CN102579408A - Doxycycline hydrochloride dual-release preparation and preparation method thereof - Google Patents
Doxycycline hydrochloride dual-release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN102579408A CN102579408A CN2012100723622A CN201210072362A CN102579408A CN 102579408 A CN102579408 A CN 102579408A CN 2012100723622 A CN2012100723622 A CN 2012100723622A CN 201210072362 A CN201210072362 A CN 201210072362A CN 102579408 A CN102579408 A CN 102579408A
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- China
- Prior art keywords
- release
- pellet
- quick
- doxycycline hydrochloride
- delayed
- 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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- PTNZGHXUZDHMIQ-UHFFFAOYSA-N 4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC=C2C(C)C(C(O)C3C(C(O)=C(C(N)=O)C(=O)C3N(C)C)(O)C3=O)C3=C(O)C2=C1O PTNZGHXUZDHMIQ-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 229960004082 doxycycline hydrochloride Drugs 0.000 title claims abstract description 78
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Abstract
The invention belongs to the field of pharmaceutical science, and particularly relates to a doxycycline hydrochloride dual-release preparation and a preparation method thereof. The preparation consists of micropills with different release performance, namely the preparation is formed by mixing 50 to 85 weight percent of quick-release micropill and 50 to 15 weight percent of sustained-release micropill. The preparation method comprises the following steps of: preparing micropill cores according to a formula, and preparing the quick-release micropills by using the micropill cores; preparing the sustained-release micropills by using the quick-release micropills; and filling the quick-release micropills and the sustained-release micropills into capsules in a ratio to obtain doxycycline hydrochloride dual-release capsules. Pharmacokinetic experiments in the dual-release capsule bodies indicate that medicines in the doxycycline hydrochloride dual-release capsules can be released twice when the doxycycline hydrochloride dual-release capsules are taken once every day, and the concentration of two-time peaks is close; the concentration peak of medicines in blood plasma is reduced by a dual-release model, the possibility of side effect is reduced, and the compliance of the administration of patients is improved; and due to the adoption of a new formula and a new process, the difference among batches is reduced, and the stability of samples is improved, so the doxycycline hydrochloride dual-release preparation is suitable for industrial production.
Description
Technical Field
The invention relates to a doxycycline hydrochloride preparation, in particular to a doxycycline hydrochloride dual-release preparation and a preparation method thereof.
Technical Field
Doxycycline hydrochloride is a tetracycline antibiotic with the chemical name 6-methyl-4- (dimethylamino) -3,5,10,12,12 a-pentahydroxy-1, 11-dioxo-1, 4,4a,5,5a,6,11,12 a-octahydro-2-tetracene carboxamide hydrochloride hemiethanol hemihydrate of the formula: C22H25ClN2O8. As C2H6O. As Beh 2O, has a molecular weight of 512.94, and the doxycycline hydrochloride is pale yellow or yellow crystalline powder, odorless and bitter. It is easily soluble in water or methanol, slightly soluble in ethanol or acetone, and hardly soluble in chloroform.
Doxycycline hydrochloride is a tetracycline antibiotic and has been used clinically for many years. The pharmacological action mechanism of the tetracycline antibacterial peptide is similar to that of tetracycline, the tetracycline antibacterial peptide mainly has an antibacterial effect by combining a bacterial membrane with target protein, the antibacterial spectrum is basically the same as that of tetracycline and oxytetracycline, the in-vivo antibacterial activity and the in-vitro antibacterial activity of the tetracycline antibacterial peptide are both stronger than those of tetracycline, and the tetracycline antibacterial peptide is good in oral absorption. The traditional Chinese medicine composition is mainly used for treating upper respiratory tract infection, tonsillitis, biliary tract infection, lymphadenitis, cellulitis, senile chronic bronchitis and the like caused by sensitive gram-positive bacteria and gram-negative bacteria, and is also used for treating typhus, incised notoriosis, mycoplasma pneumonia and the like.
Due to the high lipid solubility and the high penetration to tissues of doxycycline, a common preparation with the traditional specification (50 mg and 100 mg) as a broad-spectrum antibacterial agent can cause a plurality of side effects. For example, gastrointestinal reactions such as nausea, vomiting, abdominal pain, diarrhea, etc. may be caused; can reduce normal flora in human body, and cause vitamin deficiency, fungus reproduction, xerostomia, pharyngitis, angular stomatitis, glossitis, etc. Therefore, there is a need to develop a new product to overcome the above problems.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: in order to reduce the toxic and side effect of doxycycline hydrochloride and improve the medication compliance, a double-release capsule preparation taking doxycycline hydrochloride as a main drug and a preparation method thereof are provided.
The technical scheme of the invention is as follows:
the doxycycline hyclate double-release capsule has the performance of releasing the medicine twice, comprises a quick-release pellet part and a delayed-release pellet part, and is prepared from doxycycline hyclate, a filling agent, a binding agent, a film-forming material, an opacifier, a delayed-release material, a plasticizer, an anti-sticking agent, a solubilizer and the like.
