CN113648297A - Pharmaceutical composition and patch containing flurbiprofen - Google Patents
Pharmaceutical composition and patch containing flurbiprofen Download PDFInfo
- Publication number
- CN113648297A CN113648297A CN202110938206.9A CN202110938206A CN113648297A CN 113648297 A CN113648297 A CN 113648297A CN 202110938206 A CN202110938206 A CN 202110938206A CN 113648297 A CN113648297 A CN 113648297A
- Authority
- CN
- China
- Prior art keywords
- flurbiprofen
- pharmaceutical composition
- patch
- stabilizer
- sensitive adhesive
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 title claims abstract description 90
- 229960002390 flurbiprofen Drugs 0.000 title claims abstract description 90
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 49
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- 239000004820 Pressure-sensitive adhesive Substances 0.000 claims abstract description 34
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- 239000004480 active ingredient Substances 0.000 claims abstract description 10
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Images
Classifications
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses a pharmaceutical composition containing flurbiprofen and a patch, namely a pharmaceutical composition. The pharmaceutical composition contains flurbiprofen as an active ingredient and pharmaceutically acceptable auxiliary materials, 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, and the components are matched with each other, so that 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
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a flurbiprofen-containing pharmaceutical composition and a patch.
Background
Flurbiprofen is a propionic acid nonsteroidal anti-inflammatory drug (NSAIDs), has good analgesic and anti-inflammatory effects by mainly inhibiting prostaglandin synthase, is commonly used for symptomatic treatment of inflammation, fever and mild and moderate pain, and can be used for treating patients who cannot tolerate aspirin or cannot tolerate the aspirin.
The currently marketed flurbiprofen-containing products include tablets, granules, injections, external preparations, and the like. The flurbiprofen oral preparation is quickly absorbed, but the half-life period of the in vivo organism is short, only 3-5 hours, frequent administration is needed in the long-term rheumatoid arthritis treatment process, and the purpose of long-acting treatment cannot be achieved. Secondly, oral administration of flurbiprofen is prone to gastrointestinal adverse reactions, such as peptic ulcer and hemorrhage, which can cause that some patients cannot use the flurbiprofen.
Compared with flurbiprofen oral preparation, the transdermal drug delivery can effectively avoid adverse reaction of gastrointestinal tract, prolong the action time of the drug, reduce the drug administration times and improve the compliance of patients. Transdermal administration is therefore the preferred form of flurbiprofen. For example, patent document CN104546803A discloses a method for preparing flurbiprofen hydrogel plaster, which comprises dispersing a drug in a hydrophilic polymer matrix using crotamiton as a solubilizer. Similarly, patent document CN1443532A disperses flurbiprofen in a hydrophilic cataplasm matrix by an emulsifier, and patent document CN106822065A stabilizes the drug in the hydrophilic matrix material by adding an additional oil phase, such as tricaprin and the like. However, flurbiprofen, which is poorly soluble in water, is often added to hydrophilic bases in the form of an oil-in-water emulsion mixed with a surfactant and water. Therefore, gel patch preparations using a water-soluble polymer matrix tend to have problems of slow absorption rate and unstable release of active substances, and further improvement is still required. In addition, the preparation process of the water-soluble gel plaster is complex, and the pH value of the matrix needs to be strictly controlled (U.S. Pat. No. 5,807,568), which causes inconvenience to the production of the preparation.
Numerous attempts have also been made in the prior art to provide transdermal formulations of other types of matrix, such as CN103211799A, which discloses a transdermal formulation using polyisobutylene and silicone as the matrix material; CN105232496A discloses a method for preparing flurbiprofen-containing film coating agent, which adopts chitosan, carbomer, glycerol and the like as matrix materials; CN103079552A adopts diethylene glycol monomethyl ether
And caprylic capric acid polyethylene glycol glyceride
And flurbiprofen are used for penetration therapy by forming a pharmaceutical composition. However, the solvent-based pressure-sensitive adhesive is easy to cause environmental pollution and large energy consumption due to the use of an organic solvent in the preparation process. Emulsion pressure-sensitive adhesives are also limited by problems such as slow drying speed and migration of the emulsifier. The Hot Melt Pressure Sensitive Adhesive (HMPSA) adopts thermoplastic polymer as a matrix, is coated in a molten state and is cooled and hardened at normal temperature, does not use organic solvent in the preparation process, has high automation degree, and is widely applied to the fields of medical treatment, health care and the like.
