CN112451493B - Abuse-preventing oxycodone oral sustained-release tablet and preparation method thereof - Google Patents
Abuse-preventing oxycodone oral sustained-release tablet and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an abuse-proof oxycodone sustained release tablet and a preparation method thereof. An abuse-resistant oxycodone sustained release tablet comprising at least: 1) 2-9 parts by weight of oxycodone-loaded cellulose with a nano-network structure; 2) 5 to 13 parts by weight of a polymer having swelling properties in alcohol and water; wherein, the oxycodone is dispersed on the surface of the cellulose with the nano-network structure. The oxycodone sustained release tablet has obvious sustained release effect, no obvious burst release and excellent abuse prevention property.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to an abuse-proof oxycodone oral sustained-release tablet and a preparation method thereof.
Background
Since 1995, james campbell, the president of the american society of pain, first suggested that pain is the fifth vital sign, and nowadays, the world health organization has identified pain as the "fifth vital sign" following blood pressure, respiration, pulse, body temperature, and the study of pain is becoming more and more important.
Oxycodone (oxycodone) is a semi-synthetic opioid drug extracted from thebaine (alkaloid), and has been clinically applied for over 80 years as a potent analgesic. The oxycodone has high bioavailability and multiple administration routes, so the oxycodone has wide clinical application. However, in clinical trials, it was found that after continuous oxycodone administration at high doses, sudden discontinuation or reduction, some patients had the onset of withdrawal syndrome. This suggests that oxycodone also has the common adverse effects of other opioids. Therefore, oxycodone is a variety regulated by United nations' Single convention on narcotics in 1961, and China also has regulated the scope of narcotics. Many abusers seek greater "excitement" by crushing, extracting oxycodone tablets and then snuffing, smoking, or injecting, etc. The physical/chemical abuse-resistant preparation technology is one of the commonly used abuse-resistant technologies, the anti-crushing and anti-extraction capabilities of the tablet are further enhanced through a new preparation process, the extraction difficulty of the medicine in the preparation can be increased, and the effect of preventing the medicine abuse is achieved.
Oxycodone hydrochloride sustained-release tablets were developed and marketed by Purdue Pharma LP in 2010 under the trade name Oxycontin and Chinese under the trade name Oxacontin, and are mainly used for patients who have continuous moderate and severe pain and need 24-hour pain relief. Oxycontin adopts Acrocontin abuse-proof technology of Purdue company to form hydrogel, so that the possibility of abuse through injection, nasal inhalation and oral administration can be eliminated, and the control cost and pressure of refined anesthetic drugs are reduced. The original AcROCONTin abuse-proof technology has an authorized patent CN100577150C in China; CN 101583360B; this technique uses polyethylene oxide having a degree of polymerization of 400 ten thousand molecular weight.
The abuse-proof preparation of the ephedrine drugs which is on the market at present is mainly PEO, the abuse-proof preparation prepared from the polymer has the advantages of high hardness, difficult extraction and the like, but the polymer is easy to oxidize, antioxidants such as vitamin E and the like need to be added in the preparation process, and meanwhile, the current abuse-proof preparation needs high-end preparation equipment and has high production cost.
The invention uses the novel slow release material, has good process feasibility and low equipment requirement, and has good slow release and abuse release effects.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an abuse-proof oxycodone sustained release tablet.
The invention also aims to provide a preparation method of the oxycodone sustained release tablets.
The purpose of the invention can be realized by the following technical scheme:
an abuse-resistant oxycodone sustained release tablet comprising at least:
1) 1-7 parts by weight of oxycodone-loaded mesh nanocellulose;
2) 4-10 parts by weight of a polymer having swelling properties in water;
wherein, oxycodone active components are distributed on the surface and in the pore channels of the mesh nanocellulose, wherein the polymer with swelling performance in water is selected from one or more of polyalkylene oxide, acrylic acid, acrylate polymer and modified ammonium polymethacrylate I.
Preferably, the oxycodone is selected from oxycodone or pharmaceutically acceptable salts thereof, preferably oxycodone hydrochloride.
As a preferable mode of the invention, the mesh nano-cellulose is prepared by the following method:
(1) hot-pressing gas-solid acidolysis: placing the microcrystalline cellulose absorbing a proper amount of acid water solution in a closed reactor, and carrying out hot-pressing gas-solid acidolysis reaction for 2-16h at the temperature of not more than 130 ℃ and higher than the acid gasification or azeotropic temperature; then adding part of purified water to be uniformly suspended, dropwise adding dilute alkali to neutralize under stirring, and then obtaining a mesh microcrystalline cellulose suspension with a nanometer framework through centrifugal filtration and water washing;
(2) And (3) carrying out combined enzyme catalysis hydrolysis: and (2) mixing the microcrystalline cellulose suspension obtained in the step (1) with a cellulase buffer solution, carrying out enzymolysis reaction for 10-24 hours at the temperature of 25-50 ℃ under stirring, and then carrying out centrifugal filtration and water washing to obtain the mesh nano-cellulose.