Wherein,
(a) the quick release pellets and the delayed release pellets have the same pellet core, the drug-carrying pellets are prepared by doxycycline hydrochloride, a filling agent, an adhesive and the like through an extrusion and rounding method, and the pellets with the diameter controlled between 0.3 and 1.5mm, preferably 0.6 +/-0.1 mm are used as the pellet cores for preparing the quick release pellets or the delayed release pellets.
(b) The quick-release pellet is prepared from a drug-carrying pellet and an isolation layer formula under certain process conditions. The auxiliary materials of the isolating layer are one or more film-forming coating materials, and the auxiliary materials of the plasticizer and the opacifier are added. The prepared pellet has smooth and round surface and good stability and fluidity.
(c) The delayed release pellet is coated with delayed release material comprising one or several of ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin, ethyl cellulose water dispersion, hydroxypropyl cellulose, hydroxyethyl cellulose acetate, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose succinate, and has antiadherent, plasticizer and solubilizer added to raise the stability of the coating liquid and make the preparation process smooth.
Compared with the intermediate-speed release part of the doxycycline hydrochloride double-release capsule, the weight percentage of each component in the quick-release pellet is as follows: 10-40% of doxycycline hydrochloride, 30-80% of filler, 0.5-15% of adhesive, 0-15% of isolating layer film-forming material, 0-5% of plasticizer A and 0-10% of opacifier;
compared with the delayed release part in the doxycycline hydrochloride double-release capsule, the weight percentage of each component in the delayed release pellet is as follows: 10-40% of doxycycline hydrochloride, 20-70% of filler, 0.5-15% of adhesive, 0-15% of isolating layer film-forming material, 0-5% of plasticizer A, 0-10% of opacifier, 0.5-30% of delayed release material, 0.3-5% of plasticizer B, 0.5-10% of anti-sticking agent and 0.1-3% of solubilizer.
The quick-release pellets or the delayed-release pellets are skeleton pellets, and the effective component is doxycycline hydrochloride;
the filler in the quick-release pellet or the delayed-release pellet is one or more of sucrose, lactose, mannitol, starch, microcrystalline cellulose, algal polysaccharide and chitosan,
the binder in the quick-release pellet or the delayed-release pellet is one or more of water, anhydrous ethanol, mixed solution of water and ethanol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone, and sodium carboxymethylcellulose,
the film forming material of the isolation layer in the quick release pellet or the delayed release pellet is one or more of Opadry I, Opadry II, Opadry AMB, Opadry MP, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone and polyvinyl alcohol,
the plasticizer A in the quick-release pellet or the delayed-release pellet is one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol and propylene glycol,
the opacifier in the quick release pellets or the delayed release pellets is one or more of titanium dioxide, iron oxide red and iron oxide yellow,
the delayed release material is one or more of ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin, ethyl cellulose water dispersion, hydroxypropyl cellulose, hydroxyethyl cellulose acetate, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, YAKEYI, hydroxypropyl methylcellulose succinate, polylactic acid, and palm wax,
the plasticizer B is one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, glyceryl stearate, tributyl citrate, diethyl succinate, rectified coconut oil and propylene glycol,
the antisticking agent is one or more of talcum powder, colloidal silicon dioxide, magnesium stearate, calcium stearate, magnesium silicate and glyceryl monostearate,
the solubilizer is one or more of sodium dodecyl sulfate, sorbitan fatty acid ester, poloxamer, polysorbate-20, polysorbate-60 and polysorbate-80.
Wherein the filler in the quick release pellet is microcrystalline cellulose, the binder is hydroxypropyl methylcellulose solution, the film forming material of the isolation layer is hydroxypropyl methylcellulose and hydroxypropyl cellulose, the plasticizer A is polyethylene glycol, and the opacifier is titanium dioxide.
The filler in the delayed-release pellet is preferably microcrystalline cellulose, the binder is preferably hydroxypropyl methylcellulose solution, the film-forming material of the isolation layer is preferably hydroxypropyl methylcellulose and hydroxypropyl cellulose, the plasticizer A is preferably polyethylene glycol, the opacifier is preferably titanium dioxide, the delayed-release material is preferably polyacrylic acid resin, the plasticizer B is preferably polyethylene glycol and triethyl citrate, the anti-sticking agent is preferably talcum powder, and the solubilizer is preferably polysorbate-80.
The doxycycline hyclate double-release capsule has the following excellent weight percentage:
quick-release pellets: 15-25% of doxycycline hydrochloride, 65-75% of filler microcrystalline cellulose, 1-2% of adhesive hydroxypropyl methyl cellulose, 5-6% of isolation layer film forming material hydroxypropyl methyl cellulose, 0.5-1.5% of plasticizer A polyethylene glycol and 2-3% of opacifier titanium dioxide;
delayed release pellets: 10-20% of doxycycline hydrochloride, 55-65% of filler microcrystalline cellulose, 0.5-1.5% of adhesive hydroxypropyl methyl cellulose, 4-5% of isolating layer film-forming material hydroxypropyl methyl cellulose, 0.5-1.5% of plasticizer A polyethylene glycol, 2-3% of opacifier titanium dioxide, 9-11% of delayed release material polyacrylic resin, 0.5-1.5% of plasticizer B polyethylene glycol, 4-6% of anti-sticking agent talcum powder and 800.1-0.6% of solubilizer polysorbate.