On the basis of the above, various patents report the preparation method of the flurbiprofen hot melt pressure sensitive adhesive transdermal preparation. Japanese patent laid-open No. 8-319234 discloses an adhesive patch comprising a rubber component, a tackifying resin and a softening agent. However, since none of the several binder components can dissolve flurbiprofen and flurbiprofen is in a crystalline state in the preparation, the release is poor. In order to improve the state of the drug in the matrix, WO93/04677 discloses a method of using L-menthol as a flurbiprofen dissolving agent, however, there is a possibility that flurbiprofen may crystallize as L-menthol volatilizes. Japanese patent laid-open No. Hei 7-309749 discloses the use of lactate as a solubilizing agent, but destroys the cohesive force of the adhesive matrix, and further generates a pasty residue on the skin, causing skin irritation. Patent document CN102028673A discloses that crystallization of flurbiprofen in an adhesive layer is suppressed by stabilizing a drug by adjusting the ratio of a tackifier resin in a matrix, but the tackifier resin is poor in compatibility with the drug, and can only increase the patch stability to about 3 months, and the patch has poor drug-loading capacity, and can only maintain effective release of the drug for about 8 hours, and clinical administration requires three times a day, and the administration frequency is too frequent.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a pharmaceutical composition, which contains flurbiprofen as an active ingredient and pharmaceutically acceptable auxiliary materials, 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), for example, 1 (0.7-1.5), and exemplarily, 1:0.5, 1:0.75, 1:1, 1:1.2, 1:1.5 or any weight ratio in a range formed by combining any two of the above proportions.
According to an embodiment of the invention, said flurbiprofen is dispersed in said pharmaceutical composition in an amorphous form.
According to an embodiment of the invention, the stabilizer is a non-ionic surfactant of the macromolecular type, which may be chosen, for example, from polyoxyethylene polyoxypropylene ether block copolymers (poloxamers; for example
) 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 material may further comprise one, two or more of a pressure sensitive adhesive matrix, a tackifier, a plasticizer, a filler, an antioxidant, a penetration enhancer, and the like.
According to an embodiment of the present invention, the pressure-sensitive adhesive matrix is a styrenic thermoplastic elastomer, which means a styrenic polymer material that exhibits rubber elasticity at normal temperature and is capable of being plasticized 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 an embodiment of the invention, the weight ratio of the pressure sensitive adhesive matrix to flurbiprofen is (1-3):1, such as (1.5-2.5):1, illustratively 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 within any two-by-two combination of the above ratios.
According to an embodiment of the present invention, the tackifier may be selected from natural tackifier and/or synthetic tackifier, and the synthetic tackifier may be selected from at least one of aliphatic resin and aromatic resin, and the like. For example, the tackifier may be selected from one, two or more of rosin, rosin modification, terpene resins, petroleum resins, and phenol resins; 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 adhesion promoter to flurbiprofen is (0.5-2):1, such as (0.8-1.5):1, exemplary 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or any weight ratio within any two combinations of the above ratios.
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 viscosity average molecular weight of the low molecular weight polyisobutylene is 3500-100000; for example, polyisobutylene with a self-average molecular weight of about 40000 may be selected.
According to an embodiment of the invention, the weight ratio of the plasticizer to flurbiprofen is (2-5):1, such as (2.5-4):1, exemplary 2.7:1, 3:1, 3.2:1, 3.5:1, 3.6:1, 3.8:1 or any weight ratio within any two combinations of the above ratios.
According to an embodiment of the invention, the filler may be chosen 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 micropowder silica gel. The filler is mainly used for improving the cohesive strength of the pressure-sensitive adhesive matrix, enhancing the toughness and the anti-deformation capability of the adhesive and improving the dispersion state of the flurbiprofen serving as an active ingredient.
According to an embodiment of the invention, the weight ratio of bulking agent to flurbiprofen is (0.001-0.006):1, such as (0.002-0.005):1, exemplary 0.0025:1, 0.003:1, 0.0035:1, 0.004:1 or any weight ratio in any two-by-two combination of any two of the above ratios.
According to an embodiment of the present invention, the antioxidant may be selected from one, two or more of dibutyl hydroxy toluene (BHT), Butyl Hydroxy Anisole (BHA) and Propyl Gallate (PG).
According to an embodiment of the invention, the weight ratio of the antioxidant to flurbiprofen is (0.01-0.06):1, such as (0.02-0.05):1, exemplary 0.025:1, 0.03:1, 0.035:1, 0.04:1 or any weight ratio within the range of any two of the above mentioned ratios in combination.
According to an embodiment of the present invention, the penetration enhancer may be one, two or more selected from the group consisting of L-menthol, 1, 8-cineole and d-limonene. In addition, the penetration enhancer can also function as a cooling agent.
