CN106924262A - A kind of solid dispersions of unformed tropsch imatinib citrate and pharmaceutic adjuvant and preparation method thereof - Google Patents
A kind of solid dispersions of unformed tropsch imatinib citrate and pharmaceutic adjuvant and preparation method thereof Download PDFInfo
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
The solid dispersions and its manufacture method of a kind of unformed tropsch imatinib citrate and pharmaceutic adjuvant, it includes tropsch imatinib citrate and pharmaceutic adjuvant, and both weight ratios are 1:0.1 ~ 100, wherein, tropsch imatinib citrate is unformed shape, and the characteristic peak of the crystal without tropsch imatinib citrate after the background peaks of pharmaceutic adjuvant is deducted in the X-ray powder diffraction spectrum of the solid dispersions.The solid dispersions stability and favorable dispersibility of tropsch imatinib citrate of the invention and pharmaceutic adjuvant, increased the dissolution rate of tropsch imatinib citrate, it is more beneficial for improving the absorption of the bioavilability and body of pharmaceutical preparation to medicine, under the conditions of accelerated test, good physical stability and chemical stability can be kept.The preparation method of unformed solid dispersions of the invention is simple to operate, with low cost, favorable reproducibility, it is easy to accomplish, it is adapted to industrialized production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, and in particular to a kind of tropsch imatinib citrate of unformed shape and pharmaceutic adjuvant
Solid dispersions, further relate to a kind of Pharmaceutical composition containing unformed tropsch imatinib citrate and pharmaceutic adjuvant and its preparation
Method.
Background technology
Tropsch imatinib（Tofacitinib, cloth is replaced also known as support method）, chemical entitled 3- ((3R, 4R) -4- methyl (7H- pyrrolo-es
[2,3-d] pyrimidine-4-yl) amino) piperidin-1-yl) -3- OPNs.Tropsch imatinib citrate is that Pfizer Inc. opens
Hair a kind of drugs for rheumatoid arthritis, trade name Xeljanz, for methotrexate for treatment response it is insufficient or intolerant to
To severe active rheumatoid arthritis (RA) adult patient in receiving.
Although tropsch imatinib citrate is evident in efficacy, but still there are some defects.Patent WO2003048162A1
Disclose crystal formation and unformed tropsch imatinib citrate.The solubility of crystal formation tropsch imatinib citrate is poor, unformed
Although tropsch imatinib citrate has preferable solubility, but amorphous state tropsch imatinib citrate physical stability and change
Learn stability and be problematic in that druggability is bad, it is difficult to reach medicinal requirement.
The solid forms of medicine directly affect the rate of dissolution of bulk drug, the dissolution rate of preparation and bioavilability, in order to
The bioavilability of medicine is improved, consumption is reduced, is reduced toxic and side effect, it will usually develop the new solid forms of medicine, therefore,
Develop the solid form that the drug solubility is more preferable, bioavilability is higher and just seem necessary.
Because not enough and unformed medicine stability of the tropsch imatinib citrate in terms of bioavilability is not enough, find
New solid dispersions of unformed tropsch imatinib citrate and preparation method thereof just seem very necessary.
The content of the invention
It is an object of the invention to provide the solid dispersions and its preparation of a kind of tropsch imatinib citrate and pharmaceutic adjuvant
Method, the tropsch imatinib citrate of unformed shape and the solid of pharmaceutic adjuvant for obtaining stability and favorable dispersibility disperses
Body, increased the dissolution rate of tropsch imatinib citric acid, and the preparation method is not limited by drying process, also by solvent species and
The limitation of quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, it is capable of achieving industrialized production.
In order to achieve the above object, technical scheme is as follows：
A kind of solid dispersions of tropsch imatinib citrate and pharmaceutic adjuvant, the solid dispersions include tropsch imatinib citric acid
Salt and pharmaceutic adjuvant, both weight ratios are 1:0.1 ~ 100, wherein, described tropsch imatinib citrate is unformed shape, institute
In stating the X-ray powder diffraction spectrum of solid dispersions, deduct after the background peaks of pharmaceutic adjuvant without tropsch imatinib citrate
The characteristic peak of crystal.
Further, the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, into membrane material
At least one in material, coating material and capsule material.
Preferably, described pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol,
Ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose calcium are adjacent
Phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic acid tree
Fat, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, carboxylic first
At least one in base sodium starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and collagen.