The doxycycline hyclate double-release capsule is a pellet form filled in the capsule into pellets, wherein the pellets comprise a pellet core and a coating, and the preparation method of the pellet core comprises the following steps:
pulverizing the medicine and filler to a certain particle size range, sieving with 80-100 mesh sieve, mixing in a stirring mixer, adding binder to obtain soft material, and making into drug-loaded pellet with uniform particle size by extrusion and spheronization method, wherein the pellet particle size is controlled within 0.3-1.5mm according to the length of the cylinder formed by extrusion, and preferably controlled within 0.6 + -0.1 mm.
The doxycycline hyclate double-release capsule of the invention has the following coating method:
the preferable coating material is coated by a fluidized bed or a coating pan, the coating material is atomized under a proper pressure and then sprayed into the fluidized bed, and the coating material forms a coating film at a certain temperature and is attached to the pellets. The pellet can obtain the drug-carrying pellet with uniform coating at a certain fluidization speed. After the pellets are placed at a certain temperature, the stability of the coating can be improved, and the influence of the pellets on external environmental factors such as illumination, high temperature and humidity can be reduced.
The doxycycline hyclate double-release capsule contains quick-release pellets and delayed-release pellets in a mass ratio of 9: 1 to 1: 1, and the preferred mass ratio is 5: 2.
The effective dosage of doxycycline hydrochloride in the dual-release preparation is 20-100mg, preferably 40mg, so as to adapt to the use of people with different weights, and different specifications of the doxycycline hydrochloride have similar or same in-vivo pharmacokinetic characteristics corresponding to different people.
The doxycycline hyclate double-release capsule of the invention comprises 50-85% of intermediate-speed release pellets and 50-15% of delayed-release pellets by weight.
The invention has the following positive beneficial effects:
(1) according to the doxycycline hydrochloride double-release capsule, the opacifier is added into the isolation layer, so that the stability of the photosensitive medicament doxycycline is improved; the delayed release layer adopts an optimized formula, and the dosage of coating materials is greatly reduced. In-vitro release rate tests of the preparation show that the preparation has stable and uniform release performance, and the relative standard error of the batch release rate is less than 3 percent, which is shown in figure 1. The therapeutic effect of the preparation is equivalent to that of a common preparation with the same specification taken every time, the peak value of plasma drug concentration can be stably controlled, the side effect and addiction brought by the drug are reduced, the bioavailability of the drug is improved, and the medication compliance of patients is improved.
(2) The preparation process of the double-release capsule is simplified, the yield reaches 90-100% by adopting a low-temperature extrusion rounding machine and a fluidized bed process, the production efficiency is high, and the loss of doxycycline hydrochloride raw material medicine in the preparation process can be reduced by adopting an extrusion rounding method compared with a laminated medicine application method. The invention can finish 10000-30000 units of scale production in laboratory scale, and can prepare 20-100mg doxycycline hydrochloride double-release capsules with different specifications to meet the requirements of different people.
(3) The in vivo pharmacokinetic experiment of the double-release capsule shows that the double-release capsule can generate drug release twice after being taken once a day, wherein the quick-release part generates release in a short time, and the concentration of the plasma drug reaches a first peak value; after about 2.5 h, a second release was initiated, resulting in a second peak of plasma drug concentration, with similar concentrations at the two peaks. In vivo pharmacokinetics research shows that the preparation has equivalent bioavailability with common preparation, does not generate the problem of reducing bioavailability due to partial delayed release, reduces the peak value of drug concentration in blood plasma and the possibility of generating side effect by using a double-release model, and improves the medication compliance of patients by only taking the preparation once every day.
(4) The double-release capsule disclosed by the invention is accelerated in stability research, the character stability, the drug content and related substances are in a controllable range within 6 months, and the double-release capsule is good in performance and suitable for industrial production through the research of influence factor tests under the conditions of high temperature, high humidity and strong light irradiation in the stability research. See tables 1-3.
Drawings
Figure 1 in vitro release profile of three batches of doxycycline hydrochloride dual release formulations of the invention.
Detailed Description
The following are specific embodiments of the present invention, and the examples are intended to further illustrate the invention and not to limit it. All technical solutions equivalent to the present invention belong to the protection scope of the present invention.
Examples
1
Doxycycline hydrochloride double-release capsule and preparation method thereof
Firstly preparing a drug-containing pellet core according to a formula, preparing quick-release pellets from the pellet core, preparing delayed-release pellets from the quick-release pellets, and finally respectively filling the quick-release pellets and the delayed-release pellets into capsules according to a proportion to obtain the doxycycline hydrochloride double-release capsule.
(1) Process for preparing pellet cores
The pill core formula comprises: 640g of microcrystalline cellulose, 177g of doxycycline hydrochloride and 640g of 2% (w/w) hydroxypropyl methyl cellulose solution.