According to an embodiment of the invention, the weight ratio of the penetration enhancer to flurbiprofen is (0.05-1):1, such as (0.08-0.5):1, exemplarily 0.1:1, 0.15:1, 0.2:1, 0.3:1 or any weight ratio within any two of the above mentioned ranges in combination.
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 penetration enhancer;
preferably, the mass ratio of flurbiprofen to the stabilizer is 1 (0.5-2), for example 1 (0.7-1.5), exemplarily 1:0.5, 1:0.75, 1:1, 1:1.2, 1: 1.5. In the proportioning range, the flurbiprofen and the stabilizer can form eutectic solid dispersion at the temperature of more than 130 ℃.
In the above pharmaceutical composition, the formation of the eutectic solid dispersion causes flurbiprofen to exist in an amorphous highly dispersed state in the pressure-sensitive adhesive matrix, 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, a pressure sensitive adhesive base, a tackifier, a plasticizer, a stabilizer, a filler, an antioxidant and a penetration enhancer 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;
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 is calcium hydroxide;
preferably, the antioxidant is selected from BHT;
preferably, the penetration enhancer is selected from 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:
according to an exemplary embodiment of the present invention, the pharmaceutical composition comprises the following raw materials in parts by weight:
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 preparation is a pharmaceutical preparation for the treatment of inflammation, fever, soft tissue disorders and/or mild to moderate pain. Wherein the inflammation is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis or the like; the soft tissue disease can be sprain and strain, and the mild and moderate 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 present invention, the patch comprises a backing layer, a cream layer comprising the above pharmaceutical composition, and an anti-adhesion layer.
Preferably, the paste layer is located between the backing layer and the release layer.
Preferably, the plaster layer is formed by dispersing the mini-drug reservoir in the pressure sensitive adhesive layer.
Preferably, the mini-drug depot comprises or consists of flurbiprofen and a stabilizing agent.
According to an embodiment of the present invention, the material of the backing layer may be selected from materials known in the art, for example, a polyester-polyethylene composite film, a polyethylene-aluminum-polyester/ethylene-vinyl acetate composite film, a polyester film, a non-woven fabric, an elastic fabric, or the like.
According to an embodiment of the present invention, the release layer may be selected from films of materials known in the art, such as release films, exemplified by polyethylene, polystyrene, polypropylene, or polycarbonate films.
According to an embodiment of the invention, the patch has a structure substantially as shown in figure 1.
According to an embodiment of the present invention, the patch is a flurbiprofen hot-melt type 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 and moderate pain. Wherein the inflammation is rheumatoid arthritis, osteoarthritis, ankylosing spondylitis or the like; the soft tissue disease can be sprain and strain, and the mild and moderate 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-moderate pain by using the pharmaceutical composition or the pharmaceutical preparation, which comprises applying the pharmaceutical composition or the pharmaceutical preparation to the disease part.
The invention also provides a preparation method of the pharmaceutical composition, which comprises the following steps: 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 the pressure-sensitive adhesive matrix and the plasticizer for swelling to obtain a swollen mixture;
(2) adding a tackifier, a penetration enhancer, a filler and an antioxidant into the swelling mixture, and stirring until the swelling mixture is molten;
(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 and the material obtained in the step (2), and cooling after the reaction is finished to obtain the pharmaceutical composition.
According to an embodiment of the present invention, the pressure sensitive adhesive matrix, the plasticizer, the filler, the penetration enhancer, the antioxidant, the tackifier and the stabilizer have the selection and weight ratio as shown above.
According to the embodiment of the invention, in the step (1), the swelling temperature is 140-.
According to an embodiment of the present invention, in the step (1), the swelling time is more than 30min, for example, 30min to 5h, for example, 30min, 1h, 2h, 3h, 4h or any point value within a combination range of any two of the above values.
According to an embodiment of the present invention, in the step (2), the tackifier, the penetration enhancer, the filler and the antioxidant are added to the swelling mixture in this order.
According to the embodiment of the invention, in the step (2), the temperature for stirring to melt is 140-.
According to the embodiment of the invention, in the step (3), the temperature of the heating and mixing is not lower than 130 ℃, for example, 140-.
According to an embodiment of the present invention, in the step (3), the solid mixture is a eutectic solid dispersion.
According to the embodiment of the present invention, in the step (4), the temperature of the heating and mixing is not lower than 130 ℃, for example, 140-.
According to an embodiment of the present invention, in the step (4), the heating and mixing time is more than 30min, for example, 30min to 5h, for example, 30min, 1h, 2h, 3h, 4h or any point value within a two-by-two combination range of any two values.
According to an embodiment of the invention, steps (1), (2) and (4) are carried out 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 pharmaceutical preparation, preferably a patch, and a preparation method of the pharmaceutical composition.