The preparation method of the solid dispersions of tropsch imatinib citrate of the invention and pharmaceutic adjuvant, including following step
Suddenly：
1) tropsch imatinib, citric acid and pharmaceutic adjuvant are mixed, is mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, and formation contains
The solution or suspension of tropsch imatinib citrate and pharmaceutic adjuvant, wherein, tropsch imatinib is 1 with the mol ratio of citric acid:
0.95 ~ 1.05, tropsch imatinib citrate is 0.001 ~ 100 with the weight ratio of solvent:1, tropsch imatinib citrate with it is medicinal
The weight ratio of auxiliary material is 1:0.1~100；
2) removing step 1）Solvent in the solution or suspension that obtain, obtains the tropsch imatinib citrate and medicine of unformed shape
With the solid dispersions of auxiliary material.
Further, the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, into membrane material
At least one in material, coating material and capsule material.
Preferably, step 1）Described in pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP,
Polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxylic first
Base cellulose phthalate, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate,
Polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, friendship
At least one in connection starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan and collagen.
The present invention provides the preparation method of another tropsch imatinib citrate and the solid dispersions of pharmaceutic adjuvant, including
Following steps：
1) tropsch imatinib citrate and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, forms method containing support
For Buddhist nun's citrate and the solution or suspension of pharmaceutic adjuvant, wherein, tropsch imatinib citrate is with the weight ratio of solvent
0.001~100:1, tropsch imatinib citrate is 1 with the weight ratio of pharmaceutic adjuvant:0.1~100；
2) removing step 1）Solvent in the solution or suspension that obtain, obtains the tropsch imatinib citrate and medicine of unformed shape
With the solid dispersions of auxiliary material.
Further, the pharmaceutic adjuvant be selected from diluent, lubricant, adhesive, disintegrant, surfactant, into membrane material
At least one in material, coating material and capsule material.
Preferably, step 1）Described in pharmaceutic adjuvant be selected from HPMC, hydroxypropyl cellulose, PVP,
Microcrystalline cellulose, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, sodium carboxymethylethyl
Cellulose, carboxymethylcellulose calcium phthalic acid ester, hydroxypropyl methylcellulose phthalate, HPMC acetic acid
It is ester succinate, polyacrylic resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pre-
Gelling starch, crosslinked starch, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and
At least one in collagen.
Also, step 1）The solvent is selected from containing less than 12 alcohols, phenols, ethers, halogenated hydrocarbons, ketone, the aldehyde of carbon atom
At least one in class, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water, step 2）The method for removing solvent includes：Evaporation, vacuum
Evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.
Solid dispersions in the present invention refer to mixture, compound, copolymer, co-precipitate, eutectic, solid dispersion
Body, solvate and hydrate.
Tropsch imatinib citrate of the invention and the solid dispersions of pharmaceutic adjuvant, are radiated, using Cu-K α to spend 2 θ tables
The characteristic peak of the background peaks without tropsch imatinib crystalline state of pharmaceutic adjuvant is deducted in the X-ray powder diffraction spectrum for showing, shows support method
It is unformed state for Buddhist nun's citrate.Normally due to the orderly and periodic arrangement of amorphous material molecule, reduces intermolecular
The energy of interaction, energy is relatively low, and tropsch imatinib citrate of the invention is unformed shape, and molecule is in highly unordered
State, the surface free energy of material is bigger, and the molecule in solid matter has energy higher compared with the molecule in crystalline solid material,
Easily disperse, increase its dissolution rate, improve the bioavilability of tropsch imatinib citrate.
After be well mixed for tropsch imatinib citrate and pharmaceutic adjuvant by the present invention, " solid dispersion " method is used, passed through
The polymer network structure of pharmaceutic adjuvant intercepts drug molecule, suppresses the generation of crystallization, it is kept dispersion and unformed shape
State.Present invention use is widely used, the pharmaceutic adjuvant that cheap, dissolubility is good, these pharmaceutic adjuvants and tropsch imatinib citron
Hydrochlorate mixes, and coordinates the technologies such as evaporation, spray drying, freeze-drying and hot-melt extruded to obtain tropsch imatinib citrate
Amorphous forms, increase the unformed of tropsch imatinib citrate in the solid dispersions of tropsch imatinib citrate of the present invention
The stability of state.
The present invention selects pharmaceutically widely used, cheap auxiliary material, obtains tropsch imatinib citrate and medicine
With the solid dispersions of auxiliary material, it is easy to develop pharmaceutical formulation, preparation method of the invention is not limited by drying process, also not received
The limitation of solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, it is capable of achieving industrialized production.
Compared with prior art, the beneficial effects of the invention are as follows：
1) unformed tropsch imatinib citrate prepared by the present invention has high dispersion with the solid dispersions of pharmaceutic adjuvant
And stability, after solid pharmaceutical preparation is made, the degree of scatter of drug particle can be made by being disintegrated more preferably, dispersion and dissolution rate are more
Hurry up, be conducive to the absorption of medicine.Therefore, the dissolution rate of unformed state medicine substantially increases, and is more beneficial for body to medicine
Absorb, improve the bioavilability of medicine, allow medicament to preferably play clinical disease treatment effect.
