A kind of pharmaceutical composition and preparation method thereof containing cinacalcet hydrochlorideTechnical field
The present invention relates to field of medicine preparations, more particularly to one kind to contain cinacalcet hydrochloride pharmaceutical composition and its preparationMethod.
Background technique
The entitled N- ((1R) -1- (1- naphthalene) ethyl)-of cinacalcet hydrochloride (Cinacalcet Hydrochlorid) chemistry3- (3- (trifluoromethyl) phenyl) propyl- 1- amine hydrochlorate, structural formula are as follows:
Cinacalcet hydrochloride has a chiral centre, and active ingredient is R configuration.Cinacalcet hydrochloride is white or off-white colorNothing draw moist crystalline powder, have a stable crystal form at normal temperature.This product water-soluble is very low, but is highly soluble in certainA little organic solvents, such as methanol and ethyl alcohol.Simultaneously the granularity of raw material and crystal form on the dissolution of preparation and bioavilability influence compared withGreatly.
The Sensipar that cinacalcet hydrochloride is researched and developed by NPS Pharmaceuticals company, the U.S., on March 8th, 2004 FDARatify the cinacalcet hydrochloride listing of Amgen company (the license optionce of NPS Pharma Inc.'s product) production, trade nameSensipar；October in the same year is ratified to list in European Union；In January, 2008, the cinacalcet hydrochloride of consonance kylin company production is in dayThis listing, trade name REGPARA, specification 25mg, 75mg (in terms of cinacalcet).Cinacalcet hydrochloride is mainly used for treatingHypercalcinemia caused by the Secondary hyperparathyroidism or parathyroid carcinoma of nephrosis dialysis patient.
Secondary hyperparathyroidism (SHPT) is the common complication of chronic kidney disease (CKD), chronic kidneyDisease leads to patient's minerals and abnormal bone metabolism, and seriousness mainly leads to cardiovascular calcifications, pre- with the existence of dialysis patientIt is closely related afterwards.Activated vitamin D class drug usually occurs together high blood for clinical treatment secondary hyperparathyroidismCalcium, hyperphospheremia and increase the danger of cardiovascular calcifications.The invalid secondary hyperparathyroidism of most drug therapies is suffered fromPerson can only receive parathyroidectomy treatment.It is high that the appearance of calcium-sensing receptor agonist changes secondary parathyroid functionThe problem treated into disease drug, makes most severe secondary hyperparathyroidism patients avoid operation risk.
Cinacalcet is known as first drug in the new class compound of Sensipar, can activate the calcium in parathyroid glandReceptor, to reduce the secretion of parathormone (PTH).It adjusts the behavior of Parathyroid Calcium Receptor, by enhancing receptor pairThe sensibility of calcium level in blood flow reduces parathyroid hormone, calcium, phosphorus and calcium-phosphorus compound level.Cinacalcet can not onlyIt is horizontal that SHPT patients serum PTH, calcium, phosphorus and calcium-phosphorus product is enough effectively reduced, improves bone metabolism disturbance, prevents blood vessel and soft tissueCalcification, and tolerance is good, and adverse reaction is few.
Skilled person will appreciate that the water solubility of cinacalcet is poor, the solubility under neutral pH in water is less than about1μg/mL.If pH is in about 3 to 5 ranges, the solubility of cinacalcet is up to 1.6mg/mL, when pH is about 1, solubilityIt reduces to 0.1mg/mL.This limited solubility can reduce the available preparation of cinacalcet and the number that option is administered, can alsoCan lead to the bioavilability of cinacalcet reduces.Also there are relevant report (CN200480032795, CN in recent years200780037397, CN201110128239, CN20120385915, WO2013/107503), it discloses containing pharmaceutical activityThe composition and preparation method thereof of ingredient cinacalcet, in disclosed document, researcher is in order to overcome cinacalcet moltenThe low defect of out-degree, proposes various improvement projects, but still without effectively solving the problems, such as that cinacalcet dissolution rate is low.
Those skilled in the art pass through a large amount of experimental study, the table of specific components in cinacalcet hydrochloride compositionFace activating agent, such surfactant can spatially form stable hydrogen bond with bulk pharmaceutical chemicals, effectively in conjunction with bulk pharmaceutical chemicals, simultaneouslyContain a large amount of hydrophilic radical in the surfactant, such group can reduce the effect of drug interfacial tension, increase tabletWetability, make moisture that capillarity be borrowed to penetrate into label rapidly and play calving disaggregation, to greatly improve the stripping property of tablet,The contact angle between solid drugs and GI fluids can also be made to become smaller simultaneously, accelerate the absorption of drug that can effectively improve drug-elutingProperty, promote drug absorption.Such surfactant is added in cinacalcet hydrochloride pharmaceutical composition to improve drug dissolutionDocument have not been reported.
