CN108078934B - Ziprasidone hydrochloride solid dispersible tablet and hot-melt extrusion method thereof - Google Patents
Ziprasidone hydrochloride solid dispersible tablet and hot-melt extrusion method thereof Download PDFInfo
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- CN108078934B CN108078934B CN201711433563.XA CN201711433563A CN108078934B CN 108078934 B CN108078934 B CN 108078934B CN 201711433563 A CN201711433563 A CN 201711433563A CN 108078934 B CN108078934 B CN 108078934B
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Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a ziprasidone hydrochloride solid dispersible tablet and a hot-melt extrusion method thereof. Ziprasidone hydrochloride is taken as a main component, one or two mixed carriers of copovidone S630(Copovidones S630) or hydroxypropyl methylcellulose acetate succinate (HPMCAS-HF) are taken as a basis, a coating material is added, and the glass transition temperature of an extrusion mixture can be reduced. And adding a surfactant. The ziprasidone hydrochloride solid dispersible tablet is prepared by uniformly mixing the above raw and auxiliary materials by using a three-dimensional mixer, extruding the mixture at high temperature by using a hot-melt extruder, crushing the mixture into powder with a proper size, and then fully and uniformly mixing the powder with a fixed amount of filler, disintegrant and lubricant for direct tabletting. The ziprasidone hydrochloride solid dispersible tablet prepared by the invention solves the problem of poor in-vitro dissolution of ziprasidone hydrochloride, improves the bioavailability of the ziprasidone hydrochloride in an empty stomach and finally improves the treatment effect of the medicine.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a hot-melt extrusion method for preparing ziprasidone hydrochloride solid dispersion.
Background
Ziprasidone hydrochloride (formula one) is one of the second generation atypical antipsychotics. Is clinically used for treating schizophrenia, manic episodes of bilateral affective disorders and polar phase surge symptoms of schizophrenia patients. Unlike typical antipsychotics, studies have shown that it is affected by antagonism of the D2, 5-HT2A, 5-HT2C and 5-HT1 receptors. Due to its higher affinity for the 5-HT2A receptor, the chance of an extrapyramidal system response to ESP is greatly reduced.
The method comprises the following steps: ziprasidone hydrochloride.
However, ziprasidone hydrochloride belongs to class II in the classification system of biopharmaceutics, is a drug with poor water solubility, and has low solubility, so that the oral bioavailability is reduced. Common preparation technologies for solving the problem of poor water solubility of insoluble drugs include nanocrystalline, micronization, anti-solvent method for preparing solid dispersion and the like. The nano crystallization technology can obviously improve the water solubility of the ziprasidone hydrochloride and improve the bioavailability. However, it is difficult to recrystallize it due to its poor stability, resulting in a short storage time. Meanwhile, the industrial mass production is difficult, and the method is only suitable for small-batch production in a laboratory. The micronization technology increases the surface free energy of the medicine, so that the micro powder has a spontaneous aggregation phenomenon and the property is unstable and reliable. The conventional methods for preparing solid dispersions include solvent method, melting method, spray drying method, etc. However, the traditional methods have the defects of complex preparation process, multiple limiting conditions, difficult process control, difficult removal of impurities in solvent residues and the like, so that the technologies are difficult to popularize generally. The application of hot melt extrusion technology in the field of pharmaceutical preparations has attracted extensive attention both at home and abroad in recent years. The preparation method has the advantages of simple preparation process, controllable process, no introduction of organic impurities, high stability of the solid dispersion and the like, and more importantly, the preparation method can be applied to actual batch-type industrial production. Dexamethasone, ritonavir, fenofibrate, azithromycin and the like are utilized in the solid dispersion medicine on the market by using a hot-melt extrusion technology. The disadvantage is firstly that drugs with poor thermal stability cannot be applied by the technology, and the application range is limited. And secondly, the pilot scale production has large batch size and high experimental cost.
Ziprasidone hydrochloride is white to light pink powder, has a melting point of more than 300 ℃, is slightly soluble in methanol and trichloromethane, and is insoluble in water and absolute ethyl alcohol. Its water solubility is very low, about 0.3ug/ml, its pKa is 6, and its solubility shows a clear pH dependence.