2) preparation method of the solid dispersions of the tropsch imatinib citrate of unformed state of the invention and pharmaceutic adjuvant
Do not limited by drying process, also do not limited by solvent species and quantity of solvent, it is easy to operate, it is with low cost, it is easy to accomplish, can
Realize industrialized production.
3) the tropsch imatinib citrate of unformed state prepared by the present invention is adding with the solid dispersions of pharmaceutic adjuvant
Under fast experimental condition（40 ± 2 DEG C, humidity 75% ± 5%）, good physical stability and chemical stability can be kept.Therefore, originally
Invention will have broad application prospects.
Brief description of the drawings
Fig. 1 is the unformed tropsch imatinib citrate of the embodiment of the present invention 1 and the solid dispersions of PVP-K30
X-ray powder diffraction figure.
Specific embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention does not receive following implementation
The limitation of example.
X-ray powder diffraction figure of the present invention is gathered on Ultima IV x-ray diffractometers.It is of the present invention
X-ray powder diffraction method parameter it is as follows：
X-ray powder parameter：Cu-Kα
Kα（）：1.5418
Voltage：40 kilovolts
Electric current：40 milliamperes
Divergent slit：Automatically
Scan pattern：Continuously
Sweep limits：From 2.0 to 60.0 degree
Sampling step length：0.0200 degree
Sweep speed：60 degrees/min
Embodiment 1
By tropsch imatinib citrate（5 grams）And PVP K30（10 grams）Add water（300 milliliters）In, it is heated to 60 DEG C of stirrings
It is molten clear.Above-mentioned solution is dried with JISL mini spray dryers LSD-48,60 DEG C of inlet temperature, 50 DEG C of outlet temperature is maintained,
Collect outlet material, obtain white solid, further vacuum drying obtain unformed tropsch imatinib citrate and PVP-
The solid dispersions of K30.X-ray powder diffraction figure is as shown in figure 1, in the X-ray powder diffraction figure of the solid dispersions, detain
Except the characteristic peak without tropsch imatinib citrate crystal formation after the background peaks of pharmaceutic adjuvant.
Embodiment 2
By tropsch imatinib citrate（1 gram）With HPMC E50（0.2 gram）It is added to water（10 milliliters）In, it is heated to
40 DEG C of stirrings are molten clear.By above-mentioned solution freeze-drying, white solid is obtained, i.e., unformed tropsch imatinib citrate and hydroxypropyl first
The solid dispersions of base cellulose E50, in the X-ray powder diffraction figure of the solid dispersions, deduct the background peaks of pharmaceutic adjuvant
Afterwards without the characteristic peak of tropsch imatinib citrate crystal formation.
Embodiment 3
By tropsch imatinib citric acid（1 gram）And PEG 8000（50 grams）Melting is heated to, room temperature is quickly cooled under stirring,
Obtain white solid.Above-mentioned solid is crushed, white powdery solids are obtained, i.e., unformed tropsch imatinib citric acid and poly- second two
The solid dispersions of alcohol 8000, in the X-ray powder diffraction figure of the solid dispersions, deduct nothing after the background peaks of pharmaceutic adjuvant
The characteristic peak of tropsch imatinib citric acid crystal formation.
Embodiment 4
By tropsch imatinib（1.00 grams）, citric acid（0.61 gram）And PEG20000（100 grams）240 DEG C are heated to, mixing is equal
It is even, room temperature is quickly cooled to, obtain white solid.Above-mentioned solid is crushed, white powdery solids is obtained, i.e., unformed support method
For Buddhist nun's citric acid and the solid dispersions of PEG20000, in the X-ray powder diffraction figure of the solid dispersions, medicine is deducted
With the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of auxiliary material.
Embodiment 5
By tropsch imatinib（1.00 grams）, citric acid（0.61 gram）, normal propyl alcohol（20 grams）And liposome（4 grams）Mixture be heated to
90 DEG C, stirring is well mixed, and is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white solid, i.e., unformed tropsch imatinib Chinese holly
Rafter acid and the solid dispersions of liposome, in the X-ray powder diffraction figure of the solid dispersions, deduct the background of pharmaceutic adjuvant
Without the characteristic peak of tropsch imatinib citric acid crystal formation behind peak.
