptable auxiliary materials may further comprise one, two or more of a pressure sensitive adhesive matrix, a tackifier, a plasticizer, a filler, an antioxidant, a permeation enhancer, and the like.
According to the embodiment of the invention, the pressure-sensitive adhesive matrix is a styrene thermoplastic elastomer, and the styrene thermoplastic elastomer means a styrene polymer material which shows rubber elasticity at normal temperature and can be plasticized and molded at high temperature. Preferably, the styrenic thermoplastic elastomer may be selected from one, two or more of styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), hydrogenated styrene-ethylene-butadiene-hydrogenated styrene block copolymer (SEBS) and hydrogenated styrene-isoprene-hydrogenated styrene block copolymer (SEPS).
According to embodiments of the present invention, the weight ratio of the pressure sensitive adhesive matrix to flurbiprofen is (1-3): 1, for example (1.5-2.5): 1, and exemplary are 1.2:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, or any weight ratio in the range of any two-to-two combinations of the foregoing.
According to an embodiment of the present invention, the tackifier may be selected from a natural tackifier and/or a synthetic tackifier, and the synthetic tackifier may be selected from at least one of an aliphatic resin, an aromatic resin, and the like. For example, the tackifier may be selected from one, two or more of rosin, rosin modified, terpene resin, petroleum resin, and phenolic resin; preferably, the tackifier is selected from terpene resins and hydrogenated rosin glycerol esters.
According to an embodiment of the invention, the weight ratio of the tackifier to flurbiprofen is (0.5-2) 1, for example (0.8-1.5) 1, and is exemplified by 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or any weight ratio in the range of any two-to-two combinations of the above.
According to an embodiment of the present invention, the plasticizer may be selected from one, two or more of liquid paraffin, low molecular weight polyisobutylene, dibutyl phthalate, tricresyl phosphate, lanolin, white oil and other pharmaceutically acceptable plasticizers, preferably liquid paraffin and/or low molecular weight polyisobutylene. Preferably, the low molecular weight polyisobutylene has a viscosity average molecular weight of 3500 to 100000; for example, may be selected from polyisobutenes having a viscosity average molecular weight of about 40000.
According to an embodiment of the invention, the weight ratio of plasticizer to flurbiprofen is (2-5): 1, for example (2.5-4): 1, exemplary is 2.7:1, 3:1, 3.2:1, 3.5:1, 3.6:1, 3.8:1 or any weight ratio in the range of any two-to-two combinations of the above.
According to an embodiment of the invention, the filler may be selected from fillers commonly used in the art, such as calcium carbonate, preferably light calcium carbonate (CaCO) 3 ) One, two or more of calcium hydroxide, talcum powder, kaolin, titanium dioxide and micro silica gel. The filler is mainly used for improving cohesive strength of the pressure-sensitive adhesive matrix, enhancing toughness and deformation resistance of colloid and improving dispersion state of flurbiprofen serving as an active ingredient.
According to an embodiment of the invention, the weight ratio of filler to flurbiprofen is (0.001-0.006) 1, for example (0.002-0.005) 1, exemplified by 0.0025:1, 0.003:1, 0.0035:1, 0.004:1 or any weight ratio in the range of any two-to-two combinations of the foregoing.
According to an embodiment of the present invention, the antioxidant may be selected from one, two or more of dibutylhydroxytoluene (BHT), butylhydroxyanisole (BHA) and Propyl Gallate (PG).
According to an embodiment of the invention, the weight ratio of antioxidant to flurbiprofen is (0.01-0.06): 1, for example (0.02-0.05): 1, exemplified by 0.025:1, 0.03:1, 0.035:1, 0.04:1 or any weight ratio in the range of any two-to-two combinations of the above.
According to an embodiment of the present invention, the penetration enhancer may be selected from one, two or more of L-menthol, 1, 8-cineole and d-limonene. In addition, the permeation enhancer can also act as a cooling agent.
According to an embodiment of the invention, the weight ratio of the penetration enhancer to flurbiprofen is (0.05-1), for example (0.08-0.5): 1, exemplified by 0.1:1, 0.15:1, 0.2:1, 0.3:1 or any weight ratio in the range of any two-to-two combinations of the above.