As a further preferable aspect of the present invention, the microcrystalline cellulose in the step (1) includes microcrystalline cellulose of refined cotton, wood pulp and bamboo fiber, and microcrystalline cellulose derived from stalks such as reed stems, corncobs, wheat straws and rice straws.
As a further preferred of the present invention, the acid in step (1) is a volatile acid, including nitric acid, hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, hydrosulfuric acid, formic acid, and acetic acid.
In a further preferred mode of the invention, in the step (1), the concentration of the acid aqueous solution is 0.1-6mol/L, and the volume of the acid solution is 0.2-6 times of the mass of the cellulose.
As a further preference of the invention, the concentration of the microcrystalline cellulose suspension in the mesh in the step (2) is less than or equal to 25% (w/v).
In the preparation process of the nano-mesh structure cellulose, the traditional liquid-solid acidolysis reaction is changed into solid-state dry-hot acidolysis reaction, the acidolysis process is similar to the traditional microcrystalline cellulose preparation mechanism, and toxic and harmful substances are not added. Compared with the traditional liquid solid acidolysis reaction, the solid dry-heat acidolysis reaction has the advantages that the surface of the cellulose is more prone to etching a non-crystalline region, so that the surface of the microcrystalline cellulose is beneficial to enzymolysis coarsening and 'engraving'. The microcrystalline cellulose prepared by the method has larger specific surface area and mesh structure, so that the microcrystalline cellulose has high drug-loading capacity, controlled release effect and excellent water suspension stability.
As a further preferred aspect of the present invention, the amount of the cellulase enzyme used in the step (2) is in the range of 5 to 120IU/g in relation to the amount of the cellulose raw material.
As a preferable mode of the invention, the oxycodone-loaded mesh nanocellulose is prepared by the following method:
the drug-loading rate of the mesh nanocellulose is adjustable within 0-5%, so that a certain amount of the mesh nanocellulose is taken to be fully mixed and dispersed with absolute ethyl alcohol according to the actual drug-loading rate requirement to prepare a mesh nanocellulose-ethyl alcohol mixed solution with the solid content of 5-30%, preferably 10-20% and more preferably 15% respectively.
Mixing oxycodone saturated water solution and mesh nano-cellulose-ethanol mixed solution, mixing oxycodone: mixing the mesh nano-cellulose in a ratio of 1: 1-1: 5, and performing spray drying or rotary evaporation to obtain the oxycodone-loaded nano-mesh structure cellulose.
The invention takes the cellulose with a nanometer mesh structure as a carrier, and the oxycodone is loaded, so that the oxycodone can grow on the surface and the mesh pore canals of the mesh nanocellulose again in situ, and the primary slow release effect can be achieved.
As a preferable aspect of the present invention, the polymer having swelling property in water is a polyalkylene oxide, acrylic acid or acrylate polymer.
As a preferable mode of the invention, the polymer with swelling property in water is modified poly ammonium methacrylate I, the preparation method is the same as that of poly ammonium methacrylate I in Chinese pharmacopoeia 2015 edition, but the charging ratio of the three monomers is determined from the original: MMA: BMA: DMAEMA ═ 60: 30: 10 to MMA: BMA: DMAEMA ═ 55: 30: 15. the invention utilizes the water swellable characteristic of the modified ammonium polyacrylate I to further improve the sustained-release effect of the drug and increase the time cost for abusers to extract the drug.
As a preferable mode of the invention, the abuse-proof oxycodone sustained release tablet further comprises 10-25 parts by weight of polyvinyl acetate (PVAC). The possibility that the preparation is washed by ethanol to remove ammonium ester and then extracted by water is avoided by utilizing the characteristic of swelling and gelling in PVAC water-insoluble alcohol.
As a preferable mode of the invention, the abuse-proof oxycodone sustained release tablet further comprises a binder and a disintegrant.
As a further preferred aspect of the present invention, the abuse-proof oxycodone sustained release tablet further comprises one or more of povidone, sodium carboxymethylcellulose, and hydroxypropyl methylcellulose. The cellulose derivative has high viscosity, and can be mixed with drug-loaded nano-cellulose to achieve good affinity, easy uniform dispersion, and avoid the possibility of accelerating drug extraction after the preparation is crushed by abusers.