Embodiment 6
By tropsch imatinib（1.00 grams）, citric acid（0.61 gram）, methyl alcohol（20 grams）With methacrylic acid copolymer A types（4 grams）'s
Mixture is heated to 50 DEG C, and stirring is molten clear, is evaporated in vacuo and removes solvent, is cooled to room temperature and obtains white solid, i.e., unformed support
Method is for Buddhist nun's citrate and the solid dispersions of methacrylic acid copolymer A types, the X-ray powder diffraction of the solid dispersions
In figure, the characteristic peak without tropsch imatinib citrate crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 7
By tropsch imatinib citric acid（1 gram）, normal propyl alcohol（20 grams）And ethyl cellulose（2 grams）Mixture be heated to 30 DEG C, stir
Mix, be well mixed, be evaporated in vacuo remove solvent, be cooled to room temperature and obtain white solid, i.e., unformed tropsch imatinib citric acid with
The solid dispersions of ethyl cellulose, in the X-ray powder diffraction figure of the solid dispersions, deduct the background peaks of pharmaceutic adjuvant
Afterwards without the characteristic peak of tropsch imatinib citric acid crystal formation.
Embodiment 8
By tropsch imatinib citrate（1 gram）, methyl alcohol（20 grams）With hydroxypropyl cellulose SSL（4 grams）Mixture be heated to 30
DEG C, stir molten clear, it is evaporated in vacuo and removes solvent, be cooled to room temperature and obtain white solid, i.e., unformed tropsch imatinib citrate
With the solid dispersions of hydroxypropyl cellulose SSL, in the X-ray powder diffraction figure of the solid dispersions, pharmaceutic adjuvant is deducted
Without the characteristic peak of tropsch imatinib citrate crystal formation after background peaks.
Embodiment 9
By tropsch imatinib citrate（1 gram）, methyl alcohol（20 grams）, water（10 grams）And polyvinyl acetate（4 grams）Mixture heating
To 30 DEG C, stir molten clear, be evaporated in vacuo and remove solvent, be cooled to room temperature and obtain white solid, i.e., unformed tropsch imatinib citron
Hydrochlorate and the solid dispersions of polyvinyl acetate, in the X-ray powder diffraction figure of the solid dispersions, deduct pharmaceutic adjuvant
Without the characteristic peak of tropsch imatinib citrate crystal formation after background peaks.
Embodiment 10
Tropsch imatinib citric acid (50 milligrams) and polyacrylic resin Eudragit L100 (100 milligrams) are added to methyl alcohol
(750 microlitres), stir molten clear at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e.,
The solid dispersions of unformed tropsch imatinib citrate and polyacrylic resin Eudragit L100, the solid dispersions
In X-ray powder diffraction figure, the characteristic peak without tropsch imatinib citrate crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 11
By tropsch imatinib citric acid（50 milligrams）With polyacrylic resin Eudragit S100（5 milligrams）It is added to methyl alcohol（4 millis
Rise）And ethyl acetate（1 milliliter）, stir molten clear at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, is obtained
To white solid, stirring is lower to separate out white solid, i.e., unformed tropsch imatinib citric acid and polyacrylic resin Eudragit
The solid dispersions of S100, in the X-ray powder diffraction figure of the solid dispersions, without support after the background peaks of deduction pharmaceutic adjuvant
Method replaces the characteristic peak of Buddhist nun's citric acid crystal formation.
Embodiment 12
By tropsch imatinib citric acid（50 milligrams）With carbopol Carbomer 940（50 milligrams）It is added to methyl alcohol（4 milliliters）With
Tetrahydrofuran（1 milliliter）, it is uniformly mixed at -30 DEG C.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, is obtained
White solid, stirring is lower to separate out white solid, i.e., unformed tropsch imatinib citric acid is consolidated with carbopol Carbomer's 940
Body dispersion, in the X-ray powder diffraction figure of the solid dispersions, without tropsch imatinib Chinese holly after the background peaks of deduction pharmaceutic adjuvant
The characteristic peak of rafter acid crystals type.
Embodiment 13
By tropsch imatinib citric acid（50 milligrams）With pregelatinized starch Pharma-Gel（100 milligrams）It is added to methyl alcohol（4 milliliters）
And water（1 milliliter）, it is well mixed at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained,
The lower solid dispersions for separating out white solid, i.e., unformed tropsch imatinib citric acid and Pharma-Gel pregelatinized starch of stirring,
In the X-ray powder diffraction figure of the solid dispersions, without tropsch imatinib citric acid crystal formation after the background peaks of deduction pharmaceutic adjuvant
Characteristic peak.
Embodiment 14
By tropsch imatinib citric acid（50 milligrams）With side chain crosslinked starch high（50 milligrams）It is added to methyl alcohol（4 milliliters）And water（1 milli
Rise）, stir molten clear at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, the lower analysis of stirring
Go out white solid, i.e., the solid dispersions of unformed tropsch imatinib citric acid and side chain crosslinked starch high, the solid dispersions
In X-ray powder diffraction figure, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 15
By tropsch imatinib citric acid（50 milligrams）With sodium carboxymethylcellulose SCMC（500 milligrams）It is added to dimethyl sulfoxide (DMSO)（5 millis
Rise）, stir molten clear at room temperature.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., it is unformed
The solid dispersions of tropsch imatinib citric acid and sodium carboxymethylcellulose SCMC, the X-ray powder diffraction figure of the solid dispersions
In, deduct the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant.