According to an embodiment of the invention, the pharmaceutical composition comprises the following components: flurbiprofen, a pressure-sensitive adhesive matrix, a tackifier, a plasticizer, a stabilizer, an antioxidant and a permeation enhancer;
preferably, the mass ratio of flurbiprofen to stabilizer is 1 (0.5-2), for example 1 (0.7-1.5), and exemplary is 1:0.5, 1:0.75, 1:1, 1:1.2, 1:1.5. Within this ratio, flurbiprofen and the stabilizer are capable of forming a eutectic solid dispersion at a temperature above 130 ℃.
In the above pharmaceutical composition, the formation of the eutectic solid dispersion allows flurbiprofen to exist in a pressure-sensitive adhesive matrix in an amorphous highly dispersed state, and the stability of flurbiprofen as an active ingredient is improved by the interaction with the pressure-sensitive adhesive matrix.
According to a preferred embodiment of the present invention, the pharmaceutical composition comprises flurbiprofen in a weight ratio of 1 (1-3): 0.5-2): 2-5): 0.5-2: (0.001-0.006): 0.01-0.06): 0.05-1, a pressure sensitive adhesive matrix, a tackifier, a plasticizer, a stabilizer, a filler, an antioxidant and a permeation enhancer;
the stabilizer is selected from poloxamer and/or polyvinylpyrrolidone, and the flurbiprofen is dispersed in an amorphous form;
preferably, the pressure sensitive adhesive matrix is selected from SIS;
preferably, the terpene resin and/or hydrogenated rosin glycerol ester;
preferably, the plasticizer is selected from liquid paraffin and/or low molecular weight polyisobutylene;
preferably, the filler calcium hydroxide;
preferably, the antioxidant is selected from BHT;
preferably, the penetration enhancer is selected from the group consisting of L-menthol.
According to an embodiment of the invention, the pharmaceutical composition is in the form of a paste.
According to an exemplary embodiment of the present invention, the pharmaceutical composition comprises the following raw materials in parts by weight:
Figure BDA0003213691120000051
Figure BDA0003213691120000061
according to an exemplary embodiment of the present invention, the pharmaceutical composition comprises the following raw materials in parts by weight:
Figure BDA0003213691120000062
the invention also provides application of the pharmaceutical composition in preparing a therapeutic pharmaceutical preparation.
According to an embodiment of the invention, the pharmaceutical formulation is a patch, preferably a transdermal patch.
According to an embodiment of the invention, the pharmaceutical formulation is a pharmaceutical formulation for the treatment of inflammation, fever, soft tissue disease and/or mild to moderate pain. Wherein the inflammation is rheumatoid arthritis, osteoarthritis or ankylosing spondylitis; the soft tissue diseases can be sprains and strains, and the light and medium pain can be dysmenorrhea, postoperative pain, toothache and the like.
The invention also provides a patch which comprises the pharmaceutical composition.
According to an embodiment of the invention, the patch comprises a backing layer, a paste layer and a release layer, the paste layer comprising the above pharmaceutical composition.
Preferably, the paste layer is located between the backing layer and the release layer.
Preferably, the paste layer is formed by dispersing a miniature drug reservoir in the pressure sensitive adhesive layer.
Preferably, the mini-drug depot comprises or consists of flurbiprofen and a stabilizer.
According to an embodiment of the present invention, the material of the backing layer may be selected from materials known in the art, such as a polyester-polyethylene composite film, a polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film, a polyester film, a nonwoven fabric, or a stretch cloth.
According to an embodiment of the present invention, the anti-adhesive layer may be selected from films of materials known in the art, such as release films, exemplified by films of polyethylene, polystyrene, polypropylene or polycarbonate.
According to an embodiment of the invention, the patch has a structure substantially as shown in fig. 1.
According to an embodiment of the invention, the patch is a flurbiprofen hot-melt pressure-sensitive adhesive transdermal formulation.