As a preferable preference of the invention, the abuse-proof oxycodone sustained release tablet further comprises 1-8 parts by weight of povidone and 5-12 parts by weight of CMC-Na.
Preferably, the opioid oral sustained-release tablet is prepared by the following formula:
1) 1-7 parts by weight of oxycodone hydrochloride-loaded mesh nanocellulose;
2) 4-10 parts of modified ammonium polymethacrylate I;
3) 8-24 parts of polyvinyl acetate;
4) 301-8 parts of povidone K;
5) 4-12 parts of sodium carboxymethylcellulose.
As a further preferred aspect of the present invention, the opioid oral sustained release tablet is formulated as follows:
1) 2-6 parts by weight of oxycodone hydrochloride-loaded mesh nanocellulose, wherein the oxycodone hydrochloride loading amount is 20% -50%;
2) 7-10 parts of modified ammonium polymethacrylate I;
3) 12-20 parts of polyvinyl acetate;
4) 302-6 parts of povidone K;
5) 5-11 parts of sodium carboxymethylcellulose.
The preparation method of the oxycodone sustained release tablet provided by the invention is characterized in that the components in the prescription are mixed, granulated and tabletted to obtain the oxycodone sustained release tablet. The oxycodone sustained release tablet has the hardness range of 30-180N, is difficult to crush by adopting a conventional means, is easy to swell when meeting alcohol and water to form viscous liquid, and is difficult to extract.
Has the beneficial effects that:
as a sustained release tablet, the oxycodone sustained release tablet has obvious sustained release effect and no obvious burst release.
The abuse-resistant drug delivery system constructed by the invention has the following characteristic bright points:
(1) the abuse deterrent drug delivery system described above allows solid formulations placed directly in, for example, water to swell and retard the release of oxycodone, and the viscosity of the dissolution system increases with the time of immersion, thereby preventing the abuser from injecting directly with the aqueous extract.
(2) Although ethanol can dissolve the modified RL resin in the solid preparation, the PVAc of the inner layer swells when meeting alcohol to wrap the drug-loaded nanocellulose to form a micelle, so that the way of obtaining the oxycodone drug by filtration and the like can be blocked.
(3) The above abuse-resistant drug delivery system functions between (1) and (2) when extracted using alcohol-water mixtures (wines) in different ratios.
(4) In-vitro dissolution experiments show that the abuse-proof drug delivery system only causes obstruction to the extraction of drugs from human bodies, and the in-vivo abuse-proof drug delivery system can be slowly released in gastric juice and intestinal juice when patients normally take the drugs, so that the abuse-proof drug delivery system has a long-acting function.
Drawings
FIG. 1 is a schematic diagram of an abuse deterrent drug delivery architecture
FIG. 2 swelling State of modified Polyammonium methacrylate I
A. The original ammonium polymethacrylate I is insoluble and suspended in water, the modified ammonium polymethacrylate I swells in water, and the swollen resin is taken out and drained.
FIG. 3 is a flow chart of a process for preparing cellulose with a nano-mesh structure
FIG. 4 is a graph showing a distribution of the particle size of cellulose having a nano-mesh structure
FIG. 5 XRD Pattern of cellulose with Nano-mesh Structure
FIG. 6 atomic force microscope photograph of cellulose with nano-mesh structure
A. AFM (atomic force microscopy) picture of cellulose after gas-solid acidolysis, and AFM picture of cellulose after acidolysis and enzymolysis
FIG. 7 scanning electron microscope image of cold field emission of nano-mesh structured cellulose
SEM picture of microcrystalline cellulose in control group A, SEM picture of cellulose after gas-solid acidolysis in control group B, and SEM picture of cellulose after acidolysis and enzymolysis in combination in control group C
FIG. 8 dissolution profile of abuse deterrent drug delivery system in artificial intestinal fluid
FIG. 9 dissolution of abuse resistant drug delivery system in purified water
FIG. 10 dissolution profile of abuse resistant drug delivery system in simulated gastric fluid
FIG. 11 graph of actual dissolution profiles for abuse deterrent drug delivery systems
The left panel is formulation D and the right panel is formulation E.
FIG. 12 dissolution curve of oxycodone hydrochloride sustained release tablets
A is the dissolution curve of oxycodone hydrochloride sustained release tablets prepared by the method 2.2 in example 4 in enzyme-free gastric juice; b and C are dissolution curves of the oxycodone hydrochloride sustained-release tablets prepared by the method 3.2 in the example 4 in an acetic acid medium and water with the pH value of 4.5 respectively; d is the dissolution curve of the oxycodone hydrochloride sustained release tablets prepared by the method 4.2 in the example 4 in a phosphate medium with pH 7.5.