According to an embodiment of the invention, the method of preparing the patch comprises the steps of: the patch is obtained by using the above pharmaceutical composition as a plaster layer, and assembling the plaster layer, a backing layer and an anti-sticking layer.
According to an embodiment of the invention, the layer of paste 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 dispersed in an amorphous form and with various components matched with each other, 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 stabilize the flurbiprofen used as an active ingredient by adding the stabilizers such as poloxamer and the like, avoid the flurbiprofen from crystallizing, and the stabilizers do not influence the cohesion of the matrix, thereby meeting the medicinal requirements.
The concrete advantages are represented in the following three aspects:
(1) the prepared patch has good adhesion with skin, and less irritation and allergy;
(2) by introducing the stabilizer, the stability of the medicine in the matrix and the concentration of the medicine in the matrix are improved, the storage time and the effective acting time of the patch are prolonged, and the addition of the stabilizer does not obviously influence the transdermal release and the adhesive property of the patch;
(3) organic solvent is not needed in the production process, drying equipment is not needed after coating, no air bubbles appear on the surface of the patch, and the patch is safe, energy-saving and beneficial to environmental protection.
Drawings
FIG. 1 is a schematic structural view of a flurbiprofen pressure-sensitive adhesive patch according to an embodiment of the present invention;
figure 2 is an in vitro transdermal drug delivery profile of the patches of examples 1-4 and comparative example 1;
figure 3 is an in vitro transdermal drug delivery profile for the patch of example 1 versus the patch of comparative example 2;
figure 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 thermal scanning spectrum (DSC) of different patches after 3 months of standing;
fig. 6 is a polarization microscope photograph of the patch (a) of example 1 and the patch (B) of comparative example 1 after being left for 3 months.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. It is to be understood that the following examples are only illustrative and explanatory of the present invention and should not be construed as limiting the scope of the present invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can 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 (model 9100, vilene, japan), a paste and a release layer (model KL12, DYNIC, japan), and the components of the paste are shown in table 1.
TABLE 1
The preparation process comprises the following steps:
(1) adding SIS, polyisobutylene and liquid paraffin into a reaction container, mixing and swelling for more than 30min at 150-160 ℃, and performing the steps 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 to melt at 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 30min at the temperature of 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 this example is composed of a backing, a paste and a mucous membrane, and the components of the paste are shown in table 2.
TABLE 2
| Components and sources thereof | Dosage of |
| Flurbiprofen (purity over 99.5%, England AESICA) | 13.28g |
| SIS (Vector 4111, U.S. DEXCO) | 20.29g |
| Polyisobutene (Oppanol B-10, BASF Germany) | 6.01g |
| Terpene resin (A135, U.S. PINOVA) | 9.02g |
| Hydrogenated rosin glycerol ester (HYDROGRAL-G5, DRT France) | 3.01g |
| Poloxamer F68 (BASF, Germany) | 13.28g |
| L-menthol (American SIGMA) | 1.50g |
| Liquid paraffin (Shanghai aladdin) | 33.21g |
| Calcium hydroxide (Shanghai aladdin) | 0.04g |
| BHT (Germany MERCK) | 0.38g |
| Total up to | 100.02g |
The preparation process comprises the following steps:
(1) adding SIS, polyisobutylene and liquid paraffin into a reaction container, mixing and swelling for more than 30min at 150-160 ℃, and performing the steps 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 to melt at 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 30min at the temperature of 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 this example is composed of a backing, a paste and a mucous membrane, and the components of the paste are shown in table 3.
TABLE 3
| Components and sources thereof | Dosage of |
| Flurbiprofen (purity over 99.5%, England AESICA) | 13.28g |
| SIS (Vector 4111, U.S. DEXCO) | 22.12g |
| Polyisobutene (Oppanol B-10, BASF Germany) | 6.55g |
| Terpene resin (A135, U.S. PINOVA) | 9.83g |
| Hydrogenated rosin glycerol ester (HYDROGRAL-G5, DRT France) | 3.28g |
| Polyvinylpyrrolidone K-90 (Germany MERCK) | 6.64g |
| L-menthol (American SIGMA) | 1.64g |
| Liquid paraffin (Shanghai aladdin) | 36.21g |
| Calcium hydroxide (Shanghai aladdin) | 0.04g |
| BHT (Germany MERCK) | 0.41g |
| Total up to | 100.00g |
The preparation process comprises the following steps:
(1) adding SIS, polyisobutylene and liquid paraffin into a reaction container, mixing and swelling for more than 30min at 150-160 ℃, and performing the steps 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 to melt at 150 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(3) adding flurbiprofen and polyvinylpyrrolidone K90 into another reaction vessel, 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 30min at the temperature of 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 this example is composed of a backing, a paste and a mucous membrane, and the components of the paste are shown in table 4.