The invention also provides application of the pharmaceutical composition or the pharmaceutical preparation in treating inflammation, fever, soft tissue diseases and/or mild-moderate pain. Wherein the inflammation is rheumatoid arthritis, osteoarthritis or ankylosing spondylitis; the soft tissue diseases can be sprains and strains, and the light and medium pain can be dysmenorrhea, postoperative pain, toothache and the like.
The invention also provides a method for treating inflammation, fever, soft tissue diseases and/or mild to moderate pain by using the pharmaceutical composition or the pharmaceutical preparation, which comprises the step of applying the pharmaceutical composition or the pharmaceutical preparation to a disease position.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: and mixing the raw material components in the weight ratio to obtain the pharmaceutical composition.
According to an embodiment of the invention, the preparation method comprises the steps of:
(1) Mixing and swelling the pressure-sensitive adhesive matrix and the plasticizer to obtain a swelling mixture;
(2) Adding a tackifier, a penetration enhancer, a filler and an antioxidant into the swelling mixture, and stirring until the mixture is melted;
(3) Heating and mixing flurbiprofen and a stabilizer to form a solid mixture of flurbiprofen and the stabilizer;
(4) And (3) heating and mixing the solid mixture with the material obtained in the step (2), and cooling after the reaction is completed to obtain the pharmaceutical composition.
According to an embodiment of the present invention, the pressure sensitive adhesive matrix, plasticizer, filler, permeation enhancer, antioxidant, adhesion promoter and stabilizer have the choices and weight ratios as shown above.
According to an embodiment of the invention, in step (1), the swelling temperature is 140-170 ℃, for example 150-160 ℃, illustratively 145 ℃, 150 ℃, 155 ℃, 160 ℃, 165 ℃ or any point value within the range of any two values in pairs.
According to an embodiment of the present invention, in the step (1), the swelling time is more than 30min, for example, 30min to 5h, and is exemplified by 30min, 1h, 2h, 3h, 4h, or any point value in the range of any two values in the two-by-two combination.
According to an embodiment of the present invention, in step (2), the adhesion promoter, penetration enhancer, filler and antioxidant are added sequentially to the swelling mixture.
According to an embodiment of the invention, in step (2), the stirring is carried out to a temperature of 140-170 ℃, for example 150-160 ℃, for example 145 ℃, 150 ℃, 155 ℃, 160 ℃, 165 ℃ or any point value within the range of any two values in pairs.
According to an embodiment of the invention, in step (3), the temperature of the heated mixture is not lower than 130 ℃, for example 140-170 ℃, preferably 150-160 ℃, and in an exemplary case 145 ℃, 150 ℃, 155 ℃, 160 ℃, 165 ℃ or any point value within the range of any two values in pairs.
According to an embodiment of the present invention, in step (3), the solid mixture is a eutectic solid dispersion.
According to an embodiment of the invention, in step (4), the temperature of the heated mixture is not lower than 130 ℃, for example 140-170 ℃, preferably 150-160 ℃, and in an exemplary case 145 ℃, 150 ℃, 155 ℃, 160 ℃, 165 ℃ or any point value within the range of any two values in pairs.
According to an embodiment of the present invention, in the step (4), the heating and mixing time is more than 30min, for example, 30min-5h, and exemplified by 30min, 1h, 2h, 3h, 4h, or any point value in the range of any two values in pairs.
According to an embodiment of the present invention, steps (1), (2) and (4) are performed under inert atmosphere or vacuum conditions. For example, the inert atmosphere may be provided by nitrogen or argon.
The invention also provides a preparation method of the medicinal preparation, preferably a patch, comprising a preparation method of the medicinal composition.
According to an embodiment of the present invention, the method for preparing the patch comprises the steps of: the patch is prepared by taking the medicinal composition as a paste layer, and combining the paste layer, a backing layer and an anti-sticking layer.
According to an embodiment of the invention, the paste layer is located between the backing layer and the release layer.