Embodiment 16
By tropsch imatinib citric acid（50 milligrams）And chitosan（500 milligrams）It is added to ethanol（5 milliliters）, stir at room temperature molten
Clearly, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtains white solid, i.e., unformed tropsch imatinib citric acid with
The solid dispersions of chitosan, in the X-ray powder diffraction figure of the solid dispersions, after deducting the background peaks of pharmaceutic adjuvant
Characteristic peak without tropsch imatinib citric acid crystal formation.
Embodiment 17
By tropsch imatinib citric acid（50 milligrams）With sodium carboxymethyl starch Explotab（500 milligrams）It is added to ethanol（5 milliliters）,
Be uniformly mixed at room temperature, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e., it is unformed
The solid dispersions of tropsch imatinib citric acid and sodium carboxymethyl starch Explotab, the X-ray powder diffraction of the solid dispersions
In figure, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 18
By tropsch imatinib citric acid（50 milligrams）With alginates E401（500 milligrams）It is added to ethanol（5 milliliters）, stir at room temperature
It is well mixed.Above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, white solid is obtained, i.e., unformed tropsch imatinib Chinese holly
Rafter acid and the solid dispersions of alginates E401, in the X-ray powder diffraction figure of the solid dispersions, deduct pharmaceutic adjuvant
Without the characteristic peak of tropsch imatinib citric acid crystal formation after background peaks.
Embodiment 19
By tropsch imatinib（100 milligrams）, citric acid（61 milligrams）With carboxymethylcellulose calcium phthalic acid ester Agucoat CPD（5
Gram）It is suspended in methyl alcohol（30 milliliters）, it is heated to 50 DEG C and is uniformly mixed.Above-mentioned solution is concentrated rapidly in a rotary evaporator
Most of solvent is removed, filtering is dried, and obtains white solid, i.e., unformed tropsch imatinib citric acid is adjacent with carboxymethylcellulose calcium
The solid dispersions of phthalic acid ester Agucoat CPD, in the X-ray powder diffraction figure of the solid dispersions, deduct medicinal auxiliary
Without the characteristic peak of tropsch imatinib citric acid crystal formation after the background peaks of material.
Embodiment 20
By tropsch imatinib citric acid（100 milligrams）, citric acid（61 milligrams）With carragheen E407（500 milligrams）It is suspended in methyl alcohol
（30 milliliters）, it is heated to 50 DEG C and is uniformly mixed, by above-mentioned solution, concentration removing is most of molten rapidly in a rotary evaporator
Agent, filtering is dried, and obtains the solid dispersions of white solid, i.e., unformed tropsch imatinib citric acid and carragheen E407, and this is consolidated
In the X-ray powder diffraction figure of body dispersion, the feature without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted
Peak.
Embodiment 21
By tropsch imatinib citric acid（100 milligrams）, citric acid（61 milligrams）And shitosan（5 grams）It is suspended in methyl alcohol（50 milliliters）,
50 DEG C are heated to be uniformly mixed.By above-mentioned solution, concentration removes most of solvent rapidly in a rotary evaporator, and filtering is done
It is dry, the solid dispersions of white solid, i.e., unformed tropsch imatinib citric acid and shitosan are obtained, the X- of the solid dispersions is penetrated
In line powder diagram, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 22
By tropsch imatinib citric acid（100 milligrams）, citric acid（61 milligrams）With polyacrylic resin Eudragit E100（30 millis
Gram）It is dissolved in normal propyl alcohol（600 microlitres）And N,N-dimethylformamide（600 microlitres）In, it is heated to 50 DEG C and stirs molten clear, will be above-mentioned
Solution cools to 10 DEG C, separates out white solid, and filtering is dried, and obtains unformed tropsch imatinib citric acid and polyacrylic resin
The solid dispersions of Eudragit E100, in the X-ray powder diffraction figure of the solid dispersions, deduct the background of pharmaceutic adjuvant
Without the characteristic peak of tropsch imatinib citric acid crystal formation behind peak.
