CN103830197A - Hydrochloric acid raloxifene dispersible tablet and preparation method thereof - Google Patents
Hydrochloric acid raloxifene dispersible tablet and preparation method thereof Download PDFInfo
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- CN103830197A CN103830197A CN201410094098.1A CN201410094098A CN103830197A CN 103830197 A CN103830197 A CN 103830197A CN 201410094098 A CN201410094098 A CN 201410094098A CN 103830197 A CN103830197 A CN 103830197A
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- China
- Prior art keywords
- acid
- dispersible tablet
- raloxifene hcl
- raloxifene
- hcl
- 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.)
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- 229960004622 raloxifene Drugs 0.000 title claims abstract description 84
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 title claims abstract description 84
- 239000007919 dispersible tablet Substances 0.000 title claims abstract description 65
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 13
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- 239000000314 lubricant Substances 0.000 claims abstract description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 22
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 15
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- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
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- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
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- 239000004471 Glycine Substances 0.000 description 1
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- 229910019142 PO4 Inorganic materials 0.000 description 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- 239000002671 adjuvant Substances 0.000 description 1
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- 239000000556 agonist Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
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- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000005211 alkyl trimethyl ammonium group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
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- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
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- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
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- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Chemical class CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
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- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
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- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
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- 231100000252 nontoxic Toxicity 0.000 description 1
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- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
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- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- BKXVVCILCIUCLG-UHFFFAOYSA-N raloxifene hydrochloride Chemical compound [H+].[Cl-].C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 BKXVVCILCIUCLG-UHFFFAOYSA-N 0.000 description 1
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- 210000002966 serum Anatomy 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- MWZFQMUXPSUDJQ-KVVVOXFISA-M sodium;[(z)-octadec-9-enyl] sulfate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCCOS([O-])(=O)=O MWZFQMUXPSUDJQ-KVVVOXFISA-M 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
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- 239000011718 vitamin C Substances 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention discloses a hydrochloric acid raloxifene dispersible tablet and a preparation method and an application thereof. The hydrochloric acid raloxifene dispersible tablet consists of the following components by weight percent: 5-50% of hydrochloric acid raloxifene, 10-40% of a filling agent, 10-50% of a disintegrating agent, 10-50% of an acidifying agent, 0.1-15% of an adhesive and 0.1-20% of a lubricating agent and flow aid. In comparison with the ordinary tablet, the hydrochloric acid raloxifene dispersible tablet does not contain surface active agents, is favorable in solubility, dispersibility and disintegrative, and can disintegrate completely within 1min. The hadrochloric acid raloxifene dispersible tablet prepared by the method is high in dissolution rate, good in biological availability, rapid in body distribution, stable in quality and good in mouth feeling. The preparation method is simple and feasible and suitable for industrial production.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of RALOXIFENE HCL dispersible tablet and preparation method thereof.
Background of invention
Since nearly over half a century, the quality of life problem that improves menopausal women more and more receives publicity, and hormone replacement therapy (HRT) has been widely used in climacteric and postmenopausal women.Although accumulated Observational data evidence for many years, in healthy menopausal women, use the pros and cons problem of HRT still among inquiring into.People, on the one hand in the more scientific more rational HRT scheme of further investigation, are applicable to the more preferably medicine of menopausal women on the one hand in searching.Selective estrogen receptor modulators (SERMS) is the medicine of a class synthetic, in some tissues, plays estrogen-like effects, plays the effect of estrogen antagonist sample in other tissues, is expected to for preventing and treating Menopausal diseases.Tamoxifen is first generation SERM, at mammary gland performance estrogenic antagonist, has been successfully used to the auxiliary treatment of breast carcinoma, but endometrium is had to stimulation.Raloxifene (raloxifene) is second filial generation SERM, to bone and Cardiovasculai appearance in patient estrogen-like effects, and at uterus and mammary gland performance estrogenic antagonist, has better potential applicability in clinical practice.
Osteoporosis chief reason is calcareous from skeletal tissue's loss, makes skeleton bulking, becomes fragile, dies down, thereby easily fracture.After women's menolipsis, may reduce because of estrogenic synthetic quantity, and osteoporosis easily occurs.The fracture of its Chang Bingfa vertebra, wrist and hip, and can increase and aggravation along with the age.