The invention aims at the application of hot-melt extrusion technology of ziprasidone hydrochloride, Copovidone S630 or HPMCAS-HF is used as a hot-melt extrusion carrier of the drug, and the two carriers are high molecular polymers which are commonly used in the hot-melt extrusion technology and have excellent performance, so that the drug dissolution and absorption of the drug in the gastrointestinal tract are increased. Improving the bioavailability of the medicine.
Disclosure of Invention
In order to improve the defects and shortcomings of the prior ziprasidone hydrochloride pharmaceutical preparation technology, the invention aims to: the preparation method adopts a hot-melt extrusion technology, takes Copovidone S630 or HPMCAS-HF as a carrier, adds other functional carriers, fully mixes the mixture, and obviously improves the solubility, the in vitro dissolution and the bioavailability of the ziprasidone hydrochloride under various pH conditions after being processed by a hot-melt extrusion process.
The technical scheme of the invention is as follows:
a ziprasidone hydrochloride solid dispersible tablet is prepared by extruding ziprasidone hydrochloride, a carrier and functional auxiliary materials by a hot melting extruder, and then crushing; and after fully mixing with other auxiliary materials again, directly tabletting by using a single-punch tablet press to obtain the ziprasidone hydrochloride solid dispersible tablet, wherein the ziprasidone hydrochloride solid dispersible tablet comprises the following components in percentage by mass:
the carrier is copovidone S630(Copovidones S630) or HPMCAS.
The functional auxiliary materials comprise coating materials and surfactants.
The other auxiliary materials comprise a filling agent, a lubricating agent and a disintegrating agent.
The coating material is one of Ewing L100, Ewing S100, Ewing FS30D, Ewing E100, and Ewing EPO.
The surfactant is one of poloxamer 188, PVP-K30, soluplus and sodium dodecyl sulfate.
The filler is one of lactose, cyclodextrin, pregelatinized starch, microcrystalline cellulose and mannitol.
The lubricant is one of polyethylene glycol, magnesium stearate, starch, calcium stearate and sodium stearyl fumarate.
A ziprasidone hydrochloride solid dispersible tablet is prepared by crushing a hot-melt extrusion, sieving with a 60-80 mesh sieve, mixing with a filler, a disintegrating agent and a lubricant uniformly, and directly tabletting to obtain the tablet with the hardness of 3Kg-4Kg, and the method comprises the following steps:
1) respectively sieving the ziprasidone hydrochloride raw material drug, the carrier and the functional auxiliary material by a sieve of 60-100 meshes, and then uniformly mixing the materials by using a three-dimensional mixer to prepare a physical mixture, wherein the carrier is copovidone S630 or HPMCAS.
2) Preheating a hot-melt extruder for 30min, setting the hot-melt extrusion temperature to be 140-185 ℃, uniformly adding the physical mixture into a filling hopper of the extruder after the temperature reaches the set temperature, melting by a screw of the extruder, uniformly mixing, extruding and extruding the strip-shaped solid.
3) And after the extruded strips are cooled, crushing the strips into particles with proper sizes by using a crusher, and sieving the particles by using a 40-80-mesh sieve to obtain the ziprasidone hydrochloride solid dispersion.
4) And (3) fully and uniformly mixing the prepared ziprasidone hydrochloride solid dispersion with the filler, the disintegrant and the lubricant, and directly tabletting by using a single-punch tablet press to obtain the ziprasidone hydrochloride solid dispersion.
Preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is copovidone S630 single carrier, and the weight ratio of the ziprasidone hydrochloride to the copovidone S630 in the formula is 1: 2-5.
Further preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is copovidone S630 single carrier, and the weight ratio of ziprasidone hydrochloride to copovidone S630 in the formula is 1: 2-3.
Preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is HPMCAS-HF single carrier, and the weight ratio of the ziprasidone hydrochloride to the HPMCAS-HF in the formula is 1: 2-5.
Further preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is HPMCAS-HF single carrier, and the weight ratio of the ziprasidone hydrochloride to the HPMCAS-HF in the formula is 1: 2-3.
Preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is a mixed carrier consisting of copovidone S630 and HPMCAS, the weight ratio of the ziprasidone hydrochloride to the Copovidone S630 in the mixed carrier formula is 1:1-2, and the weight ratio of the ziprasidone hydrochloride to the HPMCAS-HF is 1: 1-2.
Further preferably, the carrier of the ziprasidone hydrochloride solid dispersible tablet is a mixed carrier consisting of copovidone S630 and HPMCAS, the weight ratio of ziprasidone hydrochloride to Copovidone S630 in the mixed carrier formula is 1:1-1.5, and the weight ratio of ziprasidone hydrochloride to HPMCAS-HF is 1: 1-1.5. The results of the carrier film formation experiments are shown in table 1.
Table 1:
as a result: through film forming investigation of different proportions of four carriers, we can see that the two carriers of Eudragit EPO and PVPK30 have poor film forming property and obvious granular sensation, and do not consider the two carriers as hot-melt extrusion carriers of ziprasidone hydrochloride, while the film forming properties of Plasdone-S630 and HPMCAS-HF are better, the film forming properties of Plasdone-S630 in all proportions are good, and only slight granular sensation on the surface of the film appears in the proportion of 1: 1; the proportion of the HPMCAS-HF to the HPMCAS-HF is 1:1, and the proportion of the dosage of the Plasdone-S630, the HPMCAS-HF and the medicament is controlled to be 1.5-3: within 1.
The ziprasidone hydrochloride solid dispersible tablet comprises pharmaceutical grade auxiliary materials including a filler, a disintegrating agent and a lubricant surfactant, wherein the filler is selected from one or more of lactose, cyclodextrin, pregelatinized starch, microcrystalline cellulose and mannitol. The filler is preferably microcrystalline cellulose. The disintegrating agent is selected from one or more of crospovidone, microcrystalline cellulose, croscarmellose sodium and alginic acid. The disintegrant is preferably croscarmellose sodium.
The lubricant is selected from one or more of polyethylene glycol, magnesium stearate, starch, calcium stearate and sodium stearyl fumarate. The lubricant is preferably magnesium stearate.
The invention utilizes the hot-melt extrusion technology and the hot-melt extrusion mixed carrier to prepare the ziprasidone hydrochloride solid dispersion which has stable property, good dissolution and no solvent residue and can be industrially produced. Compared with solid dispersion prepared by other techniques, the method has a plurality of advantages. The amount of the added carrier in the prescription directly influences the dissolution and the stability of the medicine. The optimum ratio of carriers is determined by the degree of dissolution of the drug and the amount of impurities introduced as a measure. The use of two carriers in combination can increase the cumulative dissolution rate of the medicine by using Copovidone S630, and can obtain a stable solid dispersible tablet which is convenient to store by using HPMCAS-HF.
Has the advantages that:
compared with the prior preparation technology, the ziprasidone hydrochloride solid dispersion prepared by the hot-melt extrusion method has the following advantages: (1) the hot-melt carrier HPMCAS-HF has obvious retention effect on ziprasidone hydrochloride in gastrointestinal tract, increases the release time of the drug, and is equivalent to increase the AUC of the drug0-∞The curative effect is prolonged, the bioavailability under the empty stomach is improved, and the curative effect of the medicine is finally improved. (2) The production process is simple, the operation is easy, the reproducibility is good, and the amount of introduced impurities is small when the process is properly controlled. (3) High stability under normal storage conditions, and no recrystallization of amorphous drug. (4) The in vivo and in vitro performance is improved (5), and the mass production and the amplified reproduction can be realized.
Drawings
FIG. 1 is an infrared spectrum of a ziprasidone hydrochloride drug substance (A), Copovidone-S630(B), HPMCAS-HF (C), a ziprasidone hydrochloride physical mixture (D) and a ziprasidone hydrochloride solid dispersion formula (E) in example 8; infrared spectrometry wavelength range: 500-4000cm-1；
FIG. 2 is a graph of the cumulative dissolution profiles of the ziprasidone hydrochloride solid dispersible tablet formulation in four dissolution media in example 10; the four media are respectively hydrochloric acid medium with pH1.2, acetic acid-sodium acetate medium with pH4.5, PBS medium with pH6.8 and water medium;
FIG. 3: cumulative dissolution profiles of ziprasidone hydrochloride marketed capsules in four dissolution media;
FIG. 4: the stability of the solid dispersion formulation of ziprasidone hydrochloride in example 8 was measured by the cumulative dissolution profile in pbs ph6.8 medium for the sample at the beginning of extrusion and after six months of standing under high temperature and high humidity conditions; the high-temperature and high-humidity conditions are as follows: 60 ℃ and 75% relative humidity.