The invention has the beneficial effects that:
the invention provides a pharmaceutical composition of flurbiprofen with amorphous dispersion and mutual matching of components, and a hot-melt pressure-sensitive adhesive transdermal preparation containing the composition has the characteristics of good stability of active ingredients and excellent transdermal absorption performance. Compared with the pressure-sensitive adhesive transdermal patch in the prior art, the invention can not only stabilize the flurbiprofen serving as an active ingredient by adding the stabilizing agent such as poloxamer and the like, avoid the crystallization of the flurbiprofen, but also ensure that the stabilizing agent does not influence the cohesive force of the matrix and meets the medicinal requirement.
The specific advantages are represented in the following three aspects:
(1) The prepared patch has good adhesion with skin and less irritation and allergy;
(2) The stability of the medicine in the matrix and the concentration of the medicine in the matrix are improved by introducing the stabilizer, the storage time and the effective acting time of the patch are prolonged, and the transdermal release and the adhesive property of the patch are not obviously affected by the addition of the stabilizer;
(3) In the production process, an organic solvent is not required, drying equipment is not required after coating, no bubbles appear on the surface of the patch, and the patch is safe, energy-saving and environment-friendly.
Drawings
FIG. 1 is a schematic structural diagram of a flurbiprofen pressure-sensitive adhesive patch according to an embodiment of the present invention;
FIG. 2 is an in vitro transdermal drug delivery profile of the patches of examples 1-4 and comparative example 1;
FIG. 3 is an in vitro transdermal drug delivery profile of the patch of example 1 and the patch of comparative example 2;
FIG. 4 is an in vitro transdermal drug delivery profile of the patch of example 1 and the patch of comparative example 1 after 3 months of placement;
FIG. 5 is a differential caloric scanning profile (DSC) of different patches after 3 months of placement;
fig. 6 is a polarized photomicrograph of the patch (a) of example 1 and the patch (B) of comparative example 1 after 3 months of standing.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Namely: the external patch of the present invention is a patch in which an adhesive layer is laminated on a support.
Example 1
The flurbiprofen pressure-sensitive adhesive patch provided in this example was composed of a backing (9100 type, japanese vilene corporation), a paste, and a release layer (KL 12 type, japan DYNIC corporation), the composition of the paste being shown in table 1.
TABLE 1
Figure BDA0003213691120000101
Figure BDA0003213691120000111
The preparation process comprises the following steps:
(1) Adding SIS, polyisobutene and liquid paraffin into a reaction container, mixing and swelling for more than 30 minutes at 150-160 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(2) Sequentially adding terpene resin, L-menthol, calcium hydroxide, BHT and hydrogenated rosin glyceride into the mixture obtained in the step (1), and stirring at 150 ℃ until the terpene resin, the L-menthol, the calcium hydroxide, the BHT and the hydrogenated rosin glyceride are molten, wherein the step is carried out under nitrogen filling or vacuum;
(3) Adding flurbiprofen and poloxamer F68 into another reaction vessel, heating to 150 ℃, mixing and stirring to form a solid mixture of flurbiprofen and poloxamer;
(4) Adding the solid mixture obtained in the step (3) into the reaction container in the step (2), and continuously stirring for more than 30 minutes at 150 ℃, wherein the step is carried out under the condition of nitrogen filling or vacuum;
(5) Stopping stirring after the reaction is finished, discharging after the reaction substances are stable, cooling and packaging.
Example 2
The flurbiprofen pressure-sensitive adhesive patch provided in the embodiment consists of a backing, a paste and an anti-mucous membrane, wherein the components of the paste are shown in table 2.