RALOXIFENE HCL (Raloxifene Hydrochloride, RH) be the non-body benzothiophene derivative that stays, 6-OH position is ER land, compared with E2, relative affinity is 0.34, hexahydropyridine side chain is estrogen antagonist region, and the structure of side chain and direction determine the tissue selectivity of raloxifene.Chemical name [6-hydroxyl-2-(4-hydroxy phenyl)-benzo [b] thiene-3-yl-] [4-[2-(1_ piperidyl) ethyoxyl] phenyl] ketone hydrochlorate, it is the selective estrogen receptor modulators (SERMs) of Lilly company of U.S. exploitation, obtain U.S. FDA approval in December, 1997, go on the market in January, 1998 in the U.S., obtaining European Union's approval the same year, is the medicine that is widely used at present prevention and treatment women's osteosporosis after menopause.
Raloxifene is a kind of active medicine simultaneously with estrogen excitement and estrogen antagonism, i.e. so-called selective estrogen receptor modulators.It has estrogenic character to skeleton, but in mammary gland and endometrium, has the effect of antagonist.There are some researches show that raloxifene reduces bone resorption, make lumbar vertebra and greater trochanter bone density increase by 2.4%, serum low-density LP cholesterol concentration declines, and without the side effect that irritates endometrium growth, occur without irregular vagina bleeding, the incidence rate of breast carcinoma also has no and increases, and has on the contrary the effect of its generation of prevention, and its safety is good.
Raloxifene belongs to second filial generation SERMs, different tissues is had to not same-action, and there is two-way function, osseous tissue and lipid metabolism are presented to the effect of similar estrogen agonist, and endometrium and mammary gland are brought into play antiestrogenic effect, be mainly used in preventing postmenopausal women's osteoporosis.Due to this tissue selectivity, in clinical practice, during in osteoporosis treatment, side effect or untoward reaction that this medicine produces are starkly lower than estrogen.
RALOXIFENE HCL dispersible tablet provided by the invention adopts acidulant by its parcel or wraps up mutually, thereby reach the effect of embedding, and through repetition test, each component screening is arrived to weight ratio of the present invention, the dispersible tablet steady quality obtaining, stripping is fast, in body, distribute rapidly, bioavailability is high, and dispersibility, disintegrative are good, can disintegrate in 1 minute complete, and this product is not containing surfactant, and can reduce stimulates body.
Summary of the invention
The invention provides a kind of new RALOXIFENE HCL dispersible tablet, is that the interpolation surfactant existing according to existing RALOXIFENE HCL ordinary tablet has the problems such as stimulation, bioavailability are not high to body.The invention provides a kind of RALOXIFENE HCL dispersible tablet, adopt acidulant by its parcel or parcel mutually, thereby reach the effect of embedding, and through repetition test by each component screening to weight ratio of the present invention, the dispersible tablet steady quality obtaining, stripping is fast, in body, distributes rapidly, and bioavailability is high, dispersibility, disintegrative are good, can disintegrate in 1 minute complete, and this product is containing surfactant, and can reduce stimulates body.
On the one hand, the invention provides a kind of RALOXIFENE HCL dispersible tablet, a kind of RALOXIFENE HCL dispersible tablet, it comprises as follows according to the component of percetage by weight meter: RALOXIFENE HCL
filler
disintegrating agent
acidulant
binding agent 0.1～15%, lubricant and fluidizer
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, it comprises as follows according to the component of percetage by weight meter: RALOXIFENE HCL 30%, filler 30%, disintegrating agent 25%, acidulant 10%, binding agent 2%, lubricant and fluidizer 3%.
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, wherein, described filler is a kind of in starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol, sorbitol or xylitol or their mixture.
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, wherein, described disintegrating agent is a kind of in microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, dried starch or their mixture.
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, wherein, described acidulant is a kind of in citric acid, lactic acid, acetic acid, ethanedioic acid, malonic acid, succinic acid, tartaric acid, adipic acid, malic acid, nicotinic acid, pectic acid, ascorbic acid, caffeic acid, fumaric acid, maleic acid, phosphoric acid solution, aspartic acid, glutamic acid, succinic acid or their mixture.