The preparation process comprises the following steps: the doxycycline hydrochloride and the microcrystalline cellulose of the filler are crushed to a certain particle size range, the mixture is mixed in a stirring mixer for 30 minutes after passing through a 80-mesh screen, and a 2% hydroxypropyl methyl cellulose solution is added to prepare a soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, placing the soft material into a low-temperature high-pressure extruder after 10min, selecting a sieve plate with a sieve pore of 0.9-1.0mm, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with moderate length, rounding in a rounding machine at the speed of 1800rpm for 10min to form drug-loaded pellets with uniform particle size, and controlling the particle size of the pellets after drying to be 0.4-1.0mm according to the length of a sheared cylinder. Taking the yield of the coating process as an evaluation index, preferentially coating the pellets with the particle size of 0.6 +/-0.1 mm, placing the pellets in an oven for drying at 50 ℃ for 15h, taking the pellets with a 20-40-mesh sieve for uniformity and water content inspection, and taking the pellets as drug-loaded pellet cores for standby after qualification.
(2) Process for preparing quick-release pellets
The quick-release pellet formula comprises the following components: 800g of drug-loaded pill core, 48g of hydroxypropyl methylcellulose, 24g of titanium dioxide, 8g of polyethylene glycol and 720g of deionized water.
The preparation process comprises the following steps: adding hydroxypropyl methylcellulose and polyethylene glycol into deionized water under stirring, dissolving to clarify, adding titanium dioxide, stirring for 1 hr, and sieving with 40 mesh sieve to obtain coating solution.
Placing 800g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 55 ℃, and adjusting the inlet air volume to about 70m3*h-1The prepared isolation layer coating liquid is sprayed at the bottom of 2ml/m by a peristaltic pumpAdding in into an atomization chamber at a flow rate of 1.4bar for atomization coating, gradually increasing the liquid supply rate to 8ml/min until the coating solution is coated, and drying in a blast oven at 60 deg.C for 2 hr to obtain the quick-release pellet.
(3) Delayed release pellet process
The formulation of the delayed-release pellet comprises: 400g of quick-release pellets, 50g of polyacrylic resin, 5g of polyethylene glycol, 22.5g of talcum powder, 2.5g of polysorbate and 800ml of 95% (mass ratio) ethanol.
The preparation process comprises the following steps: adding 95% ethanol into polyacrylic acid resin, polyethylene glycol and polysorbate under stirring, dissolving to clear, adding pulvis Talci, stirring for 1 hr, and sieving with 40 mesh sieve to obtain delayed release coating solution.
Placing the quick-release pellet in fluidized bed, adjusting air inlet temperature to 50 deg.C, and drying air flow rate to about 80m3*h-1Taking the coating liquid, pumping into an atomizing chamber for atomizing coating (the atomizing pressure is 1.8bar) by a peristaltic pump in a bottom spraying mode of 1.5ml/min, gradually increasing the liquid supply rate to 8ml/min until the coating liquid is coated, putting into a blast oven for drying at 50 ℃ for 2h after the coating is finished, selecting pellets which are sieved by a sieve of 18-40 meshes, checking the properties and the release degree, and obtaining the delayed release pellets after the pellets are qualified.
(4) Doxycycline hydrochloride double-release capsule filling
The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 5: 2, and then the doxycycline hydrochloride double-release capsules are obtained.
Through calculation, the doxycycline hydrochloride dual-release capsule in the embodiment comprises the following components in percentage by weight:
quick-release pellets: 19.4% of doxycycline hydrochloride, 70.1% of filler, 1.4% of adhesive, 5.5% of isolating layer film-forming material, 0.9% of plasticizer A and 2.7% of opacifier;
delayed release pellets: 16.2 percent of doxycycline hydrochloride, 58.4 percent of filling agent, 1.2 percent of adhesive, 4.5 percent of isolating layer film forming material, 0.8 percent of plasticizer A, 2.3 percent of opacifier, 10.5 percent of delayed release material, 1.1 percent of plasticizer B, 4.7 percent of anti-sticking agent and 0.4 percent of solubilizer.
The doxycycline hyclate double-release capsule obtained in the embodiment contains the doxycycline hyclate with the total effective dose of 40mg (calculated by anhydrous and ethanol-free doxycycline), and is suitable for inflammatory skin lesions such as rosacea, rosacea and the like; it is administered orally once a day, 1 granule each time, with an empty stomach in the morning, preferably 1-2 hr before meal.
Examples
2
Doxycycline hydrochloride double-release capsule and preparation method thereof
(1) The pill core formula comprises: 640g of microcrystalline cellulose, 177g of doxycycline hydrochloride and 640g of 2% (w/w) povidone solution.