Invention technician uses the preparation process of wet granulation film coating on this basis, develops a kind of steadyQualitative cinacalcet hydrochloride piece strong, dissolution rate is fast, dissolution rate is high.
Summary of the invention
A kind of pharmaceutical composition containing cinacalcet hydrochloride, containing cinacalcet hydrochloride, other pharmaceutically may be used in compositionThe drug excipient of receiving wherein contains specific surfactant in composition.
Excipient in cinacalcet hydrochloride composition contains filler, adhesive, disintegrating agent, lubricant, by weight hundredDivide than calculating its content are as follows: filler 40% ~ 60%, disintegrating agent 2 ~ 11.6%, lubricant 0.6 ~ 6%.
In the composition surfactant can be selected from one of polysorbate, methylcellulose, polyvinyl alcohol, tween orSeveral, wherein the weight ratio of surfactant is 2% ~ 8%.
Surfactant is further selected from methylcellulose and polysorbate or polyvinyl alcohol, tween and poly- mountain in the compositionOne of pears alcohol or polyvinyl alcohol compositions.
Wherein the ratio of methylcellulose and polysorbate or polyvinyl alcohol is 6:1 ~ 1:6, tween and polysorbate or gathersThe ratio of vinyl alcohol is 7:1 ~ 1:2.2.
Wherein filler can be selected from one of microcrystalline cellulose, pregelatinized starch, lactose, mannitol, sucrose or a variety of.
Wherein filler is microcrystalline cellulose and pre-paying starch, and the two ratio is 1:2 ~ 2:1.
Wherein lubricant can be selected from one or more of magnesium stearate, superfine silica gel powder and talcum powder, preferably magnesium stearate.
Cinacalcet hydrochloride pharmaceutical composition uses wet granulation technology, and preparation process is as follows:
(1) it is pre-mixed: the cinacalcet hydrochloride of recipe quantity, filler, interior dosage disintegrating agent is uniformly mixed；
(2) will be above-mentioned uniformly mixed that adhesive softwood is added in supplementary material, 60 DEG C of bakings in baking oven are set in the granulation of 20 meshesIt is dry, cross 24 mesh sieves；
(3) outer dosage disintegrating agent and recipe quantity is added in above-mentioned resulting material lubricant, surfactant are uniformly mixed,Label is made in tabletting, controls label and hardness；
(4) film coating obtains cinacalcet hydrochloride piece.
In cinacalcet hydrochloride composition tablet preparation process, the hardness of cinacalcet hydrochloride piece is between 5 ~ 9kp modelIt encloses, the concentration of coating solution is 10% ~ 14%, coating to label weight gain 2% ~ 5%, and inlet air temperature is 50 DEG C ~ 70 when film coatingDEG C, the control of piece bed tempertaure is 35 DEG C ~ 50 DEG C.
Researcher of the present invention uses purified water as adhesive in production process, not only reduces the application of auxiliary material,The drug safety of drug is increased, while also simplifying production technology.By a large amount of screenings to filler, the present invention selects ratioThe microcrystalline cellulose and pregelatinized starch that example be 1:2 ~ 2:1 are filler, make made from the appearance of particle, mobility and can pressProperty is all significantly improved.In the dosage screening of disintegrating agent, by a large amount of experimental study, inventor passes through to disintegrating agentThe control of dosage, using the method for interior external feeding, obtained intragranular disintegration is fast with degree, effectively raises the dissolution speed of drugRate is not only made obtained coating tablet good appearance using film coating procedure, swallowed convenient for patient, while also acting flavoringEffect, mask the discomfort of patient caused by the bitter taste of raw material, greatly improve patient to the compliance of drug.It is makingSpecific surfactant is added during agent, not only increases the stability of drug, while accelerating the disintegration rate of drug,Effectively increase the dissolution rate of drug.
To sum up, the present invention provides a kind of pharmaceutical composition and its preparation process containing cinacalcet hydrochloride, use are wetPrepared by the technique of legal system grain film coating, simplified supplementary product kind, simplified production technology, reduced production cost.It is obtainedCinacalcet hydrochloride flake products dissolution rate is high, stability is good, effectively raises the vivo biodistribution availability of drug.