TABLE 4
| Components and sources thereof | Dosage of |
| Flurbiprofen (purity over 99.5%, England AESICA) | 13.28g |
| SIS (Vector 4111, U.S. DEXCO) | 20.29g |
| Polyisobutene (Oppanol B-10, BASF Germany) | 6.01g |
| Terpene resin (A135, U.S. PINOVA) | 9.02g |
| Hydrogenated rosin glycerol ester (HYDROGRAL-G5, DRT France) | 3.01g |
| Polyvinylpyrrolidone K-90 (Germany MERCK) | 13.28g |
| L-menthol (American SIGMA) | 1.50g |
| Liquid paraffin (Shanghai aladdin) | 33.21g |
| Calcium hydroxide (Shanghai aladdin) | 0.04g |
| BHT (Germany MERCK) | 0.38g |
| Total of | 100.02g |
The preparation process comprises the following steps:
(1) adding SIS, polyisobutylene and liquid paraffin into a reaction container, mixing and swelling for more than 30min at 150-160 ℃, and performing the steps 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 to melt at 150 ℃, wherein the step is carried out under the condition of filling nitrogen or vacuum;
(3) adding flurbiprofen and polyvinylpyrrolidone K90 into another reaction vessel, 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 30min at the temperature of 150 ℃, wherein the step is carried out under the condition of filling nitrogen 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 prepared in a manner different from that of example 1 in that poloxamer as a stabilizer was not added to the formulation, and the components of the ointment were as shown in Table 5.
TABLE 5
| Components and sources thereof | Dosage of |
| Flurbiprofen | 13.28g |
| SIS | 23.95g |
| Polyisobutenes | 7.10g |
| Terpene resin | 10.65g |
| Hydrogenated rosin glycerol ester | 3.55g |
| L-menthol | 1.77g |
| Liquid paraffin | 39.22g |
| Calcium hydroxide | 0.04g |
| BHT | 0.44g |
| Total up to | 100.00g |
Comparative example 2
Patent document CN102028673A discloses a transdermal patch (patch) in example 2, and the paste components are shown in table 6.
TABLE 6
| Components and sources thereof | Dosage of |
| Flurbiprofen | 3g |
| SIS | 15g |
| Rosin resin | 40g |
| Liquid paraffin | 40g |
| BHT | 2g |
| Total up to | 100g |
Test example
(ii) adhesion Performance test
The adhesive force of the patch is examined according to four methods under the item of the adhesive force measurement method of four parts 0952 in the year version of Chinese pharmacopoeia 2015.
1. Initial adhesion detection
The initial adhesion detection is specifically performed as follows: before the test, the emplastrum (together with the packaging material) is placed for more than 2 hours at the temperature of 18-25 ℃ and the relative humidity of 40-70%. Scrubbing the surfaces of the inclined plate and the stainless steel ball by using a wiping material dipped with absolute ethyl alcohol, carefully wiping the surfaces by using clean dust-free cloth, and repeatedly cleaning for more than 3 times until the surfaces of the inclined plate and the stainless steel ball are clean through visual inspection. The inclined plate is adjusted according to the inclination angle specified under each variety item, 3 test articles are taken, the adhesive faces upwards and are fixed between two scale marks on the inclined plate by using double-sided adhesive tapes respectively, wherein the lower end of the test article is positioned at the horizontal off-line position of the inclined plate, and the test articles are smoothly attached to the plate. The steel balls specified under various items are placed on the initial line and fall freely from the top end of the inclined plane. In the steel balls stuck by the 3 test articles respectively, if 3 steel balls are the maximum steel ball number, or 2 steel balls are the maximum steel ball number, the other steel ball number is only one number smaller, and the maximum steel ball number is taken as a result; if one steel ball is the largest steel ball number and the other two steel balls are only one smaller, three additional pieces of the test should be taken again, and 3 pieces of the test can stick the largest steel ball as an experimental result.
2. Measurement of holding power
According to the method specified by pharmacopoeia, 3 test articles are taken, the test articles are adhered to the middle parts of a test plate and a loading plate in a manner of being parallel to the longitudinal direction of the plate, a press roller rolls back and forth for 3 times to adhere to the test article plate and roll back and forth for three times to adhere the adhesive surface of the test articles to the surface of the test plate, the test articles are vertically placed, a weight with specified mass is hung along the length direction of the test articles, and the time for the test articles to slide until falling off or the displacement distance within a certain time is recorded.