Embodiment 23
By tropsch imatinib citric acid（30 milligrams）With collagen Peptan（300 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And second
Nitrile（600 microlitres）In, it is heated to 50 DEG C of stirrings molten clear.Above-mentioned solution is cooled to 10 DEG C, white solid is separated out, filtering is dried,
Obtain the solid dispersions of unformed tropsch imatinib citric acid and collagen Peptan, the X-ray powder of the solid dispersions
In diffraction pattern, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 24
By tropsch imatinib citric acid（30 milligrams）With gummy Galactosol（300 milligrams）It is dissolved in normal propyl alcohol（600 microlitres）And first
Alcohol（600 microlitres）In, it is heated to 50 DEG C of stirrings molten clear.Above-mentioned solution is cooled to 10 DEG C, white solid is separated out, filtering is dried,
Obtain the solid dispersions of unformed tropsch imatinib citric acid and natural gum Galactosol, the X-ray powder of the solid dispersions
In diffraction pattern, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 25
By tropsch imatinib citrate（30 milligrams）With hydroxypropyl methylcellulose phthalate HPMCP（30 milligrams）It is added to
Ethanol（750 microlitres）And water（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.Above-mentioned solution is fast in a rotary evaporator
Speed concentration removes solvent, obtains white solid, i.e., unformed tropsch imatinib citrate and HPMC O-phthalic
The solid dispersions of acid esters HPMCP, in the X-ray powder diffraction figure of the solid dispersions, after deducting the background peaks of pharmaceutic adjuvant
Characteristic peak without tropsch imatinib citrate crystal formation.
Embodiment 26
By tropsch imatinib citrate（30 milligrams）With ion exchange resin Amberlite IR-120（300 milligrams）It is added to second
Alcohol（750 microlitres）And water（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.Above-mentioned solution is rapid in a rotary evaporator
Concentration removes solvent, obtains brown solid, i.e., unformed tropsch imatinib citrate and ion exchange resin Amberlite IR-
120 solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, without support method after the background peaks of deduction pharmaceutic adjuvant
For the characteristic peak of Buddhist nun's citrate crystal formation.
Embodiment 27
By tropsch imatinib citric acid（30 milligrams）And caprolactone（300 milligrams）It is added to ethanol（750 microlitres）And water
（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains
To brown solid, i.e., the solid dispersions of unformed tropsch imatinib citric acid and caprolactone, the X- of the solid dispersions
In ray powder diffraction pattern, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 28
By tropsch imatinib citric acid（30 milligrams）With dextrin Maltrin M100（300 milligrams）It is added to ethanol（750 microlitres）With
Water（750 microlitres）, it is heated to 80 DEG C and is uniformly mixed.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator,
Obtain the solid dispersions of brown solid, i.e., unformed tropsch imatinib citric acid and dextrin Maltrin M100, solid dispersion
In the X-ray powder diffraction figure of body, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 29
By tropsch imatinib citrate（30 milligrams）With sodium carboxymethylcellulose SCMS（3 milligrams）It is added to water（30 milliliters）, plus
Heat is uniformly mixed to 100 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white solid,
The solid dispersions of i.e. unformed tropsch imatinib citrate and sodium carboxymethylcellulose SCMC, the X-ray of the solid dispersions
In powder diagram, the characteristic peak without tropsch imatinib citrate crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 30
By tropsch imatinib citrate（30 milligrams）And beta-schardinger dextrin（30 milligrams）It is added to methyl alcohol（300 microlitres）And water（300 is micro-
Rise）, stir molten clear at room temperature.By above-mentioned solution in a rotary evaporator rapidly concentration remove solvent, obtain white solid, i.e., without
The solid dispersions of sizing tropsch imatinib citrate and beta-schardinger dextrin, in the X-ray powder diffraction figure of the solid dispersions,
Deduct the characteristic peak without tropsch imatinib citrate crystal formation after the background peaks of pharmaceutic adjuvant.
Embodiment 31
By tropsch imatinib citric acid（30 milligrams）With sodium carboxymethylcellulose SCMC（30 milligrams）It is added to methyl alcohol（300 microlitres）With
Water（60 microlitres）, it is uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white
The solid dispersions of color solid, i.e., unformed tropsch imatinib citric acid and sodium carboxymethylcellulose SCMC, the solid dispersions
In X-ray powder diffraction figure, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 32
By tropsch imatinib citric acid（5 milligrams）With PEO Polyox WSR301（60 milligrams）It is added to methyl alcohol（300 is micro-
Rise）And water（60 microlitres）, it is uniformly mixed at 60 DEG C.By above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator,
The solid dispersions of white solid, i.e., unformed tropsch imatinib citric acid and PEO Polyox WSR301 are obtained, this is consolidated
In the X-ray powder diffraction figure of body dispersion, the feature without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted
Peak.