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, wherein, described binding agent is a kind of in hypromellose, sodium carboxymethyl cellulose, starch, pregelatinized Starch, polyvidone, gelatin, Polyethylene Glycol, ethanol, water or their mixture.
Some embodiments therein, RALOXIFENE HCL dispersible tablet of the present invention, wherein, described lubricant and fluidizer are a kind of of micropowder silica gel, magnesium stearate, silicon dioxide, Pulvis Talci, Polyethylene Glycol apoplexy due to endogenous wind or their mixture.
On the other hand, the invention provides a kind of preparation method of RALOXIFENE HCL dispersible tablet, it comprises the steps: that (1) sieve RALOXIFENE HCL and pharmaceutic adjuvant respectively; Binding agent be dissolved in concentration be 85% or following alcoholic solution or aqueous solution in after, then the acidulant of recipe quantity is dissolved in the solution containing binding agent, obtain acid solution; (2) RALOXIFENE HCL is mixed homogeneously with filler, disintegrating agent, fluidizer after adopting the made acid solution embedding of step (1), adds binding agent, mixes, and makes soft material; (3) by soft material mistake
mesh sieve, 40～60 DEG C are dry,
order granulate; (4) add lubricant, mix homogeneously; (5) tabletting, makes RALOXIFENE HCL dispersible tablet.
Some embodiments therein, the preparation method of RALOXIFENE HCL dispersible tablet of the present invention, wherein, described in step (2), be that RALOXIFENE HCL and acid solution are passed through to fluid bed embedding with sour embedding, or RALOXIFENE HCL is put into together with acid solution to colloid mill and sheared, drier.
The prescription ratio of RALOXIFENE HCL dispersible tablet of the present invention is not by teaching material or other reference material gained, but by the testing program gained conforming with the regulations in a large number, made dispersible tablet has carried out quality research, meets " Chinese Pharmacopoeia " 2010 editions two and make by oneself about dispersible tablet and other requirement of quality standard.In research, find the obvious existing conventional tablet of dissolution of technical solution of the present invention.
Compared with prior art, the present invention has following beneficial effect:
(1) RALOXIFENE HCL is made tablet formulation by the present invention, belongs to the whole world pioneering, can improve like this its bioavailability;
(2) the present invention granulates after adopting acidulant to process in the preparation of RALOXIFENE HCL dispersible tablet, greatly improves its bioavailability;
(3) tablet formulation that the present invention makes, compared with ordinary tablet, stripping is rapid, and disintegrative is good, and disintegrate completely in 1 minute absorbs soon, and bioavailability is high, stable in properties;
(4) tablet formulation that the present invention makes, does not use surface active agent solubilization in manufacturing process, reduce body is stimulated, and has reduced the untoward reaction of medicine, has increased patient's compliance.
Excipient of the present invention comprises, but be not limited to, ion-exchanger, aluminum, aluminium stearate, lecithin, serum albumin, as human albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, the partial glycerol ester admixture of saturated vegetable fatty acid, water, salt or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloid silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanoline, sugar, as lactose, dextrose plus saccharose, starch is as corn starch and potato starch, the derivant of cellulose and it is as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, natural gum powder, Fructus Hordei Germinatus, gelatin, Pulvis Talci, adjuvant is as cocoa butter and suppository wax, oily as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines, glycols compound, as propylene glycol and Polyethylene Glycol, esters is as ethyl oleate and ethyl laurate, agar, buffer agent is as magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating dress material, sweeting agent, flavoring agent and spice, antiseptic and antioxidant.
Pharmaceutical composition of the present invention can also optionally contain one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferred diluent is microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH101, Avicel PH102, Avicel PH103, Avicel PH105 and Avicel PH200 that FMC Corporation manufactures.