3. Measurement of peeling Strength
Fixing a sample backing on a test board by using a double-sided adhesive tape, adhering the viscous surface of the sample by using a crystallized polyester film, rolling the surface of the sample back and forth three times by using a 2kg compression roller to ensure that no bubbles exist at the adhering part, and carrying out an experiment after storing the sample backing for 30 minutes at room temperature. 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 from top to bottom, and the stripping surface is consistent with the tester line. The test machine continuously peels at a dropping speed of 300mm/min + -10 mm/min, and the peel strength is calculated according to the peeling curve.
4. Adhesion measurement
Taking 3 test samples, cutting into 50mm × 70mm pieces with the adhesive surface facing upwards, placing on a sample loading module, aligning with the scale mark, fixing the samples according to the specification, and detecting with a tester, wherein the advancing speed and the retreating speed of the compression roller are respectively 600mm/min and 21 mm/min.
The test results are shown in table 7.
TABLE 7
| Sample name | Initial adhesion results | Result of constant adhesion | Peel strength results | Results of adhesive force |
| Example 1 | No. 23 ball | 10min25s | 359±17N/m | 4771±245mN |
| Example 2 | No. 22 ball | 10min12s | 348±23N/m | 5074±213mN |
| Example 3 | No. 23 ball | 9min33s | 292±30N/m | 4659±668mN |
| Example 4 | No. 22 ball | 10min55s | 321±6N/m | 5007±366mN |
| Comparative example 1 | No. 25 ball | 10min30s | 335±16N/m | 5077±297mN |
| Comparative example 2 | Number 18 ball | 8min20s | 311±21N/m | 4777±247mN |
The results in Table 7 show that comparative example 1, which was formulated to have better adhesion properties than comparative example 2, is mainly reflected in improvement of initial adhesion and holding adhesion of the patch; examples 1-4 containing the stabilizer showed no significant change in adhesion (p > 0.05) compared to comparative example 1, indicating that the addition of the stabilizer did not adversely affect the adhesion properties of the formulation.
(II) in vitro transdermal test
1. Skin treatment:
skin of suckling pig in vitro: slaughtering 20-30 days old suckling pig, peeling back skin of pig, preparing into uniform thickness with skin grafting knife, and refrigerating at-80 deg.C for use. Before use, the product is naturally thawed at room temperature and washed with physiological saline.
2. Transdermal test
The transdermal test was performed using a vertical diffusion cell. The transdermal area is 2.83cm2The volume of the receiving pool is 6.8mL, the temperature of the water bath is 37 ℃, the stirring speed is 250r/min, and the receiving solution is 20 percent of PEG 400-physiological saline solution by volume percentage concentration. The transdermal patches prepared in examples and comparative examples were attached to the skin surface, fixed to a receiving reservoir, and a transdermal test was started after replenishing the receiving medium to a prescribed height value in the receiving reservoir, and 1.0ml of the receiving medium was sampled at regular intervals and then replenished with an equal amount of fresh receiving solution at the same temperature. The concentration of the absorption liquid obtained by sampling is measured by using a high performance liquid phase, and the conditions of the high performance liquid phase are as follows:
a chromatographic column: kromasil 150 x 4.6mm 5 μm, filler: c18;
column temperature: 40 ℃;
flow rate: 1.0 ml/min;
ultraviolet detection wavelength: 245 nm;
mobile phase: methanol, water, glacial acetic acid (70:30: 1);
sample introduction amount: 20 mu l of the mixture;
and (3) an elution mode: isocratic elution.
The results in 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 drug delivery process; the results in FIG. 3 show that the drug release capacity of example 1 was significantly enhanced after 8 hours compared to comparative example 2, indicating that increasing the drug loading in the patch could prolong the duration of the patch; the result of fig. 4 shows that after the patch is sealed and placed in the dark at normal temperature for 3 months, the transdermal release capacity of the patch containing the stabilizer in example 1 is obviously higher than that of comparative example 1, which may be caused by the fact that the main drug ingredient flurbiprofen in comparative example 1 is transformed from an amorphous state with higher thermodynamic activity to a crystalline state, and the transdermal release capacity of the drug is reduced. In conclusion, the examples according to the invention containing the stabilizer have a higher stability against the tendency of the active ingredient flurbiprofen to crystallize than the comparative examples not according to the invention and thus retain the transdermal delivery capacity of flurbiprofen for a longer period of time.
(III) stability testing of samples
Analyzing and measuring with DSCQC200 differential scanning calorimeter, collecting 5-10mg samples of each group stored at room temperature for more than 3 months, precisely weighing, placing into small crucible special for DSC, and performing DSC analysis at a scanning range of 40-200 deg.C and a heating rate of 10 deg.C/min-1The scanning environment is nitrogen.
