CN109833306B - Roxatidine acetate medicinal salt sustained-release pellet as well as preparation method and application thereof - Google Patents
Roxatidine acetate medicinal salt sustained-release pellet as well as preparation method and application thereof Download PDFInfo
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Abstract
A slow-release pellet of roxatidine acetate medicinal drug-carrying salt comprises a slow-release material, a pore-forming agent, a plasticizer and a coating solvent, wherein the coating solvent is 70-100% ethanol water solution in parts by weight, and the slow-release pellet has good dissolution property and quality stability.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to roxatidine acetate medicinal salt sustained-release pellets, a preparation method and application thereof.
Background
Roxatidine acetate hydrochloride (roxa) is another H developed after ranitidine, famotidine, etc2The selective antagonist of the receptor can block the histamine H2 receptor of gastric mucosal wall cells to show a continuous gastric acid secretion inhibition effect, also has a mucosal protection effect, and is an ideal medicament for clinically treating peptic gastric ulcer diseases and having a moderate acid inhibition effect. Compared with Proton Pump Inhibitors (PPIs), roxatidine acetate hydrochloride has many clinical advantages: the composition has the advantages that the composition has an effect in a histamine activation way, moderately inhibits gastric acid secretion, has an exact prevention effect on stress ulcer of a patient in a hospital, effectively prevents and treats the stress ulcer, has the prevention and treatment effect equivalent to that of lansoprazole, and has the effect on treating duodenal ulcer equivalent to that of ranitidine; the flexible carbon chain in the roxatidine acetate hydrochloride structure can stimulate gastric mucosa cells to secrete mucin and mucus, has a unique gastric mucosa protection function, and has the gastric acid secretion inhibition effect 6 times that of cimetidine and 2 times that of ranitidine; ③ the acetamido group in the roxatidine acetate hydrochloride structure replaces guanidine/amidine group, thus forming H2RA with strong action, high bioavailability and long half-life; fourthly, the acetate structure in the roxatidine acetate hydrochloride structure is subjected to ester hydrolysis reaction in vivo without liver enzyme metabolism and drug interaction; no other anti-androgen side effects of H2 RAs; sixthly, adverse reactions caused by PPI medication are avoided, including the risk of hospital acquired pneumonia and the risk of clostridium difficile infectious diarrhea (CDI) of patients caused by PPI medication, such as the increase of cardiovascular affairs when the PPI medication is combined with clopidogrelPiece occurrence risk, etc.
The original research company of the roxatidine acetate hydrochloride sustained-release capsule is Japanese あすか (ASKA) pharmaceutical institute, and the specific composition dosage and preparation method of あすか (ASKA) pharmaceutical institute sustained-release capsule are not disclosed in the prior art.
Liaopeng et al disclose a pulse controlled release pellet of roxatidine acetate hydrochloride (Chinese pharmacy, 2010, volume 21, stage 17) prepared by a time controlled-disintegration method with a double-layer film, and the preparation has many kinds of auxiliary materials and a complex preparation process.
The sustained release preparation can overcome the peak-valley phenomenon of the blood concentration, keep the blood concentration in a stable and lasting effective range and improve the safety of the medicament. The sustained release preparation can also reduce the times of taking medicine, improve the compliance of patients and is convenient to use.
Disclosure of Invention
The invention aims to provide a roxatidine acetate medicinal salt sustained-release pellet with good stability. The invention also aims to solve the problem of low drug-loading rate of the drug-loading layer coating of the roxatidine acetate medicinal salt sustained-release pellet. The invention also aims to solve the problem of coating and hardening of drug-loaded pellets of roxatidine acetate pharmaceutical salt sustained-release pellets. The invention also aims to improve the dissolution rate and the quality stability of the roxatidine acetate medicinal salt sustained-release pellet.
One of the purposes of the invention is to provide a drug-loaded pellet of roxatidine acetate medicinal salt, which comprises a blank pellet core and a drug-loaded layer, wherein the drug-loaded layer contains micronized roxatidine acetate medicinal salt, the particle size D90 of the micronized roxatidine acetate medicinal salt is less than or equal to (less than or equal to) 50 μm, and preferably D90 is less than or equal to (less than or equal to) any one of 40 μm, 30 μm, 25 μm, 22.2 μm, 20 μm, 16 μm or 9 μm.
The roxatidine acetate medicinal salt drug-loaded pellet comprises a blank pellet core and a drug-loaded layer, wherein the drug-loaded layer uses 95% or more ethanol aqueous solvent or absolute ethanol by weight as a drug-loaded layer coating solvent, and preferably, the weight of ethanol in the drug-loaded layer coating solvent is more than or equal to (more than or equal to) 96%, 97%, 98%, 99%, 99.2%, 99.5% or 99.7%.
In the preferred technical scheme of the invention, the weight ratio of the pharmaceutically acceptable salt of roxatidine acetate to the coating solvent in the drug-carrying layer coating solution is any one of 75:750-250, preferably 75:750-281.25, 75:700-350, 75:700-400 and 75: 656.25-406.25.
In a preferred embodiment of the present invention, a binder is added to the drug-loaded layer, preferably the binder is an alcohol-soluble binder, and more preferably any one or a combination of hydroxypropyl cellulose and polyvinylpyrrolidone.