FIG. 5 stability of the solid dispersion formulation of ziprasidone hydrochloride from example 2, measured as cumulative dissolution profile in pH6.8PBS medium for the initial sample extruded and after six months of exposure to high temperature and high humidity conditions; the high-temperature and high-humidity conditions are as follows: 60 ℃ and 75% relative humidity.
FIG. 6: ziprasidone hydrochloride solid dispersible tablets (ZH-SD, example 12) and ziprasidone hydrochloride commercial capsules (Zeldox) are compared in the fasting condition dosing profiles in beagle dogs.
Detailed Description
The invention is further described with reference to the following figures and embodiments. It should be understood that the drawings and examples below are for purposes of illustrating the invention only and are not limiting.
Soluplus is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, available from BASF chemical Limited company;
eudragit EPO is Utex EPO, purchased from winning Industrial group;
CopovidoneS630 was purchased from bekkaido chemical industries;
hypromellose acetate succinate (HPMCAS-HF) was purchased from bekka chemical industries co.
Preheating a hot-melting extruder for 30min, setting the hot-melting extrusion temperature to be 140-185 ℃, setting the rotating speed of a screw to be 45-75 rpm, uniformly adding the physical mixture into a filling hopper of the extruder after the temperature reaches the set temperature, melting by the screw of the extruder, uniformly mixing, extruding, and extruding strip-shaped solid;
example 1
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 2
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 3
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 4
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 5
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 6
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 7
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 8
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 9
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 10
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 11
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melting extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filler microcrystalline cellulose, a disintegrant croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 12
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filling agent microcrystalline cellulose, a disintegrating agent croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion again, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 13
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filling agent microcrystalline cellulose, a disintegrating agent croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion again, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 14
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filling agent microcrystalline cellulose, a disintegrating agent croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion again, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 15
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filling agent microcrystalline cellulose, a disintegrating agent croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion again, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
Example 16
Prescription:
the preparation method comprises the following steps: fully and uniformly mixing ziprasidone hydrochloride, HPMCAS-HF, Copovidone S630, Eudragit EPO and Soluplus, extruding a strip-shaped object by a double-screw hot-melt extruder, cooling and solidifying, crushing the extruded strip-shaped object for 90S to prepare a solid dispersion, adding a filling agent microcrystalline cellulose, a disintegrating agent croscarmellose sodium and a lubricant magnesium stearate, uniformly mixing the solid dispersion and the solid dispersion again, and directly performing powder tabletting by using a single-punch tablet press, wherein the weight of the tablet is within 3-4 kg, and the disintegration time limit is within 1-2 min.
In vitro dissolution test conditions were as follows:
dissolution test conditions:
selection of four dissolution media:
hydrochloric acid at ph 1.2: adding 1000ml of water into 9ml of hydrochloric acid, and shaking up.
Acetic acid-sodium acetate buffer at ph 4.5: taking 18g of sodium acetate, adding 9.8ml of glacial acetic acid, and then adding water to dilute to 1000 ml.
phosphate buffer at ph 6.8: taking 250ml of 0.2mol/l potassium dihydrogen phosphate solution, adding 118ml of 0.2mol/l sodium hydroxide solution, diluting with water to 1000ml, and shaking up to obtain the final product.
The water is deionized water.
Selection of reference formulation: pharmaceutical preparation of medicine "Zhuoledine
Setting parameters of a dissolution instrument:
temperature: 37 ℃, rotation speed: 75rpm, medium volume: 900ml, total sampling time: the time of 120min is not needed,
sampling time points are as follows: 5min, 10min, 15min, 20min, 25min, 30min, 40min, 60min, 90min, 120 min.