The results are shown in fig. 5, where it can be seen that examples 1-3 containing a stabilizer have a significant improvement in stability, and that the drug is present in the patch in an amorphous form for a long period of time, and the specific data show that: both comparative example 1 and comparative example 2, which did not contain a stabilizer, showed a distinct endothermic peak near 110 ℃, indicating that crystalline form of flurbiprofen was present after the patch was left for 3 months; examples 1 to 3 containing the stabilizer had no corresponding endothermic peak at around 110 ℃, indicating that flurbiprofen, the active ingredient in the patch, was still present in the matrix in an amorphous state, and further, the endothermic peak at around 50 ℃ in examples 1 and 2 was estimated to correspond to the characteristic endothermic peak of poloxamer.
Further examining the crystallinity of the patch by using a polarization microscope method, the results are shown in fig. 6, and no crystal is precipitated after the patch is placed for 3 months in experimental example 1, and a large amount of crystal is precipitated in comparative example 1, which indicates that the addition of a stabilizer to the patch can effectively prevent the drug from being precipitated as crystals, 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, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A pharmaceutical composition is characterized by comprising flurbiprofen as an active ingredient and pharmaceutically acceptable auxiliary materials, 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).
2. The pharmaceutical composition according to claim 1, wherein the flurbiprofen is dispersed in the pharmaceutical composition in an amorphous form.
Preferably, the stabilizer is a high molecular nonionic surfactant, for example, one, two or more selected from polyoxyethylene polyoxypropylene ether block copolymer, polyvinyl alcohol and polyvinylpyrrolidone, preferably poloxamer or polyvinylpyrrolidone, illustratively poloxamer F68 or polyvinylpyrrolidone K-90.
3. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutically acceptable excipient further comprises one or two or more of a pressure sensitive adhesive matrix, a tackifier, a plasticizer, a filler, an antioxidant, and a penetration enhancer.
Preferably, the pressure sensitive adhesive matrix is a styrenic thermoplastic elastomer. Preferably, the weight ratio of the pressure-sensitive adhesive matrix to the flurbiprofen is (1-3): 1.
Preferably, the tackifier is selected from natural tackifiers and/or synthetic tackifiers selected from at least one of aliphatic resins and aromatic resins. Preferably, the weight ratio of the tackifier to the flurbiprofen is (0.5-2): 1.
Preferably, the plasticizer is 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, the viscosity average molecular weight of the low molecular weight polyisobutylene is 3500-100000. Preferably, the weight ratio of the plasticizer to the flurbiprofen is (2-5): 1.
Preferably, the filler is selected from one, two or more of calcium carbonate, calcium hydroxide, talc, kaolin, titanium dioxide and aerosil. Preferably, the weight ratio of the filler to the flurbiprofen is (0.001-0.006): 1.
Preferably, the antioxidant is selected from one, two or more of dibutylhydroxytoluene (BHT), Butylhydroxyanisole (BHA) and Propyl Gallate (PG).
Preferably, the weight ratio of the antioxidant to the flurbiprofen is (0.01-0.06): 1.
Preferably, the penetration enhancer is selected from one, two or more of L-menthol, 1, 8-cineole and d-limonene. Preferably, the weight ratio of the penetration enhancer to the flurbiprofen is (0.05-1): 1.
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutical composition comprises the following components: flurbiprofen, a pressure-sensitive adhesive matrix, a tackifier, a plasticizer, a stabilizer, an antioxidant and a penetration enhancer;
preferably, the mass ratio of the flurbiprofen to the stabilizer is 1 (0.5-2), and the flurbiprofen and the stabilizer can form eutectic solid dispersion at the temperature of more than 130 ℃.
Preferably, the pharmaceutical composition comprises flurbiprofen, a pressure-sensitive adhesive matrix, a tackifier, a plasticizer, a stabilizer, a filler, an antioxidant and a penetration enhancer 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;
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 is calcium hydroxide;
preferably, the antioxidant is selected from BHT;
preferably, the penetration enhancer is selected from L-menthol.
Preferably, the pharmaceutical composition is in the form of a paste.
5. Use of a pharmaceutical composition according to any one of claims 1 to 4 for the preparation of a therapeutic pharmaceutical preparation.
Preferably, the pharmaceutical formulation is a patch, preferably a transdermal patch.
Preferably, the pharmaceutical formulation is a pharmaceutical formulation for the treatment of inflammation, fever, soft tissue disorders and/or mild to moderate pain.