Detailed description of the invention
Fig. 1 is the dissolution drug release profiles figure of the cinacalcet piece of embodiment 1 ~ 6 and comparative example 1 ~ 5.
The present invention will be further described for embodiment, comparative example and Figure of description With reference to embodiment.
Specific embodiment
Embodiment 1
Preparation prescription: 25mg dosage
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 21.5 | 26.9% |
| Microcrystalline cellulose | 21.5 | 26.9% |
| Crospovidone-Nei Jia | 3.125 | 3.9% |
| Crospovidone-is additional | 1.875 | 2.3% |
| Purified water | 30.0 | -- |
| Methylcellulose | 3.0 | 3.7% |
| Polysorbate | 0.5 | 0.6% |
| Magnesium stearate | 1.0 | 1.3% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polysorbate, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 2
Preparation prescription: 25mg dosage
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 30.0 | 37.5% |
| Microcrystalline cellulose | 15.0 | 18.7% |
| Crospovidone-Nei Jia | 1.5 | 1.9% |
| Crospovidone-is additional | 1.5 | 1.9% |
| Purified water | 30.0 | -- |
| Methylcellulose | 0.5 | 0.6% |
| Polysorbate | 3.0 | 3.7% |
| Magnesium stearate | 1.0 | 1.3% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polysorbate, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 3
Preparation prescription:
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 15.0 | 18.7% |
| Microcrystalline cellulose | 30.0 | 37.5% |
| Crospovidone-Nei Jia | 2.0 | 2.5% |
| Crospovidone-is additional | 1.0 | 1.3% |
| Purified water | 30.0 | -- |
| Methylcellulose | 2.0 | 2.5% |
| Polyvinyl alcohol | 2.0 | 2.5% |
| Magnesium stearate | 0.5 | 0.6% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polyvinyl alcohol, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 4
Preparation prescription: 75mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 82.5 | 34.4% |
| Pregelatinized starch | 64.5 | 26.9% |
| Microcrystalline cellulose | 64.5 | 26.9% |
| Crospovidone-Nei Jia | 9.0 | 3.7% |
| Crospovidone-is additional | 6.0 | 2.5% |
| Purified water | 60.0 | -- |
| Methylcellulose | 7.5 | 3.1% |
| Polyvinyl alcohol | 3.0 | 1.2% |
| Magnesium stearate | 3.0 | 1.3% |
| Label | 240 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 60g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polyvinyl alcohol, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 5
Preparation prescription: 75mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 82.5 | 34.4% |
| Pregelatinized starch | 62.75 | 26.1% |
| Microcrystalline cellulose | 62.75 | 26.1% |
| Crospovidone-Nei Jia | 10.0 | 4.2% |
| Crospovidone-is additional | 10.0 | 4.2% |
| Purified water | 60.0 | -- |
| Tween | 2.5 | 1.0% |
| Polysorbate | 5.5 | 2.3% |
| Magnesium stearate | 4.0 | 1.7% |
| Label | 240 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 60g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added tween, polysorbate, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 6
Preparation prescription: 75mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 82.5 | 34.4% |
| Pregelatinized starch | 84.0 | 35.0% |
| Microcrystalline cellulose | 42.0 | 17.5% |
| Crospovidone-Nei Jia | 9.0 | 3.7% |
| Crospovidone-is additional | 6.0 | 2.5% |
| Purified water | 60.0 | -- |
| Tween | 9.0 | 3.8% |
| Polyvinyl alcohol | 6.0 | 2.5% |
| Magnesium stearate | 1.5 | 0.6% |
| Label | 240 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 60g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added tween, polyvinyl alcohol, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 7
Preparation prescription: 25mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 16.0 | 20.0% |
| Microcrystalline cellulose | 16.0 | 20.0% |
| Crospovidone-Nei Jia | 6.2 | 7.7% |
| Crospovidone-is additional | 3.1 | 3.9% |
| Purified water | 30.0 | -- |
| Tween | 5.6 | 7.0% |
| Polysorbate | 0.8 | 1.0% |
| Magnesium stearate | 4.8 | 6.0% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added tween, polysorbate, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Embodiment 8
Preparation prescription: 75mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 82.5 | 34.4% |
| Pregelatinized starch | 96.0 | 40.0% |