TABLE 2
Component and source thereof Dosage of
Flurbiprofen (purity over 99.5%, AESICA, uk) 13.28g
SIS (Vector 4111, DEXCO in U.S.) 20.29g
Polyisobutene (Oppanol B-10, germany BASF) 6.01g
Terpene resin (A135, PINOVA) 9.02g
Glycerol ester of hydrogenated rosin (HYDROGRAL-G5, french DRT) 3.01g
Poloxamer F68 (German BASF) 13.28g
L-menthol (USA SIGMA) 1.50g
Liquid paraffin (Shanghai aladin) 33.21g
Calcium hydroxide (Shanghai aladin) 0.04g
BHT (Germany MERCK) 0.38g
Totalizing 100.02g
The preparation process comprises the following steps:
(1) Adding SIS, polyisobutene and liquid paraffin into a reaction container, mixing and swelling for more than 30 minutes at 150-160 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(2) Sequentially adding terpene resin, L-menthol, calcium hydroxide, BHT and hydrogenated rosin glyceride into the mixture obtained in the step (1), and stirring at 150 ℃ until the terpene resin, the L-menthol, the calcium hydroxide, the BHT and the hydrogenated rosin glyceride are molten, wherein the step is carried out under nitrogen filling or vacuum;
(3) Adding flurbiprofen and poloxamer F68 into another reaction vessel, heating to 150 ℃, mixing and stirring to form a solid mixture of flurbiprofen and poloxamer;
(4) Adding the solid mixture obtained in the step (3) into the reaction container in the step (2), and continuously stirring for more than 30 minutes at 150 ℃, wherein the step is carried out under the condition of nitrogen filling or vacuum;
(5) Stopping stirring after the reaction is finished, discharging after the reaction substances are stable, cooling and packaging.
Example 3
The flurbiprofen pressure-sensitive adhesive patch provided in the embodiment consists of a backing, a paste and an anti-mucous membrane, wherein the components of the paste are shown in table 3.
TABLE 3 Table 3
Component and source thereof Dosage of
Fluorine ratioProfen (purity over 99.5%, AESICA, uk) 13.28g
SIS (Vector 4111, DEXCO in U.S.) 22.12g
Polyisobutene (Oppanol B-10, germany BASF) 6.55g
Terpene resin (A135, PINOVA) 9.83g
Glycerol ester of hydrogenated rosin (HYDROGRAL-G5, french DRT) 3.28g
Polyvinylpyrrolidone K-90 (MERCK Germany) 6.64g
L-menthol (USA SIGMA) 1.64g
Liquid paraffin (Shanghai aladin) 36.21g
Calcium hydroxide (Shanghai aladin) 0.04g
BHT (Germany MERCK) 0.41g
Totalizing 100.00g
The preparation process comprises the following steps:
(1) Adding SIS, polyisobutene and liquid paraffin into a reaction container, mixing and swelling for more than 30 minutes at 150-160 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(2) Sequentially adding terpene resin, L-menthol, calcium hydroxide, BHT and hydrogenated rosin glyceride into the mixture obtained in the step (1), and stirring at 150 ℃ until the terpene resin, the L-menthol, the calcium hydroxide, the BHT and the hydrogenated rosin glyceride are molten, wherein the step is carried out under nitrogen filling or vacuum;
(3) Adding flurbiprofen and polyvinylpyrrolidone K90 into another reaction container, heating to 150 ℃, mixing and stirring to form a solid mixture of flurbiprofen and polyvinylpyrrolidone K90;
(4) Adding the solid mixture obtained in the step (3) into the reaction container in the step (2), and continuously stirring for more than 30 minutes at 150 ℃, wherein the step is carried out under the condition of nitrogen filling or vacuum;
(5) Stopping stirring after the reaction is finished, discharging after the reaction substances are stable, cooling and packaging.
Example 4
The flurbiprofen pressure-sensitive adhesive patch provided in the embodiment consists of a backing, a paste and an anti-mucous membrane, wherein the components of the paste are shown in table 4.