In a preferred embodiment of the present invention, the hydroxypropyl cellulose has a viscosity of 2.0 to 10.0 mPas (measurement conditions 20 ℃ C. HPC concentration of 2%), preferably one or more of 2.0 to 2.9, 3.0 to 5.9, and 6.0 to 10.0 mPas, and may be selected from HPC-L, HPC-SL, HPC-SSL, and any one or a combination thereof.
In the prior technical scheme, the polyvinylpyrrolidone is selected from any one of PVP-K12, PVP-K25, PVP-K30, PVP-K60 and PVP-K90 or a combination thereof.
In the prior technical scheme of the invention, the pharmaceutical salt of roxatidine acetate in the drug-carrying layer coating solution is as follows: the mass ratio of the adhesive is 75:1-25, preferably 75:3.75-20, or 75: 3.75-15.
In the prior technical scheme of the invention, a water-insoluble plasticizer is added into the drug-loaded layer, and preferably the water-insoluble plasticizer is selected from any one or the combination of triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol and silicone oil.
In a preferred embodiment of the present invention, the amount of the plasticizer in the drug-loaded layer is 0 to 4%, preferably 1%, 2%, 3%, 3.5% or 3.75%.
In the prior technical scheme, the blank pellet core material is selected from any one or combination of microcrystalline cellulose, sucrose, starch, lactose and silicon dioxide.
In a preferred embodiment of the present invention, the weight gain of the drug-loaded coating of the drug-loaded pellet is selected from 120% to 150%, preferably any one of 125%, 130%, 135%, 140%, 145%, most preferably any one of 141%, 142%, 143%, 144%, 145%, 146%, 147%, 148%, 149%.
In a preferred technical scheme of the invention, the anti-sticking agent in the drug-loaded layer is selected from any one or combination of talcum powder, superfine silica gel powder, silica colloid, sodium fumarate stearate, magnesium stearate, polyethylene glycol and potassium chloride.
The pharmaceutically acceptable salt of the roxatidine acetate is selected from any one of hydrochloride, oxalate and acetate of the roxatidine acetate or the combination of the roxatidine acetate and the oxalate and the acetate of the roxatidine acetate.
The absolute ethanol of the invention generally refers to ethanol with a concentration of more than 99% (W/W%), and can be selected to meet the requirements of pharmacopoeia standards (such as United states pharmacopoeia, British pharmacopoeia, European pharmacopoeia, Japanese pharmacopoeia, and the like), preferably, the absolute ethanol has a grade selected from pharmaceutical grade, chemical purity, analytical purity and any one of the above standards, and the weight part of ethanol in the absolute ethanol is more than or equal to 99.2%, 99.5% or 99.7%.
The roxatidine acetate medicinal salt drug-loaded pellet is used for preparing oral preparations and can be prepared by adopting the conventional preparation technology in the field.
The roxatidine acetate medicinal salt drug-loaded pellet is applied to preparation of common preparations, sustained-release preparations or controlled-release preparations, and preferably the preparation is any one of tablets, capsules or enteric preparations.
The invention also aims to provide a preparation method of the roxatidine acetate medicinal salt drug-loaded pellet, which comprises the following steps: mechanically pulverizing or micronizing roxatidine acetate medicinal salt, weighing the components according to the prescription amount, mixing uniformly, preparing the components into drug-carrying coating liquid for later use, spraying the drug-carrying coating liquid onto a blank pellet core, drying, and sieving to obtain the drug-carrying pellet.
In a preferred embodiment of the present invention, the micronization treatment method is selected from any one or a combination of ball milling, vibrating membrane milling or jet milling.
In a preferred technical scheme of the invention, the drug-loaded layer coating method is selected from any one of fluidized bed coating and coating pan rolling or a combination thereof.
In a preferred technical scheme of the invention, the fluidized bed coating conditions are as follows: the air inlet volume is 120-160m3The air inlet temperature is 30-50 ℃, and the atomization pressure is 1.6-2.2kg/cm2Stopping coating after theoretical weight gain, and drying for 20-40 min.
The invention also aims to provide a roxatidine acetate medicinal salt sustained-release pellet which is characterized in that a sustained-release coating solution is used for coating the drug-loaded pellet, and the sustained-release coating solution comprises a sustained-release coating material, a pore-forming agent, a plasticizer and a coating solvent.
In a preferred embodiment of the present invention, the slow release coating material is selected from any one or a combination of ethyl cellulose, acrylic resin and cellulose acetate.
In a preferred technical scheme of the invention, the slow-release coating solvent is ethanol water solution, and preferably, the ethanol in the ethanol water solution accounts for 70-100% by weight, preferably any one of 80%, 85%, 90%, 95% and 100% by weight.
In a preferred technical scheme of the invention, the pore-forming agent in the sustained-release coating solution is selected from any one or a combination of PEG6000, hydroxypropyl cellulose, hydroxypropyl methylcellulose, sorbitol, sodium chloride and a surfactant.
In a preferable technical scheme of the invention, the plasticizer in the slow-release coating solution is any one or combination of triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol and silicone oil.
In a preferred technical scheme of the invention, the slow-release coating solution comprises the following components in percentage by weight: the weight ratio of the pore-foaming agent is 10-7:0.9 to 3, preferably 9.99 to 7.37: 0.94-2.5.