Pharmaceutical composition of the present invention can also optionally contain disintegrating agent.Disintegrating agent can be the one in several modified starches, modified cellulose polymer or polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also optionally contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprises sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and the sodium laurate mixing with stearate and Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.Neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
The present invention can also optionally join antioxidant in preparation, thereby gives its chemical stability.Antioxidant is selected from the extract of a-tocopherol, Y-tocopherol, S-tocopherol, tocopherol enrichment natural origin, sodium or calcium salt, the Vitamin C acyl cetylate of L-AA and it, amass wealth by heavy taxation propyl propionate, amass wealth by heavy taxation misery ester, amass wealth by heavy taxation sour dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet of preparing by compression method.Described tablet can carry out film with the mixture such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG), contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Or any other suitable instant-free coating agent.Coating provides taste masked and other stability to final tablet.What commercially available film provided for Colorcon is preparation mixture of powders
The present invention can also add sweeting agent and/or fumet.
Detailed description of the invention
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
Embodiment 1
RALOXIFENE HCL 120g
Lactose 120g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 4g
Micropowder silica gel 15g
Magnesium stearate 10g
Water 60g
95% ethanol 106g
Make 1000.
Preparation method:
Step 1: the RALOXIFENE HCL of having pulverized and pharmaceutic adjuvant are crossed respectively to 120 mesh sieves, and hydroxypropyl methylcellulose first uses hot water swelling, is stirred to dissolving, then adds ethanol, makes concentration of alcohol reach 70%.
Step 2: by recipe quantity, RALOXIFENE HCL, lactose, polyvinylpolypyrrolidone, micropowder silica gel are mixed to equal Uniform, add the solution of hypromellose described in step 1 to make soft material.
Step 3: made soft material in step 2 is crossed to 18 mesh sieves and granulate, 50 DEG C dry, and moisture is 2.6%, 18 mesh sieve granulate.
Step 4: mix homogeneously with magnesium stearate making granule in step 3.
Step 5: semi-finished product detect, and determine sheet weight, and tabletting, obtains RALOXIFENE HCL dispersible tablet.
Embodiment 1 dispersible tablet smooth in appearance, dispersibility meets relevant regulations, but dissolution is poor.
Embodiment 2
RALOXIFENE HCL 120g
Lactose 80g
Crospolyvinylpyrrolidone 14g
Carboxymethylstach sodium 20g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.5g
Water 60g
95% ethanol 60g
Make 1000.
Preparation method:
Step 1: the RALOXIFENE HCL of having pulverized and pharmaceutic adjuvant are crossed respectively to 120 mesh sieves, and hydroxypropyl methylcellulose first uses hot water swelling, is stirred to dissolving, then adds ethanol, makes concentration of alcohol reach 70%.Separately get above-mentioned hydroxypropyl methylcellulose solution 50g, add 60g water, add citric acid mix homogeneously.
Step 2: recipe quantity RALOXIFENE HCL and citric acid solution in step 1 are mixed homogeneously with recipe quantity lactose, crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel after fluid bed acid embedding, adds described in step 1, to remain hypromellose solution and make soft material.
Step 3: made soft material in step 2 is crossed to 16 mesh sieves and granulate, 50 DEG C dry, and moisture is 2.5%, 16 mesh sieve granulate.
Step 4: mix homogeneously with magnesium stearate making granule in step 3.
Step 5: semi-finished product detect, and determine sheet weight, and tabletting, obtains RALOXIFENE HCL dispersible tablet.
Embodiment 2 has added acidulant, has reduced the amount of disintegrating agent, and technique is optimized on the basis of embodiment 1, after first acidification, granulates again, finds dispersible tablet smooth in appearance, and dissolution is better, can disintegrate completely in 2min.
Embodiment 3
RALOXIFENE HCL 120g
Crospolyvinylpyrrolidone 40g
Carboxymethylstach sodium 40g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.5g
Water 80g
95% ethanol 44g
Make 1000.
Preparation method is with embodiment 2.
Implementing 3 increases crospolyvinylpyrrolidone, carboxymethylstarch sodium content, and dispersible tablet dispersibility meets 2010 editions pharmacopeia requirements, and dissolution is better.
Embodiment 4
It is identical that embodiment 4 and embodiment 3 write out a prescription, and selects different acidify embedding modes, and RALOXIFENE HCL and acidulant solution are put into colloid mill and sheared, then spraying is dry.The indices of dispersible tablet and the embodiment 3 made dispersible tablet there was no significant difference of writing out a prescription.