TABLE 4 Table 4
Component and source thereof Dosage of
Flurbiprofen (purity over 99.5%, AESICA, uk) 13.28g
SIS (Vector 4111, DEXCO in U.S.) 20.29g
Polyisobutene (Oppanol B-10, germany BASF) 6.01g
Terpene resin (A135, PINOVA) 9.02g
Glycerol ester of hydrogenated rosin (HYDROGRAL-G5, french DRT) 3.01g
Polyvinylpyrrolidone K-90 (MERCK Germany) 13.28g
L-menthol (USA SIGMA) 1.50g
Liquid paraffin (Shanghai aladin) 33.21g
Calcium hydroxide (Shanghai aladin) 0.04g
BHT (Germany MERCK) 0.38g
Totals to 100.02g
The preparation process comprises the following steps:
(1) Adding SIS, polyisobutene and liquid paraffin into a reaction container, mixing and swelling for more than 30 minutes at 150-160 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(2) Sequentially adding terpene resin, L-menthol, calcium hydroxide, BHT and hydrogenated rosin glyceride into the mixture obtained in the step (1), and stirring at 150 ℃ until the terpene resin, the L-menthol, the calcium hydroxide, the BHT and the hydrogenated rosin glyceride are molten, wherein the step is carried out under nitrogen filling or vacuum;
(3) Adding flurbiprofen and polyvinylpyrrolidone K90 into another reaction container, heating to 150 ℃, mixing and stirring to form a solid mixture of flurbiprofen and polyvinylpyrrolidone K90;
(4) Adding the solid mixture obtained in the step (3) into the reaction container in the step (2), and continuously stirring for more than 30 minutes at 150 ℃, wherein the step is carried out under the condition of nitrogen filling or vacuum;
(5) Stopping stirring after the reaction is finished, discharging after the reaction substances are stable, cooling and packaging.
Comparative example 1
A transdermal patch was different from example 1 in that poloxamer was not added as a stabilizer to the formulation, and the composition of the paste was as shown in Table 5.
TABLE 5
Component and source thereof Dosage of
Flurbiprofen 13.28g
SIS 23.95g
Polyisobutene (S) 7.10g
Terpene resin 10.65g
Hydrogenated rosin glyceride 3.55g
L-menthol 1.77g
Liquid paraffin 39.22g
Calcium hydroxide 0.04g
BHT 0.44g
Totalizing 100.00g
Comparative example 2
A transdermal patch (patch) disclosed in example 2 of patent document CN102028673a has a paste composition shown in table 6.
TABLE 6
Component and source thereof Dosage of
Flurbiprofen 3g
SIS 15g
Rosin resin 40g
Liquid paraffin 40g
BHT 2g
Totalizing 100g
Test case
(one) adhesion Performance detection
The adhesion of the patch was examined according to four methods under the four-part 0952 adhesion assay item of the chinese pharmacopoeia 2015.
1. Primary adhesion detection
The primary adhesion detection is specifically performed as follows: before testing, the patch (together with packaging material) should be placed at 18-25deg.C under 40-70% relative humidity for more than 2 hr. The surfaces of the inclined plate and the stainless steel ball are scrubbed by wiping materials dipped with absolute ethyl alcohol, and are carefully scrubbed by clean dust-free cloth, and the inclined plate and the stainless steel ball are repeatedly cleaned for more than 3 times until the surfaces of the inclined plate and the stainless steel ball are clean through visual inspection. And (3) adjusting the inclined plate according to the inclination angle regulated under each variety item, and taking 3 samples to be tested, wherein the adhesive surface is respectively fixed between two scale marks on the inclined plate by using a double-sided adhesive tape, the lower end of the sample to be tested is positioned at the horizontal line-down position of the inclined plate, and the sample to be tested is flatly attached to the plate. The steel balls specified under each variety item are placed on an initial line and fall freely from the top end of the inclined plane. If 3 steel balls stuck by each of the 3 test samples are the largest steel ball number, or 2 steel balls are the largest steel ball number, the other steel ball number is only one number smaller, and the largest steel ball number is taken as a result; if one is the maximum ball number and the other two are only one smaller, three more test sheets should be taken, and 3 steel balls with the maximum ball number can be stuck to the test results.
2. Measurement of holding power
According to a pharmacopoeia regulation method, taking 3 pieces of a test sample, sticking the test sample on the middle parts of a test board and a loading board in a way of being parallel to the longitudinal direction of the board, rolling the test sample back and forth for 3 times by a compression roller, sticking the test sample on the board, rolling the test sample back and forth for three times, sticking the adhesive surface of the test sample on the surface of the test board, standing vertically, hanging a weight with a regulated mass along the length direction of the test sample, and recording the sliding time of the test sample or the displacement distance within a certain time.