In a preferred technical scheme of the invention, the slow-release coating solution comprises the following components in percentage by weight: pore-forming agent: the weight ratio of the plasticizer is 10-7: 0.9-3: 0.9-2, preferably 9.99-7.37:0.94-2.5: 0.94-1.72.
In a preferred technical scheme of the invention, the slow-release coating solution comprises the following components in percentage by weight: pore-forming agent: plasticizer: the weight ratio of the coating solvent is 10-7: 0.9-3: 0.9-2:90-140, preferably 9.99-7.37:0.94-2.5: 0.94-1.72:94.97-137.11.
In a preferable technical scheme of the invention, the weight of the slow-release coating layer of the drug-carrying pellet is 6.0-10.0%, and is preferably any one of 6.5%, 7.5%, 8%, 8.5% and 9%.
The sustained-release pellet of the roxatidine acetate medicinal salt is coated with an isolating layer between a medicine carrying layer and a sustained-release layer or is not coated with the isolating layer.
The invention also aims to provide a preparation method of the roxatidine acetate medicinal salt sustained-release pellet, which comprises the following steps: 1. preparing drug-loaded pellets; 2. preparing a slow-release coating solution: weighing the components of the slow-release coating solution according to the prescription amount, and uniformly mixing the coating solvent and other auxiliary materials under the stirring condition; 3. coating a slow release layer: and (4) stopping coating after the weight of the coating of the sustained-release layer is increased, and drying to obtain the sustained-release pellet.
In a preferred technical scheme of the invention, the slow release layer coating method is selected from any one of fluidized bed coating and coating pan rolling or the combination of the fluidized bed coating and the coating pan rolling.
In a preferred technical scheme of the invention, the fluidized bed coating conditions are as follows: the air inlet volume is 120-160m3The air inlet temperature is 30-50 ℃, and the atomization pressure is 1.6-2.2kg/cm2Stopping coating after theoretical weight gain, and drying for 20-40 min.
In the preferred technical scheme of the invention, the drug-loaded pellets are subjected to slow release coating to prepare roxatidine acetate medicinal salt slow release pellets. The sustained-release pellet can be further prepared into capsules. The capsule preparation comprises drug-loaded pellets and/or sustained-release pellets.
In a preferable technical scheme of the invention, the composition prepared from the roxatidine acetate medicinal salt drug-loaded pellets and the sustained-release pellets further comprises any one or combination of a gastric acid inhibitor, a gastric mucosa protective agent and a helicobacter pylori inhibitor.
In a preferred technical scheme of the invention, the roxatidine acetate medicinal salt drug-loaded pellets or sustained-release pellets and any one of gastric acid inhibitor, gastric mucosa protective agent and helicobacter pylori inhibitor or the combination thereof are jointly administered, preferably, the joint administration is selected from any one of sequential administration, simultaneous administration and sequential administration or the combination thereof.
The invention also aims to provide the roxatidine acetate medicinal salt drug-loaded pellets or the sustained-release pellets and the application of the composition further prepared from the roxatidine acetate medicinal salt drug-loaded pellets or the sustained-release pellets in preparing drugs for treating or preventing gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, reflux esophagitis, acute gastritis, chronic gastritis, upper gastrointestinal hemorrhage or preoperative anesthesia and aspiration prevention.
In a preferred embodiment of the present invention, the gastric ulcer is selected from any one of peptic ulcer and acute stress ulcer, or a combination thereof.
In the preferred technical scheme of the invention, the patient is a patient with low risk of upper gastrointestinal hemorrhage.
The drug-loaded pellet comprises a blank pellet core and a drug-loaded layer. The sustained-release pellet comprises a blank pellet core, a drug-loaded layer and a sustained-release layer.
Unless otherwise indicated, when the present invention relates to percentages between liquids, said percentages are volume/volume percentages; the invention relates to the percentage between liquid and solid, said percentage being volume/weight percentage; the invention relates to the percentages between solid and liquid, said percentages being weight/volume percentages; the balance being weight/weight percent.
Compared with the prior art, the invention has the following beneficial effects:
1. the roxatidine acetate medicinal salt sustained-release pellet prepared by the invention solves the technical problem of low drug-loading rate of the drug-loading layer coating. By micronization technology, the drug-loading rate of active ingredients in the drug-loading layer is increased from about 95% to more than 98%.
2. By adjusting the weight percentage of ethanol in the drug-carrying layer coating solvent, the roxatidine acetate medicinal salt sustained-release pellet prepared by the invention solves the problem of drug-carrying micro-layer coating hardening.
3. The roxatidine acetate medicinal salt sustained-release pellet prepared by the invention has good stability. The increase of the ethanol concentration in the sustained-release coating solvent can slow the dissolution rate of the preparation and improve the sustained-release effect. Under the condition of accelerated experiment, the content of related substances of the roxatidine acetate salt sustained-release capsule prepared by the invention is lower than that of a commercial product. In addition, under the condition of accelerated experiment, the dissolution rate change difference of the roxatidine acetate medicinal salt sustained-release capsule prepared by the invention in the first 60min is superior to that of the commercial product.