In example 8, the infrared spectra of ziprasidone hydrochloride bulk drug (A), Copovidone-S630(B), HPMCAS-HF (C), ziprasidone hydrochloride physical mixture (D) and ziprasidone hydrochloride solid dispersion formula (E) are shown. As in fig. 1.
Infrared spectrometry wavelength range in example 8: 500-4000cm-1. In FIG. 1, (A) is the infrared spectrum of the ziprasidone hydrochloride drug, and the characteristic peaks are 3413cm-1(N-H), 1713cm-1 (C = O) and 738cm-1(Ar-Cl), and (B) and (C) are the infrared spectra of Copovidone S630 and HPMCAS-HF, respectively. The characteristic peaks corresponding to 3413cm-1(N-H) and 1713cm-1 (C = O) of the amide bond of ziprasidone hydrochloride disappear in the infrared spectrum (E) of the solid dispersion of ziprasidone hydrochloride, and the characteristic peaks corresponding to 3500cm-1 and 1000cm-1 of the lactam group of Copovidone S630 and 1100cm-1 of HPMCAS-HF disappear in the spectrum (E) of FIG. 1. This indicates that intermolecular force is generated between the drug and the carrier during the hot-melt extrusion process, and the amino group and the hydroxyl group thereof act to form hydrogen bonds, which makes the drug stably and uniformly dispersed in the carrier.
Cumulative dissolution profiles of ziprasidone hydrochloride solid dispersible tablet formulation and commercially available capsules in four dissolution media of example 10 are shown in figures 2 and 3. The four media for determining the cumulative dissolution curve are hydrochloric acid medium of pH1.2, acetic acid-sodium acetate medium of pH4.5, PBS medium of pH6.8 and water medium, respectively. The results in fig. 2 show that the cumulative dissolution rates of the self-grinding ziprasidone hydrochloride solid dispersible tablet in four dissolution media are 86%, 89%, 95% and 97%, respectively, which are significantly better than the dissolution rate of the commercially available capsule shown in fig. 3, and the cumulative dissolution rates correspond to: 59%, 79%, 54% and 74%.
In example 8, the stability of the ziprasidone hydrochloride solid dispersion mixed carrier formulation is examined, and the cumulative dissolution profile of the sample at the beginning of extrusion and the sample after being placed for six months under the high temperature and high humidity condition in the PBS medium with pH6.8 is measured, and the stability of the ziprasidone hydrochloride solid dispersion mixed carrier formulation is examined, wherein the high temperature and high humidity condition is as follows: 60 ℃ and 75% relative humidity, the results are shown in FIG. 4. As can be seen from fig. 4, the f2 factor of the cumulative release curve and the release curve of the original sample after six months storage under high temperature and high humidity conditions was 68.8, which is greater than 50. This indicates that the release behavior is substantially consistent and also laterally reflects the stability effect of the carrier on the drug. As a comparison of the cumulative release rates before and after 6 months for the copovidone single carrier formulation in example 2 in fig. 5, it can be clearly seen from the figure that the cumulative release rate of 120min after 6 months for the copovidone single carrier is less than 65%, and the f2 factor of the two release curves is 24.1, less than 50. This indicates that the release behavior is not consistent, the drug is not stable in a single carrier, and problems such as drug degradation or recrystallization occur.
In example 12, a comparison of the pharmacokinetics of ziprasidone hydrochloride solid dispersible tablets and commercially available capsules in beagle dogs was examined. As can be seen in FIG. 6, C for the self-ground ziprasidone solid dispersion is shown under fasting conditionsmaxAnd AUC is obviously higher than that of the commercially available capsule, and the HPMCAS-HF increases the retention time and solubility of the drug in intestinal tract with relatively high pH, so that the area under the drug time curve of ziprasidone hydrochloride within 4-12h is obviously larger than that of the commercially available capsule, and the bioavailability of the drug in the fasting state is improved.