Embodiment 5
RALOXIFENE HCL 120g
Lactose 80g
Crospolyvinylpyrrolidone 30g
Carboxymethylstach sodium 50g
Starch 3.5g
Citric acid 70g
Malic acid 30g
Micropowder silica gel 15g
Magnesium stearate 7.5g
Water 94g
Make 1000.
Preparation method:
Step 1: the RALOXIFENE HCL of having pulverized and pharmaceutic adjuvant are crossed respectively to 120 mesh sieves, and starch adds water and makes starch slurry.Get the starch slurry 50g preparing, stir and add 94g water, then add citric acid, mix equal Uniform.
Step 2: recipe quantity RALOXIFENE HCL is mixed homogeneously with recipe quantity lactose, crospolyvinylpyrrolidone, carboxymethylstach sodium, micropowder silica gel, malic acid after fluid bed acid embedding with part acid solution in step 1, adds remaining starch slurry described in step 1 to make soft material.
Step 3: made soft material in step 2 is crossed to 24 mesh sieves and granulate, 60 DEG C dry, and moisture is 2.5%, 24 mesh sieve granulate.
Step 4: mix homogeneously with magnesium stearate making granule in step 3.
Step 5: semi-finished product detect, and determine sheet weight, and tabletting, obtains RALOXIFENE HCL dispersible tablet.
Embodiment 5 starch in replace hydroxypropyl methylcellulose, all the other are constant, find that made dispersible tablet hardness declines to some extent at equal pressure condition lower sheeting, but also meet 2010 editions pharmacopeia dispersible tablet standards.
Embodiment 6
RALOXIFENE HCL 120g
Starch 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3g
Succinic acid 100g
Micropowder silica gel 15g
Magnesium stearate 8g
Water 70g
95% ethanol 31g
Make 1000.
Preparation method is with embodiment 2.
Embodiment 6 changes filler, and replace lactose with starch, and succinic acid is replaced to citric acid, the made dispersible tablet there was no significant difference of dispersible tablet and embodiment 3, dispersibility and dissolution are all better.
Embodiment 7
RALOXIFENE HCL 120g
Icing Sugar 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Citric acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.5g
Water 70g
95% ethanol 31g
Make 1000.
Preparation method is with implementing 2.
Embodiment 7 changes filler, replaces lactose with Icing Sugar, all the other with embodiment 3 together, the made dispersible tablet there was no significant difference of dispersible tablet and embodiment 3, dispersibility and dissolution are all better.
Embodiment 8
RALOXIFENE HCL 120g
Starch 80g
Crospolyvinylpyrrolidone 25g
Carboxymethylstach sodium 50g
Hydroxypropyl methylcellulose 3.5g
Malic acid 100g
Micropowder silica gel 15g
Magnesium stearate 7.5g
Water 60g
95% ethanol 41g
Make 1000.
Preparation method is with embodiment 7.
The made dispersible tablet smooth in appearance of embodiment 8, dissolution are good, and dispersibility is slightly poorer than adopting the dispersible tablet of citric acid, but adopts the dispersible tablet of succinic acid to get well.
Biological test
(1) table 1 is for selling the dissolution comparative result of RALOXIFENE HCL ordinary tablet in RALOXIFENE HCL dispersible tablet and market.
With reference to dissolution method (2010 editions two annex XC bis-methods of Chinese Pharmacopoeia).
The comparison of ordinary tablet cumulative percentage dissolution is sold in table 1 RALOXIFENE HCL dispersible tablet and market
As can be seen from Table 1, the dissolution in vitro of RALOXIFENE HCL dispersible tablet in 10-30min is obviously better than ordinary tablet.
(2) RALOXIFENE HCL dispersible tablet assay
Measure with reference to high-efficient liquid phase technique (two annex VD of Chinese Pharmacopoeia version in 2010).
Table 2 RALOXIFENE HCL dispersible tablet assay
| Batch | RALOXIFENE HCL dispersible tablet content (%) |
| Batch 1 | 100.46 |
| Batches 2 | 100.32 |
| Batches 3 | 100.52 |
As can be seen from Table 2, the content of the RALOXIFENE HCL dispersible tablet requirement that conforms with the regulations.