4. The roxatidine acetate medicinal salt sustained-release pellet prepared by the invention is more beneficial to exerting a plurality of clinical advantages of roxatidine acetate hydrochloride: the composition has the advantages that the composition has an effect in a histamine activation way, moderately inhibits gastric acid secretion, has an exact prevention effect on stress ulcer of a patient in a hospital, effectively prevents and treats the stress ulcer, has the prevention and treatment effect equivalent to that of lansoprazole, and has the effect on treating duodenal ulcer equivalent to that of ranitidine; the flexible carbon chain in the roxatidine acetate hydrochloride structure can stimulate gastric mucosa cells to secrete mucin and mucus, has a unique gastric mucosa protection function, and has the gastric acid secretion inhibition effect 6 times that of cimetidine and 2 times that of ranitidine; ③ the acetamido group in the roxatidine acetate hydrochloride structure replaces guanidine/amidine group, thus forming H2RA with strong action, high bioavailability and long half-life; fourthly, the acetate structure in the roxatidine acetate hydrochloride structure is subjected to ester hydrolysis reaction in vivo without liver enzyme metabolism and drug interaction; no other anti-androgen side effects of H2 RAs; sixthly, adverse reactions caused by PPI medication are avoided, including the risk of hospital acquired pneumonia and the risk of clostridium difficile infectious diarrhea (CDI) of patients caused by PPI medication, such as the increase of the risk of cardiovascular events when the PPI medication is combined with clopidogrel, and the like.
Drawings
FIG. 1 dissolution profiles of commercial products and examples 13 to 16
FIG. 2 dissolution curves of the commercial products and examples 20 to 22
FIG. 3 dissolution curves of commercial product and example 23
Detailed Description
The present invention will be described in detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit of the present invention.
Example 1Preparation of roxatidine acetate hydrochloride drug-loaded pellets
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
Hydroxypropyl cellulose-SL 3.75mg
Talcum powder 15mg
95% ethanol 656.25mg
Mechanically pulverizing raw materials, weighing 95% ethanol, adding hydroxypropyl cellulose-SL and principal drugs under stirring, adding pulvis Talci after stirring, and sieving. Spraying the drug-loaded coating solution onto the blank pellet core by using a fluidized bed granulation coating machine, wherein the fluidized bed coating conditions are as follows: air inlet volume: 120-160m3H, inlet air temperature: at 30-50 deg.C, atomizing pressure is 1.6-2.2kg/cm2. In the coating process, the coated pellets are bonded by the bonding plates, so that the coating cannot be finished and the theoretical weight increment cannot be achieved.
Example 2Preparation of roxatidine acetate hydrochloride drug-loaded pellets
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
Hydroxypropyl cellulose-SL 3.75mg
Talcum powder 15mg
Anhydrous ethanol 656.25mg
Mechanically pulverizing raw materials, weighing anhydrous ethanol, adding hydroxypropyl cellulose-SL under stirring, stirring to dissolve, adding principal drug, stirring, adding pulvis Talci, stirring, and sieving. Spraying the drug-loaded coating solution onto the blank pellet core by a fluidized bed granulation coating machine, drying and sieving to obtain the drug-loaded pellet. The coating conditions are the same as example 1, the absolute ethyl alcohol is chemically pure or more, and the weight part of the ethanol is more than 99.5%.
Example 3Roxatidine acetate hydrochloride drug-carrying pellet
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
Hydroxypropyl cellulose-L3.75 mg
Talcum powder 15mg
Anhydrous ethanol 656.25mg
Mechanically pulverizing raw materials, weighing anhydrous ethanol, adding hydroxypropyl cellulose-L under stirring, stirring to dissolve, adding principal drug, stirring, adding pulvis Talci, stirring, and sieving. The drug-loaded coating solution is sprayed on the blank pellet core by a fluidized bed granulation coating machine under the same conditions as in the example 2, and the drug-loaded pellets are obtained after drying and sieving.
Example 4Roxatidine acetate hydrochloride drug-carrying pellet
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
Hydroxypropyl cellulose-SL 3.75mg
Anhydrous ethanol 671.25mg
Mechanically pulverizing raw materials, weighing anhydrous ethanol, adding hydroxypropyl cellulose-L under stirring, stirring to dissolve, adding main drug, stirring, and sieving. The drug-loaded coating solution is sprayed on the blank pellet core by a fluidized bed granulation coating machine under the same conditions as in the example 2, and the drug-loaded pellets are obtained after drying and sieving.
Example 5Roxatidine acetate hydrochloride drug-carrying pellet
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
PVP K30 3.75mg
Talcum powder 15mg
95% ethanol 656.25mg
Mechanically pulverizing raw materials, weighing 95% ethanol, adding PVP K30 under stirring, stirring to dissolve, adding principal drug, stirring, adding pulvis Talci, stirring, and sieving. The drug-loaded coating solution is sprayed on the blank pellet cores by a fluidized bed granulation coating machine under the same conditions as in example 1, and the coating pellets are bonded with each other in the coating process, so that the coating cannot be finished and the theoretical weight gain cannot be achieved.
Example 6Roxatidine acetate hydrochloride drug-carrying pellet
Sucrose pill core 65mg
75mg of roxatidine acetate hydrochloride
PVP K30 3.75mg
Talcum powder 15mg
Anhydrous ethanol 656.25mg
Mechanically pulverizing the raw materials, weighing anhydrous ethanol according to the prescription amount, adding PVP K30 under stirring, stirring to dissolve, adding principal drug, stirring, adding pulvis Talci, stirring, and sieving. The drug-loaded coating solution is sprayed on the blank pellet core by a fluidized bed granulation coating machine under the same conditions as in the example 2, and the drug-loaded pellets are obtained after drying and sieving.