6. A patch comprising a pharmaceutical composition according to any one of claims 1 to 4.
7. The patch according to claim 6, characterized in that it comprises a backing layer, a plaster layer and an anti-adhesive layer, said plaster layer containing said pharmaceutical composition.
Preferably, the paste layer is located between the backing layer and the release layer.
Preferably, the plaster layer is formed by dispersing the mini-drug reservoir in the pressure sensitive adhesive layer.
Preferably, the mini-drug depot comprises or consists of flurbiprofen and a stabilizing agent.
Preferably, the patch is a flurbiprofen hot melt pressure sensitive adhesive transdermal preparation.
8. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, characterized in that it comprises the following steps: mixing the raw material components in the weight ratio of any one of claims 1 to 4 to obtain the pharmaceutical composition.
9. The method of claim 8, comprising the steps of:
(1) mixing the pressure-sensitive adhesive matrix and the plasticizer for swelling to obtain a swollen mixture;
(2) adding a tackifier, a penetration enhancer, a filler and an antioxidant into the swelling mixture, and stirring until the swelling mixture is molten;
(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 and the material obtained in the step (2), and cooling after the reaction is finished to obtain the pharmaceutical composition.
10. A process for the preparation of a pharmaceutical formulation, comprising the process for the preparation of a pharmaceutical composition according to claim 8 or 9.
Preferably, the pharmaceutical preparation is a patch, and the preparation method of the patch comprises the following steps: and assembling a plaster layer, a backing layer and an anti-sticking layer with the pharmaceutical composition as the plaster layer, wherein the plaster layer is positioned between the backing layer and the anti-sticking layer to obtain the patch.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310287597.1A CN116270575A (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
| CN202110938206.9A CN113648297B (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110938206.9A CN113648297B (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
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| CN202310287597.1A Division CN116270575A (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
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| CN113648297A true CN113648297A (en) | 2021-11-16 |
| CN113648297B CN113648297B (en) | 2023-07-14 |
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| CN202310287597.1A Pending CN116270575A (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
| CN202110938206.9A Active CN113648297B (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
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| CN202310287597.1A Pending CN116270575A (en) | 2021-08-16 | 2021-08-16 | Pharmaceutical composition and patch containing flurbiprofen |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115192552A (en) * | 2022-07-15 | 2022-10-18 | 新领医药技术(深圳)有限公司 | Traditional Chinese medicine transdermal patch for effectively relieving rheumatic pain and preparation method thereof |
| CN116459238A (en) * | 2023-05-08 | 2023-07-21 | 乐明药业(苏州)有限公司 | Composition for promoting sustained release of glucosamine and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1387842A (en) * | 2002-06-19 | 2003-01-01 | 中国人民解放军第二军医大学 | Transdermal plaster of aryl propionic non-steroid antiphlogistic |
| CN102000043A (en) * | 2010-11-19 | 2011-04-06 | 沈阳药科大学 | Flurbiprofen salt transdermal patch and preparation method thereof |
| CN102099020A (en) * | 2008-05-30 | 2011-06-15 | 迈兰股份有限公司 | Stabilized transdermal drug delivery system |
| CN112891324A (en) * | 2021-01-19 | 2021-06-04 | 北京亚宝生物药业有限公司 | Transdermal patch |
-
2021
- 2021-08-16 CN CN202310287597.1A patent/CN116270575A/en active Pending
- 2021-08-16 CN CN202110938206.9A patent/CN113648297B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1387842A (en) * | 2002-06-19 | 2003-01-01 | 中国人民解放军第二军医大学 | Transdermal plaster of aryl propionic non-steroid antiphlogistic |
| CN102099020A (en) * | 2008-05-30 | 2011-06-15 | 迈兰股份有限公司 | Stabilized transdermal drug delivery system |
| CN102000043A (en) * | 2010-11-19 | 2011-04-06 | 沈阳药科大学 | Flurbiprofen salt transdermal patch and preparation method thereof |
| CN112891324A (en) * | 2021-01-19 | 2021-06-04 | 北京亚宝生物药业有限公司 | Transdermal patch |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115192552A (en) * | 2022-07-15 | 2022-10-18 | 新领医药技术(深圳)有限公司 | Traditional Chinese medicine transdermal patch for effectively relieving rheumatic pain and preparation method thereof |
| CN116459238A (en) * | 2023-05-08 | 2023-07-21 | 乐明药业(苏州)有限公司 | Composition for promoting sustained release of glucosamine and application thereof |
| CN116459238B (en) * | 2023-05-08 | 2023-12-05 | 乐明药业(苏州)有限公司 | Composition for promoting sustained release of glucosamine and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113648297B (en) | 2023-07-14 |
| CN116270575A (en) | 2023-06-23 |
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