(3) the quality stability comparison of RALOXIFENE HCL dispersible tablet
RALOXIFENE HCL dispersible tablet accelerated test: the RALOXIFENE HCL dispersible tablet of blister package is put under 2 DEG C of 40 DEG C of scholars of temperature, relative humidity 75% scholar's 5% condition and placed six months, outcome quality is stable, and indices is as shown in table 3.
Six months accelerated test testing results of table 3 RALOXIFENE HCL dispersible tablet
| Inspection batch | Outward appearance | Disintegration | Dispersing uniformity | Dissolution % | Content % |
| Batch 1 | Faint yellow smooth | 40 | Conform with the regulations | 100.02 | 100.00 |
| Batches 2 | Faint yellow smooth | 41 | Conform with the regulations | 100.26 | 100.10 |
| Batches 3 | Faint yellow smooth | 39 | Conform with the regulations | 99.97 | 99.97 |
Claims (9)
1. a RALOXIFENE HCL dispersible tablet, it comprises as follows according to the component of percetage by weight meter: RALOXIFENE HCL
filler
disintegrating agent
acidulant
binding agent 0.1～15%, lubricant and fluidizer
2. RALOXIFENE HCL dispersible tablet according to claim 1, it comprises as follows according to the component of percetage by weight meter: RALOXIFENE HCL 30%, filler 30%, disintegrating agent 25%, acidulant 10%, binding agent 2%, lubricant and fluidizer 3%.
3. RALOXIFENE HCL dispersible tablet according to claim 1 and 2, wherein, described filler is a kind of in starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol, sorbitol or xylitol or their mixture.
4. RALOXIFENE HCL dispersible tablet according to claim 1 and 2, wherein, described disintegrating agent is a kind of in microcrystalline Cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, crosslinked carboxymethyl fecula sodium, dried starch or their mixture.
5. RALOXIFENE HCL dispersible tablet according to claim 1 and 2, wherein, described acidulant is a kind of in citric acid, lactic acid, acetic acid, ethanedioic acid, malonic acid, succinic acid, tartaric acid, adipic acid, malic acid, nicotinic acid, pectic acid, ascorbic acid, caffeic acid, fumaric acid, maleic acid, phosphoric acid solution, aspartic acid, glutamic acid, succinic acid or their mixture.
6. RALOXIFENE HCL dispersible tablet according to claim 1 and 2, wherein, described binding agent is a kind of in hypromellose, sodium carboxymethyl cellulose, starch, pregelatinized Starch, polyvidone, gelatin, Polyethylene Glycol, ethanol, water or their mixture.
7. RALOXIFENE HCL dispersible tablet according to claim 1 and 2, wherein, described lubricant and fluidizer are a kind of of micropowder silica gel, magnesium stearate, silicon dioxide, Pulvis Talci, Polyethylene Glycol apoplexy due to endogenous wind or their mixture.
8. a preparation method for RALOXIFENE HCL dispersible tablet described in any one claim in claim 1-7, it comprises the steps: that (1) sieve RALOXIFENE HCL and pharmaceutic adjuvant respectively; Binding agent be dissolved in concentration be 85% or following alcoholic solution or aqueous solution in after, then the acidulant of recipe quantity is dissolved in the solution containing binding agent, obtain acid solution; (2) RALOXIFENE HCL is mixed homogeneously with filler, disintegrating agent, fluidizer after adopting the made acid solution embedding of step (1), adds binding agent, mixes, and makes soft material; (3) by soft material mistake
mesh sieve, 40～60 DEG C are dry,
order granulate; (4) add lubricant, mix homogeneously; (5) tabletting, makes RALOXIFENE HCL dispersible tablet.
9. the preparation method of RALOXIFENE HCL dispersible tablet according to claim 8, wherein, described in step (2), be that RALOXIFENE HCL and acid solution are passed through to fluid bed embedding with sour embedding, or RALOXIFENE HCL put into together with acid solution to colloid mill and sheared, drier.
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| CN113842369A (en) * | 2021-10-29 | 2021-12-28 | 澳美制药(苏州)有限公司 | Raloxifene hydrochloride tablet and preparation method thereof |
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