The preparation process comprises the following steps: the doxycycline hydrochloride and the microcrystalline cellulose are crushed, pass through a 80-mesh screen and are mixed in a stirring mixer for 30 minutes, and then the povidone solution is added to prepare a soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, placing the soft material into a low-temperature high-pressure extruder after 10min, passing through a sieve plate with sieve pores of 0.9-1.0mm, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with moderate length, rolling the cylindrical soft material in a rolling machine at the speed of 1800rpm for 10min to form drug-loaded pellets with uniform particle size, and controlling the particle size of the dried pellets within the range of 0.4-1.0mm according to the length of a sheared cylinder. Taking the yield of the coating process as an evaluation index, preferentially coating the pellets with the particle size of 0.6 +/-0.1 mm, drying the pellets in an oven at 50 ℃ for 15 hours, checking the uniformity and the water content of the pellets with a 20-40-mesh sieve, and taking the pellets as drug-loaded pellet cores for standby after the pellets are qualified.
(2) The quick-release pellet formula comprises the following components: 800g of drug-loaded pill core, 80g of Opadry I and 720g of deionized water.
The preparation process comprises the following steps: adding Opadry I into deionized water under stirring, stirring for 1 hr, and sieving with 40 mesh sieve to obtain coatingAnd (4) liquid. Placing 800g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 60 ℃, and the inlet air volume to about 70m3*h-1The prepared coating liquid of the isolating layer is firstly added into an atomizing chamber for atomizing coating at the flow rate of 1.5ml/min by a peristaltic pump in a bottom spraying mode, the atomizing pressure is 1.6bar, and the liquid supply rate is gradually increased to 7ml/min until the coating liquid is completely coated. And (3) after the coating is finished, placing the coated pellets in a blast oven to dry for 2 hours at the temperature of 60 ℃ to obtain the quick-release pellets.
(3) The formulation of the delayed-release pellet comprises: 400g of quick-release pellets, 160g of Yake MP and 640g of deionized water.
The preparation process comprises the following steps: adding Jack-adapted MP into deionized water under stirring, stirring for 1h, and sieving with 40 mesh sieve to obtain
The delayed release layer is coated with the coating liquid. Placing the quick-release pellet in fluidized bed, adjusting inlet air temperature to 50 deg.C, and drying air flow rate to about 85m3*h-1Taking the coating liquid, pumping into an atomizing chamber by a peristaltic pump in a bottom spraying mode of 1.5ml/min for atomizing coating (the atomizing pressure is 1.6bar), gradually increasing the liquid supply rate to 7ml/min until the coating liquid is coated, putting into a blast oven for drying at 50 ℃ for 2h after the coating is finished, selecting pellets which are sieved by a sieve of 18-40 meshes, checking the properties and the release degree, and obtaining the delayed release pellets after the pellets are qualified.
(4) Doxycycline hydrochloride double-release capsule filling
The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 15: 7, and then the doxycycline hydrochloride double-release capsules are obtained.
Examples
3
Doxycycline hydrochloride double-release capsule and preparation method thereof
(1) The pill core formula comprises: 640g of microcrystalline cellulose, 177g of doxycycline hydrochloride, 20g of crospovidone and 640g of 2% hydroxypropyl methyl cellulose aqueous solution.
The preparation process comprises the following steps: the doxycycline hydrochloride, the microcrystalline cellulose and the crospovidone are crushed, sieved by a sieve of 80 meshes, mixed in a stirring mixer for 30 minutes, and added with 640g of hydroxypropyl methylcellulose aqueous solution to prepare a soft material. Opening a low-temperature refrigerator, controlling the temperature at 4-15 ℃, placing the soft material into a low-temperature high-pressure extruder after 10min, passing through sieve holes of a sieve plate with the size of 0.9-1.0mm, adjusting the extrusion speed to 40rpm to form a cylindrical soft material with moderate length, rolling the cylindrical soft material in a rolling machine at the speed of 1800rpm for 10min to form drug-loaded pellets with uniform particle size, and controlling the particle size of the pellets after drying to be 0.4-1.0mm according to the length of a sheared cylinder. Taking the yield of the coating process as an evaluation index, preferably coating pellets with the particle size of 0.6 +/-0.1 mm, placing the pellets in an oven for drying at 50 ℃ for 15h, checking the uniformity and the water content of the pellets with a 20-40-mesh sieve, and taking the pellets as drug-loaded pellet cores for standby after the pellets are qualified.
(2) The quick-release pellet formula comprises the following components:
800g of drug-loaded pill core, 120g of hydroxypropyl methylcellulose and 2000g of deionized water.
The preparation process comprises the following steps: taking deionized water according to the prescription amount, adding hydroxypropyl methylcellulose under the stirring state to obtain the coating liquid of the isolation layer. Placing 800g of pellet core of the drug-loaded pellet into a fluidized bed, adjusting the temperature of inlet air to 45 ℃, and adjusting the inlet air volume to about 80m3*h-1Adding the prepared coating solution of the isolation layer into an atomizing chamber by a peristaltic pump in a bottom spraying mode at the flow rate of 1.5ml/min for atomizing and coating, wherein the atomizing pressure is 1.8bar, gradually increasing the liquid supply rate to 10ml/min until the coating solution is coated, and placing the coated coating solution into a blast oven to dry for 2 hours at the temperature of 60 ℃ after the coating is finished to obtain the quick-release pellets.
(3) The formulation of the delayed-release pellet comprises: 400g of quick-release pellets and 160g of ethyl cellulose aqueous dispersion with the solid content of 15 percent.