Example 7Effect of drug-loaded layer formation on coating
The coating process of the drug-loaded layer as described in examples 1-6 and the pellet appearance after the drug-loaded layer coating were recorded separately. The results show that the pellet hardening condition occurs in the coating process by using 95% ethanol as the drug-carrying layer coating solvent, the coating can not be completed, and the problem of the drug-carrying pellet hardening can not be improved by adding the anti-sticking agent talcum powder. Compared with 95% ethanol, the anhydrous ethanol is used for preparing the bulk drug into suspension coating, so that the hardening phenomenon of the coating of the drug-loaded layer is obviously improved.
TABLE 1 drug loading layer formation on coating process and appearance
And (3) standing the solution at room temperature for 24h, respectively detecting related substances in the solution for 0h and the solution for 24h, and inspecting the stability of the drug-loaded coating solution. The results show that compared with ethanol water solution, the stability of the active ingredients in the drug-loaded pellets can be improved by using absolute ethanol as a coating solvent.
TABLE 2 Effect of different coating solvents on the substances involved in the drug-loaded layer
| Name (R) | Example 1 solution | Example 2 solution |
| 0h Total hetero (%) | 0.161 | 0.161 |
| 24h Total impurities (%) | 0.269 | 0.190 |
Examples 8 to 12Influence of particle size of raw material medicine on medicine loading amount of medicine-loaded pellets
The roxatidine acetate hydrochloride is prepared into D through mechanical dispersion90Is 50um granule, and is prepared by jet milling crude drug to obtain D9022.2 μm, 16 μm and 9 μm. Weighing anhydrous ethanol according to the prescription amount, adding triethyl citrate (TEC) and hydroxypropyl cellulose (HPC) under stirring, stirring to dissolve, adding the pulverized main drug, stirring uniformly, and sieving for later use. And (3) spraying the drug-loaded coating solution onto the blank pellet cores by using a fluidized bed granulation coating machine, drying and sieving the blank pellets under the same coating conditions as in example 1 to obtain the drug-loaded pellets, wherein the prepared drug-loaded pellets do not have hardening phenomenon and have smooth appearance. And (3) determining the content of roxatidine acetate hydrochloride in the drug-loaded pellets relative to a theoretical value. The active ingredient in the pellet is present in an amount of actual measured/theoretical content of 100% relative to the theoretical amount.
TABLE 3 influence of particle size of crude drug on drug-loaded amount in drug-loaded pellets
| Composition (I) | Example 8 | Example 9 | Example 10 | Example 11 | Example 12 |
| Blank pill core | 65 | 65 | 65 | 65 | 65 |
| Bulk drug D9050μm | 75 | 75 | |||
| Bulk drug D9022.2μm | 75 | ||||
| Bulk drug D9016μm | 75 | ||||
| Bulk drug D909μm | 75 | ||||
| |
15 | 15 | 15 | 15 | 15 |
| TEC | 3.75 | 3.75 | 3.75 | 3.75 | 3.75 |
| Anhydrous ethanol | 656.25 | 281.25 | 406.25 | 406.25 | 406.25 |
| Content relative to theoretical value | 94.95％ | 95.85％ | 98.81％ | 99.74％ | 100.8％ |
The drug-loaded layer adopts absolute ethyl alcohol (the weight part is more than 99.5%) to prepare a coating solution, the main drugs can not be completely dissolved, the coating solution is a suspension, part of the main drugs which are not dissolved in the coating process are not easy to adhere to the surfaces of the pellets, the phenomenon of spray drying is caused, the coating solution is not adhered to the surfaces of the pellets in equal proportion, and the content is lower. Mechanically pulverizing the raw materials to D90Is 50um, the content of roxatidine acetate hydrochloride in the medicine carrying pill is 94.95 percent of the theoretical value; the raw material is subjected to jet milling treatment to D9022 μm, 16 μm or 9 μm, the content of roxatidine acetate hydrochloride is higher than that of D90Examples 8-9 at 50 um. Therefore, micronization of the roxatidine acetate hydrochloride raw material medicine is beneficial to improving the actual content of active ingredients in the drug-loaded pellets, solves the technical problem that the actual drug-loaded amount of the drug-loaded layer coating is lower, and improves the content stability of the final product.
Examples 13 to 18Roxatidine acetate hydrochloride sustained-release pellet
Selecting the drug-loaded pellets prepared in example 11, weighing 95% ethanol and purified water according to the prescription amount, adding other auxiliary materials under the stirring state, stirring until the auxiliary materials are dissolved, sieving, and carrying out slow-release layer coating, wherein the coating conditions are as follows: air inlet volume: 120-160m3H, inlet air temperature: at 30-50 deg.C, atomizing pressure is 1.6-2.2kg/cm2Stopping coating after the weight gain of the coating reaches 6.5 percent, continuing drying for 20-40min, and performing total mixing and filling to obtain the sustained-release capsules of examples 12-18 after the coating is finished.