Detailed Description
Example 1 modified Polyammonium polymethacrylate I
1) Preparation method
The monomer is similar to ammonium polymethacrylate I in the 'Chinese pharmacopoeia 2015 edition', but the feeding ratio of the three monomers is as follows: methyl methacrylate: ethyl acrylate: trimethylammonioethyl methacrylate 60:30:10, to methyl acrylate: ethyl acrylate: trimethylammonioethyl methacrylate ═ 55: 30: 15.
2) main properties
The synthesized polymer has the main performance similar to that of ammonium polymethacrylate I and can be dissolved in ethanol, but the modified ammonium polymethacrylate I is not only soluble in ethanol, but also has the performance of swelling in water and even being soluble, as shown in figure 2.
The modified ammonium polymethacrylate I with 11-14% of trimethyl ammonium chloride ethyl methacrylate content can swell in water, the dissolving speed is accelerated along with the increase of ammonium monomer content, and the swelling speed in cold water is slower and the swelling speed in hot water is accelerated. The water-swellable modified ammonium polymethacrylate I is gelled due to swelling in water (or human body fluid) and makes the preparation difficult to disintegrate, and the drug release is slowed and has no burst release.
Example 2
The preparation process flow chart of the mesh nanocellulose is shown in figure 3, and the preparation method is detailed in example 3 of CN 110452305A. From FIG. 4, it can be seen that the self-made cellulose has a particle size of 500-5000nm, an average particle size of 2025nm, and an overall dimension in the micrometer range; it has no potential toxic hazard to human body and inflammation risk due to nano cellulose (less than or equal to 100nm), and can be directly used as pharmaceutical adjuvant. As shown in the atomic force microscope chart of fig. 6, some ravines have been carved on the surface of the cotton fiber after the gas-solid acid hydrolysis, and the roughness of the surface is increased after the acid hydrolysis, so that more and deeper ravines are carved. From the scanning electron microscope image in fig. 7, it can be seen that the surface of the cotton fiber is roughened after gas-solid acid hydrolysis, and cellulose is further degraded by cellulase to form a multi-nanopore (aperture of 100-300nm) network structure. The reason is that the surface roughness of the nano-cellulose is large, and the nano-cellulose has more gullies with different depths and the network structure with the plurality of nano-pores (the pore diameter is 100-300nm) provides growing points for later-stage drug loading, so that the nano-cellulose has higher drug loading capacity and better slow release effect when releasing the drug, and can be used as a drug slow release carrier.
Example 3
Since oxycodone hydrochloride is a controlled drug, metformin is used for replacing oxycodone hydrochloride in formula screening.
Formula A, B, C preparation method:
(1) preparing a modified ammonium polymethacrylate I solution (11%) ethanol solution for later use.
(2) The prescribed amount of sodium carboxymethylcellulose (CMC-Na) was mixed with 11% ethanol solution of ammonium polymethacrylate I and oven-dried at 50 ℃ for 1 h.
(3) Uniformly mixing the mixture in the step (3) with the prescribed amount of metformin, vinyl acetate and PVP K30, and tabletting.
Preparation method of formula D, E:
(1) adding the metformin saturated aqueous solution, the metformin saturated alcohol solution and the cellulose alcohol solution with a mesh structure into a reaction kettle, and uniformly mixing.
(2) And (2) drying the mixture in the step (1) by using a spray drying method, wherein the spray drying parameters are 55 ℃ at an inlet temperature, 50 ℃ at an outlet temperature, 6ml/min at a spray speed and 2.5bar at a spray pressure, and finally collecting the dried cellulose-loaded metformin with a nano-mesh structure.
(3) Preparing a modified ammonium polymethacrylate I solution (11%) ethanol solution for later use.
(4) The prescribed amount of sodium carboxymethylcellulose (CMC-Na) was mixed with 11% ethanol solution of ammonium polymethacrylate I and oven-dried at 50 ℃ for 1 h.
(5) Uniformly mixing the prescription amount of the mixture of the cellulose with the metformin nano-net structure, the vinyl acetate, the PVP K30 and the mixture in the step (3), and tabletting.