| Microcrystalline cellulose | 48.0 | 20.0% |
| Crospovidone-Nei Jia | 2.4 | 1.0% |
| Crospovidone-is additional | 2.4 | 1.0% |
| Purified water | 60.0 | -- |
| Tween | 2.4 | 1.0% |
| Polyvinyl alcohol | 2.4 | 1.0% |
| Magnesium stearate | 3.9 | 1.6% |
| Label | 240 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 60g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added tween, polyvinyl alcohol, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Comparative example 1
Preparation prescription:
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 21.5 | 26.9% |
| Microcrystalline cellulose | 21.5 | 26.9% |
| Crospovidone-Nei Jia | 5.0 | 6.2% |
| Crospovidone-is additional | -- | -- |
| Purified water | 30.0 | -- |
| Methylcellulose | 3.5 | 4.3% |
| Magnesium stearate | 1.0 | 1.3% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshesMethylcellulose is added in 24 mesh sieves, magnesium stearate is uniformly mixed, tabletting, obtained label.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Comparative example 2
Preparation prescription:
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 27.5 | 34.4% |
| Pregelatinized starch | 21.5 | 26.9% |
| Microcrystalline cellulose | 21.5 | 26.9% |
| Crospovidone-Nei Jia | 4.4 | 5.5% |
| Crospovidone-is additional | 2.6 | 3.2 |
| Purified water | 30.0 | -- |
| Methylcellulose | 0.2 | 0.2% |
| Polysorbate | 1.3 | 1.2% |
| Magnesium stearate | 1.0 | 1.3% |
| Label | 80 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 30g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polysorbate, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Comparative example 3
Preparation prescription: 75mg
| Ingredient | Dosage (g) | Specific gravity % |
| Cinacalcet hydrochloride | 82.5 | 34.4% |
| Pregelatinized starch | 62.75 | 26.1% |
| Microcrystalline cellulose | 62.75 | 26.1% |
| Crospovidone-Nei Jia | 5.3 | 2.2% |
| Crospovidone-is additional | 2.7 | 1.1% |
| Purified water | 60.0 | -- |
| Methylcellulose | 19.0 | 8.0% |
| Polyvinyl alcohol | 2.0 | 0.8 |
| Magnesium stearate | 3.0 | 1.3% |
| Label | 240 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, the poly- dimension of interior plus crosslinking are weighed by recipe quantityKetone is uniformly mixed, and 60g purified water is added as adhesive softwood, 55 ~ 65 DEG C of drying, mistake in baking oven are set in the granulation of 20 meshes24 mesh sieves are added methylcellulose, polyvinyl alcohol, magnesium stearate and are uniformly mixed, and label is made in tabletting.
Coating: label is put into coating pan, starts seed-coating machine, air blast adds by the coating solution that compound concentration is 10% ~ 14%Then heat sprays into prepared film coating liquid using spray gun, until weight gain 2 ~ 5%, inlet air temperature is controlled at 60 DEG C ± 10DEG C, piece bed tempertaure is controlled at 38 DEG C ~ 45 DEG C.
Comparative example 4 is prepared according to CN200480032795
Preparation prescription: 30mg
| Ingredient | Dosage (g) | Specific gravity %(w/w) |
| Cinacalcet hydrochloride | 33.06 | 18.367% |
| Pregelatinized starch | 60.08 | 33.378% |
| Microcrystalline cellulose | 12.02 | 6.678% |
| Polyvinylpyrrolidone | 3.68 | 2.044% |
| Crospovidone | 2.22 | 1.233% |
| Pure water | -- | -- |
| Microcrystalline cellulose | 61.74 | 34.3% |
| Colloidal anhydrous silica | 0.9 | 0.5% |
| Magnesium stearate | 0.6 | 0.5% |
| Crospovidone | 5.4 | 3.0% |
| Label | 180 | 100% |
Label preparation: cinacalcet hydrochloride, microcrystalline cellulose, pregelatinized starch, polyvinylpyrrolidine are weighed by recipe quantityKetone, crospovidone are uniformly mixed, and the granulation of 30% ~ 36% w/w purified water is added, and after completing wet pulverizing technique, gained particle is mixedIt closes object and sets 75 DEG C of ± 5 DEG C of drying in baking oven.Dry granulate mixture and microcrystalline cellulose, colloidal anhydrous silica and crosslinkingPovidone premixing uniformly, adds magnesium stearate and is uniformly mixed, and label is made in tabletting.
Coating: preparing coating solution, label be put into coating pan, starts seed-coating machine, then blast heating is sprayed using spray gunEnter prepared film coating liquid.