The preparation process comprises the following steps: placing the quick-release pellet in fluidized bed, adjusting air inlet temperature to 45 deg.C, and dry air flow rate to about 80m3*h-1Taking ethyl cellulose water dispersion, adding water to dilute into suspension with solid content of 15%, and using peristaltic pump to make bottomPumping into an atomizing chamber for atomizing coating (the atomizing pressure is 1.6bar) in a spraying mode of 1.5ml/min, gradually increasing the liquid supply rate to 5ml/min until the coating liquid is coated, placing the coating liquid in a blast oven for curing for 15h at the temperature of 45 ℃ after the coating is finished, selecting pellets which are sieved by a sieve of 18-40 meshes, checking the properties and the release degree, and obtaining the delayed release pellets after the pellets are qualified.
(4) Doxycycline hydrochloride double-release capsule filling
The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 25: 9, and then the doxycycline hydrochloride double-release capsules are obtained.
Examples
4
Doxycycline hydrochloride double-release capsule and preparation method thereof
(1) The pill core formula comprises: 760g of sugar pills (30-35 meshes), 200g of doxycycline hydrochloride, 40g of hydroxypropyl methylcellulose and 1000g of deionized water.
The preparation process comprises the following steps: taking deionized water with the prescription amount, adding hydroxypropyl methylcellulose under stirring, dissolving to clarify, adding doxycycline hydrochloride, stirring for 1h, and sieving with 40 mesh sieve to obtain medicine layer coating solution.
Placing 760g blank pellet core of the sugar pellet into a fluidized bed, adjusting inlet air temperature to 50 deg.C, and adjusting inlet air volume to about 60m3*h-1Adding the prepared coating solution of the drug layer into an atomizing chamber by a peristaltic pump in a bottom spraying mode at a flow rate of 2ml/min for atomizing coating, wherein the atomizing pressure is 1.0bar, gradually increasing the liquid supply rate to 6ml/min until the coating solution is coated, and placing the coating solution in a blast oven for drying at 60 ℃ for 2h after the coating is finished to obtain the drug layer pill core.
(2) The quick-release pellet formula comprises the following components: 1000g of drug-loaded pill core, 100g of Opadry beige and 900g of deionized water.
The preparation process comprises the following steps: adding the Opadry beige into deionized water according to the prescription amount under the stirring state, continuously stirring for 1h, and sieving by a 40-mesh sieve to obtain the coating liquid of the isolating layer. Taking the drug-loaded pelletPlacing the core in fluidized bed, adjusting inlet air temperature to 60 deg.C, and adjusting inlet air volume to about 70m3*h-1Adding the prepared coating solution of the isolation layer into an atomizing chamber by a peristaltic pump in a bottom spraying mode at the flow rate of 1.5ml/min for atomizing and coating, wherein the atomizing pressure is 1.6bar, gradually increasing the liquid supply rate to 7ml/min until the coating solution is coated, and placing the coating solution in a blast oven for drying at 60 ℃ for 2 hours after the coating is finished to obtain the quick-release pellets.
(3) The formulation of the delayed-release pellet comprises: 400g of quick-release pellet, 30 g of Eudragit L30D-55200 g, 9g of triethyl citrate and talcum powder
31g and deionized water 200 ml.
The preparation process comprises the following steps: adding the aqueous polyacrylic resin dispersion Eudragit L30D-55 (aqueous polyacrylic resin dispersion, enteric coating layer slow-release material), triethyl citrate and talcum powder into deionized water according to the prescription amount under stirring, continuously stirring for 1h, and sieving with a 40-mesh sieve to obtain the delayed-release coating liquid. Placing the quick-release pellet in fluidized bed, adjusting inlet air temperature to 40 deg.C, and drying air flow rate to about 70m3*h-1Taking the coating liquid, pumping into an atomizing chamber by a peristaltic pump in a bottom spraying mode at 2ml/min for atomizing coating (the atomizing pressure is 1.6bar), gradually increasing the liquid supply rate to 5ml/min until the coating liquid is coated, placing in a blast oven at 50 ℃ for drying for 2h after the coating is finished, selecting pellets which are sieved by a sieve of 18-40 meshes, checking the properties and the release degree, and obtaining the delayed release pellets after the coating is qualified.
(4) Doxycycline hydrochloride double-release capsule filling
The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 12: 5, and then the doxycycline hydrochloride double-release capsules are obtained.
Examples of the experiments
5
: degree of release test
The pellets prepared in example 1 were used as test samples for the release test, as follows:
taking a test sample, carrying out a test according to a release rate determination method (second method of appendix X D of second part of Chinese pharmacopoeia 2010 version), adopting a dissolution rate determination device, rotating at 75rpm and 37 ℃, wherein a release medium is shown below, the detection method is an ultraviolet spectrophotometry, and sampling time points are as follows: 15 minutes, 30 minutes, 60 minutes, 120 minutes, 135 minutes, 150 minutes, 180 minutes, 240 minutes. Taking a proper amount of the solution at each time point, filtering, taking the subsequent filtrate as a test solution, and calculating the release amount at different moments by adopting an external standard method.