TABLE 4 compositions of the sustained-release preparations of examples 13 to 18
Example 19 dissolution examination
Dissolution data for commercial products and capsules prepared according to examples 13-16 were measured according to paddle + settling basket, 50rpm, 900ml purified water. Commercially available (manufacturer: Japanese ASKA, lot No. K623A). The dissolution method comprises the following steps: taking the product, adding a settling basket by a paddle method, and performing the method according to a dissolution and release determination method (0931 second method of the general rules of the four parts of the pharmacopoeia 2015 edition) by using 900ml of water as a dissolution medium and rotating at 50 revolutions per minute.
TABLE 5 dissolution test of commercial products and examples 12-17
Example 14 uses PEG6000, which acts as both a plasticizer and a porogen, and the dissolution rate is slower than that of the commercially available product. Under the same weight increasing condition, the dissolution of the micro-pill without the pore-forming agent is slower than that of the commercial product. The dissolution of the sustained-release capsule is not influenced significantly by the adjustment of the proportion of the dosage of the plasticizer and the sustained-release agent.
Examples 20 to 23Roxatidine acetate hydrochloride sustained-release pellet
Selecting the drug-loaded pellets prepared in example 11, weighing the solvent according to the prescription amount, adding other auxiliary materials under stirring, stirring until the solvent is dissolved, sieving, performing sustained-release coating, wherein the weight of the coating is increased by 8.5%, performing total mixing and filling after the coating is finished, and packaging after the sustained-release capsules according to examples 20-22 are prepared. The sustained-release capsule of example 23 was prepared according to the formulation and method of example 21, and the weight gain of the coating was adjusted to 8.0%.
TABLE 6 compositions of examples 20-22 sustained release formulations
Example 24Dissolution study
Dissolution experiments were carried out according to the method of example 18, and the dissolution of examples 20 to 22 was examined, as shown in Table 7.
TABLE 7 dissolution test of commercially available products and examples 20 to 22
| Time (min) | Commercially available product | Example 20 | Example 21 | Example 22 |
| 0 | 0.00 | 0.00 | 0.00 | 0.00 |
| 15 | 3.20 | 6.65 | 4.01 | 1.92 |
| 30 | 12.20 | 20.41 | 13.31 | 9.10 |
| 45 | 25.90 | 31.87 | 23.11 | 21.27 |
| 60 | 38.11 | 40.22 | 31.40 | 30.80 |
| 90 | 51.82 | 53.30 | 44.72 | 43.73 |
| 120 | 59.66 | 62.19 | 53.78 | 52.64 |
| 180 | 68.93 | 72.09 | 64.32 | 63.58 |
| 240 | 74.62 | 79.74 | 72.44 | 71.23 |
| 300 | 78.30 | 83.43 | 77.26 | 76.26 |
| 360 | 81.70 | 86.83 | 80.13 | 80.15 |
| 480 | 87.78 | 91.34 | 85.31 | 85.12 |
| 600 | 91.17 | 93.74 | 89.70 | 88.06 |
70% -100% ethanol coated granules are round and have no hardening, and can be used as a slow release coating solvent. The experimental result shows that the concentration of ethanol in the sustained-release coating solvent can influence the release characteristics of the sustained-release pellets, and the increase of the concentration of ethanol in the sustained-release coating solvent can slow down the dissolution rate of the preparation and improve the sustained-release effect.
Example 256 month accelerated test stability study
The commercially available products and examples were allowed to stand at 40 ℃ 2 ℃ and a relative humidity of 75% + -5% for 6 months, and the dissolution curves and/or related substances were examined.
TABLE 8 commercial products and EXAMPLE 23 accelerated test dissolution test
The dissolution rate changes of the 0-day group and the 6-month accelerated group of the commercial product are remarkably different in the first 60 min. The sustained-release preparation prepared in example 23 has a small change in dissolution in accelerated tests for 0 day and 6 months, and is superior to the commercially available product. Under accelerated experimental conditions, the sustained-release preparation prepared by the invention has better dissolution stability, which is shown in table 8 and fig. 3.
TABLE 9 commercial products and EXAMPLE 23 accelerated test on substances
| Name (R) | Commercially available product | Example 23 |
| Day 0 (%) | 0.189 | 0.165 |
| Accelerated for 6 months (%) | 10.633 | 0.301 |
In an accelerated test, the content of related substances of the sustained-release preparation in example 23 is remarkably reduced compared with that of a commercial product. The contents of related substances of the sustained-release preparations of examples 20 to 22 were also significantly lower than those of the commercially available products. Therefore, the sustained-release preparation prepared by the invention has better quality stability compared with the commercial product.
Claims (72)
1. A sustained-release pellet of roxatidine acetate pharmaceutical salt is composed of a blank pellet core, a drug-carrying layer and a sustained-release layer, wherein the drug-carrying pellet is coated by a sustained-release coating solution, the sustained-release coating solution comprises a sustained-release material, a pore-forming agent, a plasticizer and a coating solvent, the pore-forming agent is selected from one or more of PEG6000, hydroxypropyl cellulose and hydroxypropyl methylcellulose, the coating solvent is an ethanol water solution, wherein the mass part of ethanol is 70-100% of the coating solvent, the weight of the sustained-release coating layer of the drug-carrying pellet is 6.0-10.0%, and the weight ratio of the sustained-release material to the pore-forming agent in the coating solution is 10-7: 0.9-3.
2. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the ethanol in the ethanol aqueous solution is 80% by weight.
3. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the ethanol in the ethanol aqueous solution is 85% by weight.
4. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the ethanol in the ethanol aqueous solution is 90% by weight.
5. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the ethanol in the ethanol aqueous solution is 95% by weight.
6. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the ethanol in the ethanol aqueous solution is 100% by weight.
7. The sustained-release pellet of roxatidine acetate medicinal salt as claimed in claim 1, wherein the sustained-release material in the sustained-release coating solution comprises one or more of ethyl cellulose, acrylic resin and cellulose acetate.
8. A sustained release pellet of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 1, wherein the plasticizer is selected from one or more of triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol, and silicone oil.
9. The sustained-release pellet of roxatidine acetate salt as claimed in claim 7, wherein the weight ratio of the ethyl cellulose to the pore-forming agent in the coating solution is 9.99-7.37: 0.94-2.5.
10. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 7, wherein the weight ratio of ethyl cellulose, pore-forming agent, plasticizer and coating solvent in the coating solution is 10-7: 0.9-3: 0.9-2:90-140.
11. The sustained-release pellet of roxatidine acetate salt as claimed in claim 7, wherein the weight ratio of the ethyl cellulose, the pore-forming agent, the plasticizer and the coating solvent in the coating solution is 9.99-7.37:0.94-2.5:0.94-1.72: 94.94-137.11.
12. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight gain of the sustained-release coating layer of the drug-loaded pellet is 6.5%.
13. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight gain of the sustained-release coating layer of the drug-loaded pellet is 7.5%.
14. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight of the sustained-release coating layer of the drug-loaded pellet is increased by 8%.
15. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight gain of the sustained-release coating layer of the drug-loaded pellet is 8.5%.
16. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight of the sustained-release coating layer of the drug-loaded pellet is 9%.
17. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the drug-loaded pellet comprises a blank pellet core and a drug-loaded layer, wherein the drug-loaded layer contains micronized roxatidine acetate pharmaceutically acceptable salt, and the particle diameter D of the micronized roxatidine acetate pharmaceutically acceptable salt is90≤50μm。
18. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 17, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤40μm。
19. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 18, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤30μm。
20. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 19, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤25μm。
21. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 20, wherein the micronized particles of a pharmaceutically acceptable salt of roxatidine acetateDiameter D90≤22.2μm。
22. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 21, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤20μm。
23. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 22, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤16μm。
24. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 23, wherein the particle size D of the micronized pharmaceutically acceptable salt of roxatidine acetate is90≤9μm。
25. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein absolute ethanol is used as a coating solvent of the drug-carrying layer.
26. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight fraction of ethanol in the coating solvent of the drug-carrying layer is not less than 99.5%.
27. The sustained-release pellet of roxatidine acetate salt as claimed in claim 26, wherein the weight fraction of ethanol in the coating solvent of the drug-carrying layer is not less than 99.7%.
28. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the weight ratio of the roxatidine acetate pharmaceutically acceptable salt to the coating solvent in the drug-carrying layer coating solution is 75: 750-250.
29. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the weight ratio of roxatidine acetate pharmaceutically acceptable salt to coating solvent is 75: 750-281.25.
30. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 1, wherein the weight ratio of the pharmaceutically acceptable salt of roxatidine acetate to the coating solvent is 75: 700-350.
31. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 1, wherein the weight ratio of the pharmaceutically acceptable salt of roxatidine acetate to the coating solvent is 75: 700-400.
32. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 1, wherein the binder is added into the drug-carrying layer coating solution, and the mass ratio of the roxatidine acetate pharmaceutically acceptable salt to the binder in the drug-carrying layer coating solution is 75: 1-25.
33. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 32, wherein the mass ratio of roxatidine acetate pharmaceutically acceptable salt to the binder in the drug-carrying layer coating solution is 75: 3.75-20.
34. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt as claimed in claim 33, wherein the mass ratio of roxatidine acetate pharmaceutically acceptable salt to the binder in the drug-carrying layer coating solution is 75: 3.75-15.
35. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the binder in the drug-loaded layer is alcohol-soluble binder selected from one or more of hydroxypropyl cellulose and polyvinylpyrrolidone.
36. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate, according to claim 35, wherein the hydroxypropyl cellulose has a viscosity value of 2.0 to 10.0 mPa-s.
37. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate, according to claim 36, wherein the viscosity value of the hydroxypropylcellulose is 2.0-2.9 Pa-s.
38. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 36, wherein the viscosity value of the hydroxypropylcellulose is 3.0-5.9 mPa-s.
39. The sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 36, wherein the viscosity value of the hydroxypropylcellulose is 6.0-10.0 mPa-s.
40. The sustained-release pellet of roxatidine acetate, according to any one of claims 36 to 39, wherein the hydroxypropylcellulose is selected from HPC-L, HPC-SL, HPC-SSL, or a combination thereof.
41. The sustained-release pellet of roxatidine acetate salt as claimed in claim 35, wherein the polyvinylpyrrolidone is any one or more selected from PVP-K12, PVP-K25, PVP-K30, PVP-K60 and PVP-K90.
42. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein a water-insoluble plasticizer is added to the drug-carrying layer,
the water-insoluble plasticizer is selected from one or more of triethyl citrate, PEG6000, castor oil, diethyl phthalate, propylene glycol and silicone oil,
the dosage of the water-insoluble plasticizer is 0-4%.
43. A sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 42, wherein the amount of said water-insoluble plasticizer is 1%.
44. A sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 42, wherein the amount of said water-insoluble plasticizer is 2%.
45. A sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 42, wherein the amount of said water-insoluble plasticizer is 3%.
46. A sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 42, wherein the amount of said water-insoluble plasticizer is 3.5%.
47. A sustained-release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to claim 42, wherein the amount of said water-insoluble plasticizer is 3.75%.
48. The slow release pellet of a pharmaceutically acceptable salt of rotigotine acetate according to claim 1, wherein the blank pellet core material is selected from one or more of microcrystalline cellulose, sucrose, starch, lactose or silicon dioxide.
49. The sustained-release pellet of roxatidine acetate salt as claimed in claim 1, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 120-160%.
50. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded pellet coated with the drug-loaded layer is increased by 125%.
51. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 130%.
52. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is 135%.
53. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 140%.
54. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 141%.
55. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 142%.
56. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 143%.
57. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is increased by 144%.
58. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight gain of the drug-loaded layer coating of the drug-loaded pellet is 145%.
59. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is 146%.
60. The sustained-release pellets of a pharmaceutically acceptable salt of roxatidine acetate according to claim 49, wherein the weight gain of the drug-loaded layer coating of the drug-loaded pellets is 147%.
61. The sustained-release pellets of a pharmaceutically acceptable salt of roxatidine acetate according to claim 49, wherein the weight gain of the drug-loaded layer coating of the drug-loaded pellets is 148%.
62. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded layer coating of the drug-loaded pellet is 149%.
63. The sustained-release pellet of roxatidine acetate salt as claimed in claim 49, wherein the weight of the drug-loaded pellet coated with drug-loaded layer is 150%.
64. The sustained-release pellet of roxatidine acetate pharmaceutically acceptable salt according to claim 1, wherein an anti-sticking agent is added in the drug-carrying layer, and the anti-sticking agent is selected from one or more of talcum powder, aerosil, colloidal silicon dioxide, sodium fumarate stearate, magnesium stearate, polyethylene glycol and potassium chloride.
65. The sustained release pellet of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 1, wherein the pharmaceutically acceptable salt of roxatidine acetate is selected from hydrochloride, oxalate, acetate thereof.
66. The sustained-release pellets of a pharmaceutically acceptable salt of roxatidine acetate as claimed in claim 1, wherein the sustained-release pellets of a pharmaceutically acceptable salt of roxatidine acetate are prepared into capsules or tablets.
67. The process for preparing sustained-release pellets of a pharmaceutically acceptable salt of roxatidine acetate as claimed in any one of claims 1 to 66, wherein the coating process of the sustained-release layer is fluidized bed coating or coating pan-rolling.
68. The method of claim 67, wherein the fluid bed coating process is: the air inlet volume is 120-160m3The air inlet temperature is 30-50 ℃, and the atomization pressure is 1.6-2.2kg/cm2Stopping coating after theoretical weight gain is achieved, and continuing drying for 20-40 min.
69. A pharmaceutical composition comprising sustained release pellets of a pharmaceutically acceptable salt of roxatidine acetate as claimed in any one of claims 1 to 66, and one or more of a gastric acid suppressing agent, a gastric mucosa protecting agent, and a helicobacter pylori inhibitor.
70. Use of the sustained release pellet of a pharmaceutically acceptable salt of roxatidine acetate according to any one of claims 1 to 66 or the pharmaceutical composition according to claim 69 for the preparation of a medicament for the treatment or prevention of gastric ulcer, duodenal ulcer, anastomotic ulcer, Zollinger-Ellison syndrome, reflux esophagitis, acute gastritis, chronic gastritis or pre-operative anesthesia for preventing aspiration.
71. The use according to claim 70, characterized in that the gastric ulcer is a peptic ulcer or an acute stress ulcer.
72. The use according to claim 70, characterized in that the patient is a low risk patient of upper gastrointestinal bleeding.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060016382A (en) * | 2004-08-17 | 2006-02-22 | 바이오네스트 주식회사 | Drug delivery system using multi-coating methods contained roxantidine acetate hydrochloride |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
| CN102018677A (en) * | 2010-12-28 | 2011-04-20 | 哈药集团三精制药股份有限公司 | Roxatidine acetate hydrochloride used for injection and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20060016382A (en) * | 2004-08-17 | 2006-02-22 | 바이오네스트 주식회사 | Drug delivery system using multi-coating methods contained roxantidine acetate hydrochloride |
| CN1795858A (en) * | 2004-12-30 | 2006-07-05 | 北京德众万全医药科技有限公司 | Oral taking tablets of Roxatidine Acetate Hydrochloride |
| CN102018677A (en) * | 2010-12-28 | 2011-04-20 | 哈药集团三精制药股份有限公司 | Roxatidine acetate hydrochloride used for injection and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 盐酸罗沙替丁醋酸酯脉冲控释微丸的研制;廖鹏;《中国优秀硕士学位论文全文数据库 医药卫生科技辑》;20110615(第6期);E079-48 * |
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