Embodiment 33
By tropsch imatinib citric acid（30 milligrams）With polyvinyl alcohol EG-40（60 milligrams）It is added to methyl alcohol（300 microlitres）And water（60
Microlitre）, stir molten clear at 60 DEG C, by above-mentioned solution, concentration removes solvent rapidly in a rotary evaporator, obtains white solid, i.e.,
The solid dispersions of unformed tropsch imatinib citric acid and polyvinyl alcohol EG-40, the X-ray powder diffraction of the solid dispersions
In figure, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 34
By tropsch imatinib citric acid（50 milligrams）With HPMC acetate succinate Agoat MG（2 grams）It is added to
Ethanol（10 milliliters）And water（2 milliliters）, it is uniformly mixed at 80 DEG C, above-mentioned solution is concentrated into rapidly in a rotary evaporator
It is dry, white solid is obtained, i.e., unformed tropsch imatinib citric acid and HPMC acetate succinate Agoat MG
Solid dispersions, in the X-ray powder diffraction figure of the solid dispersions, deduct pharmaceutic adjuvant background peaks after replaced without support method
The characteristic peak of Buddhist nun's citric acid crystal formation.
Embodiment 35
By tropsch imatinib citric acid（50 milligrams）And carboxymethylethylcellulose（2 grams）It is added to ethanol（10 milliliters）And water（1 milli
Rise）, be uniformly mixed at 80 DEG C, above-mentioned solution is concentrated to dryness rapidly in a rotary evaporator, obtain white solid, i.e., without
The solid dispersions of sizing tropsch imatinib citric acid and carboxymethylethylcellulose, the X-ray powder diffraction of the solid dispersions
In figure, the characteristic peak without tropsch imatinib citric acid crystal formation after the background peaks of pharmaceutic adjuvant is deducted.
Embodiment 36：Unformed tropsch imatinib citrate is tested with the influence factor of PVP K30 solid dispersions
Material：The solid dispersions of the unformed tropsch imatinib citrate of the gained of embodiment 1 and PVP K30
Table 1：
Table 1 is illustrated：Unformed tropsch imatinib citrate under high temperature, super-humid conditions, is placed with PVP K30 solid dispersions
10 days, relevant material was crystallized without tropsch imatinib citrate and separated out without significantly changing.
Embodiment 37：Unformed tropsch imatinib citrate is tested with the influence factor of PVP K30 solid dispersions
Material：The solid dispersions of the unformed tropsch imatinib citrate of the gained of embodiment 1 and PVP K30
Experiment condition：Temperature 40 oC±2 oC, humidity 75% ± 5%
Table 2：
Table 2 is illustrated：Unformed tropsch imatinib citrate under the conditions of accelerated test, places 6 with PVP K30 solid dispersions
Individual month, relevant material was crystallized without tropsch imatinib citrate and separated out without significantly changing.
The unformed solid dispersions of tropsch imatinib citrate of the invention and pharmaceutic adjuvant, its dissolution rate substantially increases, more
Be conducive to improving the bioavilability of medicine, allow medicament to preferably play clinical disease treatment effect, the amorphous article exists
Under the conditions of accelerated test（40 ± 2 DEG C, humidity 75% ± 5%）, good physical stability and chemical stability can be kept.
Claims (11)
1. a kind of solid dispersions of tropsch imatinib citrate and pharmaceutic adjuvant, it is characterised in that the solid dispersions bag
Citrate containing tropsch imatinib and pharmaceutic adjuvant, both weight ratios are 1:0.1 ~ 100, wherein, described tropsch imatinib citron
Hydrochlorate is unformed shape, in the X-ray powder diffraction spectrum of the solid dispersions, deducts nothing after the background peaks of pharmaceutic adjuvant
The characteristic peak of tropsch imatinib citrate crystal.
2. solid dispersions of tropsch imatinib citrate according to claim 1 and pharmaceutic adjuvant, it is characterised in that institute
At least one stated in pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, bag
At least one in clothing material and capsule material.
3. solid dispersions of tropsch imatinib citrate according to claim 1 and pharmaceutic adjuvant, it is characterised in that institute
State at least one in pharmaceutic adjuvant and be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl are fine
Dimension element, microcrystalline cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethyl are fine
The plain phthalic acid ester of dimension, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, poly- third
Olefin(e) acid resin, carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinking are formed sediment
In powder, sodium carboxymethyl starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and collagen extremely
Few one kind.
4. a kind of tropsch imatinib citrate and the preparation method of the solid dispersions of pharmaceutic adjuvant, comprise the following steps：
Tropsch imatinib, citric acid and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, form method containing support and replace
The solution or suspension of Buddhist nun's citrate and pharmaceutic adjuvant, wherein, tropsch imatinib is 1 with the mol ratio of citric acid:0.95~
1.05, tropsch imatinib and citric acid and the weight ratio of solvent are 0.001 ~ 100:1, tropsch imatinib and citric acid and pharmaceutic adjuvant
Weight ratio is 1:0.1~100；
Removing step 1）Solvent in the solution or suspension that obtain, obtain the tropsch imatinib citrate of unformed shape with it is medicinal
The solid dispersions of auxiliary material.