Acid stage: releasing the sample in a hydrochloric acid solution with the pH of 1.1 and 750ml within 0-2 hours;
pH 6.0 buffer stage: at 2 hours, 200ml of 200mM phosphate buffer (containing 3g more sodium hydroxide to neutralize the acid phase) was added to 750ml of release medium, adjusting the buffer pH to 6.0; the drug release is carried out in the phosphate buffer solution for 2-4 hours, and the total volume of the medium is 950 ml.
The experimental results show that: the doxycycline hyclate dual release formulation has a cumulative release rate of about 77% in acid for 2 hours and a cumulative release rate of 100.2% in buffer at pH 6.0 for 2 hours. Referring to the attached figure 1, the capsule is shown to have double-release behavior, and the delayed-release pellet has pH sensitivity, can be released at a specific position in a human body, and has small difference among different batches.
The products of examples 2, 3 and 4 have the same experimental results as example 1 under the same test conditions, and all meet the requirements.
Examples of the experiments
6
: stability test
The capsules prepared in example 1 were subjected to an influence factor test in conventional drug stability examination (see appendix XI X C of the second part of pharmacopoeia 2010 of the people's republic of China), and the results show that the product has good stability.
Table 1 stability of doxycycline hydrochloride dual release formulation under high heat conditions
Table 2 stability of doxycycline hydrochloride dual release formulations under high humidity conditions
Table 3 stability of doxycycline hydrochloride dual release formulation under high light irradiation
Claims (10)
1. A doxycycline hydrochloride double-release capsule comprises quick-release pellets and delayed-release pellets, and is characterized in that: compared with the intermediate-speed release part of the doxycycline hydrochloride double-release capsule, the weight percentage of each component in the quick-release pellet is as follows: 10-40% of doxycycline hydrochloride, 30-80% of filler, 0.5-15% of adhesive, 0-15% of isolating layer film-forming material, 0-5% of plasticizer A and 0-10% of opacifier; compared with the delayed release part in the doxycycline hydrochloride double-release capsule, the weight percentage of each component in the delayed release pellet is as follows: 10-40% of doxycycline hydrochloride, 20-70% of filler, 0.5-15% of adhesive, 0-15% of isolating layer film-forming material, 0-5% of plasticizer A, 0-10% of opacifier, 0.5-30% of delayed release material, 0.3-5% of plasticizer B, 0.5-10% of anti-sticking agent and 0.1-3% of solubilizer.
2. Doxycycline hydrochloride dual release capsule according to claim 1, characterized in that: the quick release pellet or the delayed release pellet is a skeleton type pellet, the filler in the quick release pellet or the delayed release pellet is one or more of sucrose, lactose, mannitol, starch, microcrystalline cellulose, algal polysaccharide and chitosan,
the binder in the quick-release pellet or the delayed-release pellet is one or more of water, anhydrous ethanol, mixed solution of water and ethanol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone, and sodium carboxymethylcellulose,
the film forming material of the isolation layer in the quick release pellet or the delayed release pellet is one or more of Opadry I, Opadry II, Opadry AMB, Opadry MP, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvidone and polyvinyl alcohol,
the plasticizer A in the quick-release pellet or the delayed-release pellet is one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, triacetin, polyethylene glycol and propylene glycol,
the opacifier in the quick-release pellets or the delayed-release pellets is one or more of titanium dioxide, iron oxide red and iron oxide yellow.
3. Doxycycline hydrochloride dual release capsule according to claim 1, characterized in that: the delayed release material is one or more of ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin, ethyl cellulose water dispersion, hydroxypropyl cellulose, hydroxyethyl cellulose acetate, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, YAKEYI, hydroxypropyl methylcellulose succinate, polylactic acid, and palm wax,
the plasticizer B is one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, glyceryl stearate, tributyl citrate, diethyl succinate, rectified coconut oil and propylene glycol,
the antisticking agent is one or more of talcum powder, colloidal silicon dioxide, magnesium stearate, calcium stearate, magnesium silicate and glyceryl monostearate,
the solubilizer is one or more of sodium dodecyl sulfate, sorbitan fatty acid ester, poloxamer, polysorbate-20, polysorbate-60 and polysorbate-80.
4. Doxycycline hydrochloride dual release capsule according to claim 1, characterized in that: the total effective dose of doxycycline hydrochloride in each doxycycline hydrochloride double-release capsule is between 20 and 100 mg.
5. Doxycycline hydrochloride dual-release capsule according to claim 4, characterized in that: the total effective dose of the doxycycline hydrochloride in each doxycycline hydrochloride double-release capsule is preferably 40 mg.
6. Doxycycline hydrochloride dual release capsule according to claim 1, characterized in that: wherein the quick-release pellet accounts for 50-85 wt%, and the delayed-release pellet accounts for 50-15 wt%.