Claims (7)
1. A ziprasidone hydrochloride solid dispersible tablet is characterized in that: the solid dispersible tablet is prepared by extruding ziprasidone hydrochloride, a carrier and functional auxiliary materials by a hot melting extruder and then crushing; and after fully mixing with other auxiliary materials again, directly tabletting by using a single-punch tablet press to obtain the ziprasidone hydrochloride solid dispersible tablet, wherein the ziprasidone hydrochloride solid dispersible tablet comprises the following components in percentage by mass:
12% -15% of ziprasidone hydrochloride, 20% -25% of a carrier, 18% -20% of a functional auxiliary material and 45% -50% of other auxiliary materials;
the carrier is copovidone S630 or HPMCAS; when the carrier is copovidone S630 single carrier, the weight ratio of ziprasidone hydrochloride to copovidone S630 in the formula is 1: 2-5; when the carrier is HPMCAS-HF single carrier, the weight ratio of ziprasidone hydrochloride to HPMCAS-HF in the formula is 1: 2-5; when the carrier is a mixed carrier consisting of copovidone S630 and HPMCAS, the weight ratio of ziprasidone hydrochloride to Copovidone S630 in the mixed carrier formula is 1:1-2, and the weight ratio of ziprasidone hydrochloride to HPMCAS-HF is 1: 1-2;
the functional auxiliary materials comprise coating materials and surfactants.
2. The ziprasidone hydrochloride solid dispersible tablet of claim 1, wherein: the other auxiliary materials comprise a filling agent, a lubricating agent and a disintegrating agent.
3. The ziprasidone hydrochloride solid dispersible tablet of claim 1, wherein: the coating material is one of Ewing L100, Ewing S100, Ewing FS30D, Ewing E100, and Ewing EPO.
4. The ziprasidone hydrochloride solid dispersible tablet of claim 1, wherein: the surfactant is one of poloxamer 188, PVP-K30, soluplus and sodium dodecyl sulfate.
5. The ziprasidone hydrochloride solid dispersible tablet of claim 2, wherein: the method is characterized in that: the filler is one of lactose, cyclodextrin, pregelatinized starch, microcrystalline cellulose and mannitol.
6. The ziprasidone hydrochloride solid dispersible tablet of claim 2, wherein: the lubricant is one of polyethylene glycol, magnesium stearate, starch, calcium stearate and sodium stearyl fumarate.
7. A hot-melt extrusion process of ziprasidone hydrochloride solid dispersible tablets according to any one of claims 1 to 6, characterized by comprising the following steps:
1) respectively sieving the raw materials, the carrier and the functional auxiliary materials with a 60-100-mesh sieve, and uniformly mixing by using a three-dimensional mixer to prepare a physical mixture;
2) preheating a hot-melt extruder for 30min, setting the hot-melt extrusion temperature to be 140-185 ℃, setting the rotating speed of a screw to be 45-75 rpm, uniformly adding the physical mixture into a filling hopper of the extruder after the temperature reaches the set temperature, and melting, uniformly mixing and extruding strip-shaped solid substances through the screw of the extruder;
3) after the extruded strips are cooled, crushing the strips into particles with proper sizes by using a crusher, and sieving the particles by using a 40-80-mesh sieve to obtain ziprasidone hydrochloride solid dispersoid;
4) and (3) fully and uniformly mixing the prepared ziprasidone hydrochloride solid dispersion with other auxiliary materials, and directly tabletting by using a single-punch tablet press to prepare the ziprasidone hydrochloride solid dispersible tablet.
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| CN1951373A (en) * | 2006-10-26 | 2007-04-25 | 徐竹青 | Method for preparing nimodipine dispersible tablet with high dissolution |
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| EP1745774A2 (en) * | 1997-08-11 | 2007-01-24 | Pfizer Products Inc. | Solid pharmaceutical dispersions with enhanced bioavailability |
| CN1951373A (en) * | 2006-10-26 | 2007-04-25 | 徐竹青 | Method for preparing nimodipine dispersible tablet with high dissolution |
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Effective date of registration: 20211209 Address after: 210003 No. 26, Majia street, Gulou District, Nanjing, Jiangsu Patentee after: Jiangsu Provincial Institute of Materia Medica Co.,Ltd. Address before: 211816 Puzhu South Road, Pukou District, Nanjing, Jiangsu Province, No. 30 Patentee before: NANJING University OF TECHNOLOGY |