Comparative example 5
Preparation prescription: 90mg
| Ingredient | Dosage (g) | Specific gravity %(w/w) |
| Cinacalcet hydrochloride | 99 | 18.33% |
| Pregelatinized starch | 110 | 20.37% |
| Microcrystalline cellulose | 299 | 55.37% |
| Polyvinylpyrrolidone | 11 | 2.04% |
| Pure water | -- | -- |
| Magnesium stearate | 5 | 0.93% |
| Crospovidone | 16 | 2.96% |
| Label | 540 | 100% |
Cinacalcet hydrochloride: (1) being micronized by preparation method, claims to match, and it is micro- at 5 ~ 15 μm to obtain average grain diameter for sievingGrain, prepares certain density binder solution, is then uniformly mixed cinacalcet hydrochloride with filler, disintegrating agent；
(2) binder is added in the powder of uniformly mixed main ingredient and excipient, granulation, whole grain, at a certain temperatureIt is dry to be met the requirements to moisture to get dry whole grain is arrived；
(3) disintegrating agent, lubricant is then added, measures granule content, selects the punch die tabletting of certain model, obtains hydrochloric acid westThat card plug piece finished product；
(4) coating material is then used, is coated, obtains finished product.
Embodiment 9
Test example 1: end product properties measurement
Above embodiments are measured to the projects such as the moisture of particle and appearance, hardness, the thickness of tablet respectively, as a result such asUnder:
The preparation nature measurement result of table 1 embodiment 1 ~ 8 and comparative example 1 ~ 5
The results show that preparation prepared by the present invention it is beautiful, without breakage, uniform color, while compared with comparative example preparation, thisInvention preparation water content is low, hardness is uniform, thickness is moderate.
Embodiment 10: the measurement of dissolution rate
It is investigated referring to 2010 editions two annex X C the second methods of dissolution method of Chinese Pharmacopoeia, dissolution medium temperatureIt is 37 DEG C, revolving speed 50r/min, sample time 0,5,10,15,30,45,60min.Using high effective liquid chromatography for measuring drugContent calculates dissolution rate.
It is medium with pH=4.5, as a result as follows:
The preparation dissolution determination result of 2 embodiment 1 ~ 8 of table and comparative example 1 ~ 5
| Time (min) dissolution rate % | 0 | 5 | 10 | 15 | 30 | 45 | 60 |
| Embodiment 1 | 0.00 | 48.90 | 75.21 | 85.46 | 90.56 | 95.31 | 98.73 |
| Embodiment 2 | 0.00 | 47.65 | 74.28 | 84.98 | 91.24 | 94.76 | 97.89 |
| Embodiment 3 | 0.00 | 48.56 | 76.21 | 86.14 | 92.14 | 95.22 | 99.01 |
| Embodiment 4 | 0.00 | 45.12 | 71.20 | 81.45 | 88.12 | 93.74 | 95.42 |
| Embodiment 5 | 0.00 | 44.82 | 70.25 | 80.12 | 86.97 | 93.15 | 96.03 |
| Embodiment 6 | 0.00 | 46.20 | 72.46 | 83.90 | 90.06 | 94.04 | 96.89 |
| Embodiment 7 | 0.00 | 45.11 | 71.42 | 80.13 | 87.51 | 93.61 | 95.86 |
| Embodiment 8 | 0.00 | 45.21 | 70.09 | 81.24 | 85.94 | 94.12 | 95.64 |
| Comparative example 1 | 0.00 | 40.01 | 64.84 | 72.09 | 81.27 | 85.45 | 88.03 |
| Comparative example 2 | 0.00 | 41.78 | 65.08 | 73.15 | 82.34 | 86.24 | 89.06 |
| Comparative example 3 | 0.00 | 37.58 | 59.64 | 69.29 | 79.28 | 81.46 | 85.07 |
| Comparative example 4 | 0.00 | 38.19 | 64.66 | 68.26 | 78.75 | 82.48 | 84.92 |
| Comparative example 5 | 0.00 | 33.84 | 57.25 | 65.30 | 76.40 | 84.90 | 87.20 |
Percentage sign is the dissolution percentage of Etoricoxib piece in table 2.Known to table 2 and Fig. 1 west prepared by the present invention thatCard plug piece, disintegration rate is fast, is hereafter able to maintain stable drug release profiles, and drug concentration reaches stable state,
Intracorporal bioavilability can be improved, compared with original grinds the product that medicine and comparative example obtain, drug-eluting is releasedMedicine degree is significantly increased.
The present invention is described in detail above by reference to specific embodiment, to those skilled in the art, it should be understood that, above-mentioned specific embodiment is not construed as limiting the scope of the invention.Therefore, do not depart from spirit of that invention andEmbodiment of the present invention can be made various changes and modifications in the case where range.