5. a kind of tropsch imatinib citrate and the preparation method of the solid dispersions of pharmaceutic adjuvant, comprise the following steps：
Tropsch imatinib citrate and pharmaceutic adjuvant are mixed in a solvent, mixing temperature is -50 ~ 150 DEG C, form method containing support and replace
The solution or suspension of Buddhist nun's citrate and pharmaceutic adjuvant, wherein, tropsch imatinib citrate is 0.001 with the weight ratio of solvent
~100:1, tropsch imatinib citrate is 1 with the weight ratio of pharmaceutic adjuvant:0.1~100；
Removing step 1）Solvent in the solution or suspension that obtain, obtain the tropsch imatinib citrate of unformed shape with it is medicinal
The solid dispersions of auxiliary material.
6. the preparation method of the solid dispersions of the tropsch imatinib citrate according to claim 4 or 5 and pharmaceutic adjuvant,
Characterized in that, the pharmaceutic adjuvant is selected from diluent, lubricant, adhesive, disintegrant, surfactant, filmogen, bag
At least one in clothing material and capsule material.
7. the preparation method of the solid dispersions of the tropsch imatinib citrate according to claim 4 or 5 and pharmaceutic adjuvant,
Characterized in that, described pharmaceutic adjuvant is selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl
Cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose calcium neighbour's benzene two
Formic acid esters, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin,
Carbopol, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, carboxymethyl
Sodium starch, dextrin, PEO, shitosan, chitosan, ion exchange resin and collagen, cyclodextrin, lactose, half
At least one in lactose, PEARLITOL 25C, sorbierite, xylitol, urea.
8. the preparation method of the solid dispersions of the tropsch imatinib citrate according to claim 4 or 5 and pharmaceutic adjuvant,
Characterized in that, step 1）The solvent is selected from containing less than 12 alcohols, phenols, ethers, halogenated hydrocarbons, ketone, the aldehyde of carbon atom
At least one in class, nitrile, acid amides, sulfone, sulfoxide, carboxylic acid and water；Step 2）The method for removing solvent includes：Evaporation, vacuum
Evaporation, spray drying, freeze-drying, hot-melt extruded, filtering, centrifugation or agitated thin film.
9. a kind of Pharmaceutical composition, it is characterised in that the Pharmaceutical composition contains unformed tropsch imatinib citric acid solid point
A prose style free from parallelism and at least one pharmaceutically acceptable auxiliary material, at least one in the pharmaceutic adjuvant be selected from diluent, lubricant,
At least one in adhesive, disintegrant, surfactant, filmogen, coating material and capsule material.
10. Pharmaceutical composition according to claim 9, it is characterised in that in the pharmaceutic adjuvant in the Pharmaceutical composition
At least one be selected from HPMC, hydroxypropyl cellulose, PVP, polyethylene glycol, ethyl cellulose, microcrystalline cellulose
Element, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethylethylcellulose, carboxymethylcellulose calcium phthalic acid
Ester, hydroxypropyl methylcellulose phthalate, HPMC acetate succinate, polyacrylic resin, poly- carboxylic
Ethene, alginates, carragheen, caprolactone, natural gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, CMS
Sodium, dextrin, PEO, shitosan, chitosan, collagen, cyclodextrin, lactose, galactolipin, PEARLITOL 25C, sorb
At least one in alcohol, xylitol, urea.
11. claim 9-10 it is any as described in composition be used to prepare treatment rheumatoid arthritis, psoriasis and leucoderma
The purposes of the medicines such as wind.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020239065A1 (en) * | 2019-05-31 | 2020-12-03 | 江苏恒瑞医药股份有限公司 | Solid dispersion and preparation method therefor |
| WO2022022434A1 (en) * | 2020-07-27 | 2022-02-03 | 杭州和正医药有限公司 | Pharmaceutical composition and preparation containing pharmaceutically acceptable salt of tofacitinib and use thereof |
| RU2816913C2 (en) * | 2019-05-31 | 2024-04-08 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Solid dispersion and method for its preparation |
-
2015
- 2015-12-31 CN CN201511014799.0A patent/CN106924262A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020239065A1 (en) * | 2019-05-31 | 2020-12-03 | 江苏恒瑞医药股份有限公司 | Solid dispersion and preparation method therefor |
| RU2816913C2 (en) * | 2019-05-31 | 2024-04-08 | Цзянсу Хэнжуй Медсин Ко., Лтд. | Solid dispersion and method for its preparation |
| WO2022022434A1 (en) * | 2020-07-27 | 2022-02-03 | 杭州和正医药有限公司 | Pharmaceutical composition and preparation containing pharmaceutically acceptable salt of tofacitinib and use thereof |
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