3. Determination of peel strength
Fixing the backing of the test sample on a test board by using double-sided adhesive tape, adhering the adhesive surface of the test sample by using a crystallized polyester film, rolling back and forth on the surface of the test sample for three times by using a 2kg press roller, ensuring that no bubbles exist at the adhering position, and storing for 30 minutes at room temperature for carrying out experiments. The polyester film is folded in half by 180 degrees, the free end of the film and the test board are respectively clamped on the tester up and down, and the stripping surface is consistent with the tester line. The tester continuously peeled at a falling rate of 300 mm/min.+ -.10 mm/min, and the peel strength was calculated from the peel curve.
4. Determination of adhesion
And 3 pieces of test sample are taken, cut into pieces with the size of 50mm multiplied by 70mm, the adhesive surface faces upwards, placed on a sample loading module, aligned with scale marks, fixed according to the stipulation, detected by using a tester, and the forward speed of a press roller is 600mm/min and the backward speed is 21mm/min respectively.
The test results are shown in Table 7.
TABLE 7
Sample ofName of the name Initial adhesion results Results of holding adhesion Peel strength results Adhesion results
Example 1 No. 23 ball 10min25s 359±17N/m 4771±245mN
Example 2 22 # ball 10min12s 348±23N/m 5074±213mN
Example 3 No. 23 ball 9min33s 292±30N/m 4659±668mN
Example 4 22 # ball 10min55s 321±6N/m 5007±366mN
Comparative example 1 25 number ball 10min30s 335±16N/m 5077±297mN
Comparative example 2 18 # ball 8min20s 311±21N/m 4777±247mN
The results in table 7 show that comparative example 1, in which the recipe was adjusted, had better adhesive properties than comparative example 2, and was mainly characterized by improvement of the initial adhesion and holding adhesion of the patch; examples 1-4 containing the stabilizer showed no significant change in adhesion properties (p > 0.05) over comparative example 1, indicating that the addition of the stabilizer did not adversely affect the adhesion properties of the formulation.
(II) in vitro transdermal experiments
1. Skin treatment:
skin ex vivo of suckling pigs: the suckling pigs of 20-30 days old are killed, the skin on the backs of the pigs is peeled off, the skin is prepared into uniform thickness by a dermatome, and the pigs are refrigerated at-80 ℃ for standby. Before use, the solution is naturally thawed under room temperature condition and washed with physiological saline.
2. Transdermal test
Transdermal experiments were performed using a vertical diffusion cell. The transdermal area was 2.83cm 2 The volume of the receiving tank is 6.8mL, the water bath temperature is 37 ℃, the stirring speed is 250r/min, and the receiving solution is PEG 400-physiological saline solution with the volume percentage concentration of 20 percent. The transdermal patches prepared in the examples and the comparative examples were adhered to the skin surface, fixed on a receiving well, and after the receiving medium was replenished to a prescribed height value of the receiving well, a transdermal test was started, 1.0ml of the receiving medium was sampled at regular time, and then an equal amount of fresh receiving liquid at the same temperature was replenished. The concentration of the absorption liquid obtained by sampling was measured by using a high performance liquid phase under the following conditions:
chromatographic column: kromasil 150 x 4.6mm 5 μm, filler: c18;
column temperature: 40 ℃;
flow rate: 1.0ml/min;
ultraviolet detection wavelength: 245nm;
mobile phase: methanol to water to glacial acetic acid (70:30:1);
sample injection amount: 20 μl;
elution mode: isocratic elution.
The results of fig. 2 show that there is no significant difference in the transdermal absorption of examples 1-4 compared to comparative example 1, indicating that the addition of the stabilizer does not negatively affect the transdermal delivery process of the drug; the results of fig. 3 show that the drug release capacity of example 1 after 8 hours is significantly enhanced compared to comparative example 2, indicating that increasing the drug loading of the drug in the patch can extend the duration of action of the patch; the results of fig. 4 show that the transdermal delivery capacity of example 1 containing the stabilizer is significantly higher than that of comparative example 1 after the patch is placed under normal temperature and light-shielding conditions for 3 months, because the main drug component flurbiprofen in comparative example 1 is likely to be converted from an amorphous state to a crystalline state with higher thermodynamic activity, and the transdermal delivery capacity of the drug is reduced. In summary, the examples according to the present invention containing a stabilizer have a higher stability against the crystallization tendency of flurbiprofen as an active ingredient than the comparative examples not according to the present invention and thus maintain the transdermal delivery capacity of flurbiprofen longer.