7. Doxycycline hydrochloride dual release capsule according to any one of claims 1 to 6, characterized in that:
the filler in the quick-release pellet is preferably microcrystalline cellulose, the adhesive is preferably hydroxypropyl methylcellulose, the film-forming material of the isolation layer is preferably hydroxypropyl methylcellulose and/or hydroxypropyl cellulose, the plasticizer A is preferably polyethylene glycol, and the opacifier is preferably titanium dioxide;
the filler in the delayed-release pellet is preferably microcrystalline cellulose, the binder is preferably hydroxypropyl methylcellulose, the isolating layer film-forming material is preferably hydroxypropyl methylcellulose and/or hydroxypropyl cellulose, the plasticizer A is preferably polyethylene glycol, the opacifier is preferably titanium dioxide, the delayed-release material is preferably polyacrylic acid resin, the plasticizer B is preferably polyethylene glycol and/or triethyl citrate, the anti-sticking agent is preferably talcum powder, and the solubilizer is preferably polysorbate-80.
8. Doxycycline hydrochloride dual release capsule according to claim 7, characterized in that: the quick-release pellet comprises the following components in percentage by weight: 15-25% of doxycycline hydrochloride, 65-75% of filler microcrystalline cellulose, 1-2% of adhesive hydroxypropyl methyl cellulose, 5-6% of isolation layer film forming material hydroxypropyl methyl cellulose, 0.5-1.5% of plasticizer A polyethylene glycol and 2-3% of opacifier titanium dioxide;
the weight percentage of each component in the delayed-release pellet is as follows: 10-20% of doxycycline hydrochloride, 55-65% of filler microcrystalline cellulose, 0.5-1.5% of adhesive hydroxypropyl methyl cellulose, 4-5% of isolating layer film-forming material hydroxypropyl methyl cellulose, 0.5-1.5% of plasticizer A polyethylene glycol, 2-3% of opacifier titanium dioxide, 9-11% of delayed release material polyacrylic resin, 0.5-1.5% of plasticizer B polyethylene glycol, 4-6% of anti-sticking agent talcum powder and 800.1-0.6% of solubilizer polysorbate.
9. The method of preparing doxycycline hyclate dual release capsules of claim 8, characterized in that: firstly preparing a pellet core, preparing quick-release pellets from the pellet core, preparing delayed-release pellets from the quick-release pellets, and finally mixing the quick-release pellets and the delayed-release pellets in proportion and filling capsules to obtain doxycycline hydrochloride double-release capsules;
(1) pellet core
The pellet core formula comprises: 640g of microcrystalline cellulose, 177g of doxycycline hydrochloride and 640g of 2% (w/w) hydroxypropyl methyl cellulose solution;
the preparation process comprises the following steps: crushing doxycycline hydrochloride and microcrystalline cellulose in a prescription amount, sieving with a 80-mesh sieve, uniformly mixing, and adding a hydroxypropyl methyl cellulose solution to prepare a soft material; preparing drug-loaded pellets with uniform particle size by an extrusion rolling method, and extruding to form cylinders, wherein the particle size of the pellets is controlled to be 0.3-1.5 mm;
(2) quick-release pellet
The quick-release pellet formula comprises the following components: 800g of drug-loaded pill core, 48g of hydroxypropyl methylcellulose, 24g of titanium dioxide, 8g of polyethylene glycol and 720g of deionized water;
the preparation process comprises the following steps: adding hydroxypropyl methylcellulose and polyethylene glycol in the prescribed amount into deionized water under stirring, dissolving until the mixture is clear, adding titanium dioxide, and continuously stirring until the mixture is uniformly mixed to obtain an isolation layer coating solution; placing 800g of the pellet core of the drug-loaded pellet into a fluidized bed, adjusting the parameters of the fluidized bed to be proper, adding the prepared coating solution of the isolating layer into an atomizing chamber by a peristaltic pump through a spray gun for atomizing and coating, and drying to obtain the quick-release pellet;
(3) delayed release pellet
The formulation of the delayed-release pellet comprises: 400g of quick-release pellets, 50g of polyacrylic resin, 5g of polyethylene glycol, 22.5g of talcum powder, 802.5 g of polysorbate-95% (mass ratio) of ethanol 800 ml;
the preparation process comprises the following steps: adding 95% ethanol into polyacrylic acid resin, polyethylene glycol and polysorbate-80 under stirring, dissolving to clear, adding pulvis Talci, and stirring to mix well to obtain delayed release coating solution; placing the quick-release pellets in a fluidized bed, adjusting the parameters of the fluidized bed to be proper, adding the prepared coating solution of the isolating layer into an atomizing chamber by a peristaltic pump through a spray gun for atomizing and coating, drying after coating, selecting pellets in a specified range, checking the properties and the release degree, and obtaining the delayed-release pellets after the pellets are qualified;
(4) doxycycline hydrochloride double-release capsule filling
The quick-release pellets and the delayed-release pellets are respectively filled into capsules according to the weight ratio of 5: 2, and then the doxycycline hydrochloride double-release capsules are obtained.
10. The preparation method of claim 9, wherein the particle size of the micropellets is controlled to be 0.6 ± 0.1 mm.
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| CN113069434A (en) * | 2021-03-11 | 2021-07-06 | 绍兴文理学院元培学院 | Tofacitinib citrate controlled-release capsule and preparation method thereof |
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