(III) sample stability detection
Analyzing and measuring with DSCQC200 differential scanning calorimeter, taking 5-10mg of each group of samples stored for more than 3 months at room temperature, precisely weighing, placing into DSC special small crucible, DSC analysis scanning range is 40-200deg.C, and heating rate is 10 deg.C min -1 The scanning environment is nitrogen.
The results are shown in fig. 5, in which it can be seen that examples 1-3 containing the stabilizer have significantly improved stability, and the drug exists in the patch in amorphous form for a long period of time, as shown in the specific data: comparative example 1 and comparative example 2, which did not contain a stabilizer, exhibited a distinct endothermic peak around 110 ℃, indicating that flurbiprofen was present in crystalline form after 3 months of patch placement; examples 1 to 3 containing the stabilizer had no corresponding endothermic peak around 110 ℃, indicating that flurbiprofen as an active ingredient in the patch was still present in the matrix in an amorphous state, and further, the endothermic peak around 50 ℃ in examples 1 and 2 was presumed to be a characteristic endothermic peak of the corresponding poloxamer.
Further, the patch crystallinity was examined by a polarization microscope method, and the results are shown in fig. 6, in which experimental example 1 shows no crystallization after 3 months of standing, and comparative example 1 shows a large amount of crystallization, indicating that the addition of the stabilizer to the patch can effectively prevent the drug from crystallization, thereby preventing the change of the transdermal permeability of the patch.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (5)

1. A pharmaceutical composition comprising:
13.28 parts by weight of flurbiprofen as active ingredient;
20.29 parts by weight of a styrene-isoprene-styrene block copolymer SIS;
6.01 parts by weight of polyisobutene;
9.02 parts by weight of a terpene resin;
3.01 parts by weight of a hydrogenated rosin glycerol ether;
13.28 parts by weight of poloxamer F68;
1.50 parts by weight of L-menthol;
33.21 parts by weight of liquid paraffin;
0.04 parts by weight of calcium hydroxide; and
0.38 parts by weight of dibutylhydroxytoluene BHT.
2. A patch comprising the pharmaceutical composition of claim 1.
3. The patch of claim 2, wherein the patch comprises a backing layer, a paste layer, and a release layer, the paste layer comprising the pharmaceutical composition, wherein the paste layer is located between the backing layer and the release layer.
4. A patch according to claim 3, wherein said paste layer is formed of mini-drug reservoirs dispersed in a pressure sensitive adhesive layer.
5. A method of preparing a pharmaceutical composition according to claim 1, comprising the steps of:
(1) Adding SIS, polyisobutene and liquid paraffin into a reaction container, mixing and swelling for more than 30 minutes at 150-160 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(2) Sequentially adding terpene resin, L-menthol, calcium hydroxide, BHT and hydrogenated rosin glyceride into the mixture obtained in the step (1), and stirring at 150 ℃ until the terpene resin, the L-menthol, the calcium hydroxide, the BHT and the hydrogenated rosin glyceride are molten, wherein the step is carried out under nitrogen filling or vacuum;
(3) Adding flurbiprofen and poloxamer F68 into another reaction vessel, heating to 150 ℃, mixing and stirring to form a solid mixture of flurbiprofen and poloxamer F68;
(4) Adding the solid mixture of flurbiprofen and poloxamer F68 obtained in the step (3) into the reaction vessel in the step (2), and continuously stirring for more than 30 minutes at 150 ℃, wherein the step is carried out under the condition of nitrogen filling or vacuum;
(5) Stopping stirring after the reaction is finished, discharging after the reaction substances are stable, cooling and packaging.
CN202110938206.9A 2021-08-16 2021-08-16 Pharmaceutical composition and patch containing flurbiprofen Active CN113648297B (en)

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