The in vitro dissolution method is described in the second method of Chinese pharmacopoeia, with a dissolution medium volume of 900ml and a rotation speed of 100 r/min
(1) The drug release effect of the delivery system in the artificial intestinal juice (pH6.8) is shown in figure 8, and the sustained release effect of the prescription D, E after the nano-cellulose loaded drug is used can be obviously improved, wherein the drug release of the prescription D is close to a zero-order release model between 1 h and 14h, the drug release is relatively stable, but the prescription E is probably more suitable because the blood concentration is maintained to achieve a long-acting analgesic effect after the mental and analgesic drugs need to take effect quickly.
(2) The drug release effect of the delivery system in the purified water (pH7.1) is shown in figure 9, and considering that the abuser can not extract the drug from the intestinal fluid, the dissolution test is carried out in the purified water, and it can be seen from figure 9 that the drug release conditions of the six prescriptions have no great difference and float from top to bottom by 1% -3%, which indicates that the salt in the dissolution medium can not influence the effect of the drug delivery system. The actual dissolution effect of the abuse deterrent drug delivery system is shown in figure 11.
(3) The release effect of the delivery system in artificial gastric juice (pH1.2) is shown in figure 10, the drug stays in human stomach for no more than 2 hours, so the dissolution is only 2 hours, and the auxiliary materials in the drug delivery system are all non-pH sensitive, so the release effect in gastric juice is similar to that of intestinal juice and water.
Example 4
1. Prescription:
note that*: the modified ammonium polymethacrylate I contains 11% of trimethylammonium ethyl chloride methacrylate.
2. Preparation of abuse-resistant drug delivery System, exemplified by formula 1
2.1 oxycodone hydrochloride sustained-release tablet prescription
2.1.1 formula of cellulose-loaded oxycodone hydrochloride with nano-mesh structure
Oxycodone hydrochloride saturated aqueous solution 8g
Oxycodone hydrochloride saturated alcohol solution 30g
Nano-mesh structure cellulose alcohol solution 3.75g
2.1.2 tableting formula
2.2 preparation Process
(1) Adding the prescription dose of oxycodone hydrochloride saturated aqueous solution, oxycodone hydrochloride saturated alcohol solution and cellulose alcohol solution with a mesh structure into a round-bottom flask, recovering ethanol, centrifuging to obtain precipitate, drying the precipitate in an oven at 50 ℃ for 20 hours, and sieving by a 20-mesh sieve for later use.
(2) Preparing a modified ammonium polymethacrylate I solution (11%) ethanol solution for later use.
(3) Mixing the prescription amount of sodium carboxymethylcellulose (CMC-Na) with 11% ethanol solution of ammonium polymethacrylate I solution, and drying in an oven at 50 ℃ for 1 h.
(4) Uniformly mixing the prescription dose of the mixture of the oxycodone hydrochloride nano-net structure cellulose, the vinyl acetate, the PVP K30 and the mixture in the step (3), and tabletting.
3. Abuse-resistant drug delivery system preparation, exemplified by formula 1
3.1 oxycodone hydrochloride sustained-release tablet prescription
3.1.1 formula of cellulose-supported oxycodone hydrochloride with nano-mesh structure
Oxycodone hydrochloride saturated aqueous solution 8g
Oxycodone hydrochloride saturated alcohol solution 30g
Nano-mesh structure cellulose alcohol solution 3.75g
3.1.2 tableting formulations
3.2 preparation Process
(1) Adding the oxycodone hydrochloride saturated aqueous solution, the oxycodone hydrochloride saturated alcohol solution and the cellulose alcohol solution with a mesh structure into a reaction kettle, and uniformly mixing.
(2) And (2) drying the mixture in the step (1) by using a spray drying method, wherein the spray drying parameters are 55 ℃ at an inlet temperature, 50 ℃ at an outlet temperature, 6ml/min at a spray speed and 2.5bar at a spray pressure, and finally collecting the dried cellulose-loaded oxycodone hydrochloride with the nano-mesh structure.
(3) Preparing a modified ammonium polymethacrylate I solution (11%) ethanol solution for later use.
(4) The prescribed amount of sodium carboxymethylcellulose (CMC-Na) was mixed with 11% ethanol solution of ammonium polymethacrylate I and oven-dried at 50 ℃ for 1 h.
(5) Uniformly mixing the prescription dose of the mixture of the oxycodone hydrochloride nano-net structure cellulose, the vinyl acetate, the PVP K30 and the mixture in the step (3), and tabletting.
4. Abuse-resistant drug delivery system preparation, exemplified by formula 1
4.1 oxycodone hydrochloride sustained-release tablet prescription
4.1.1 formula of cellulose-loaded oxycodone hydrochloride with nano-mesh structure
Oxycodone hydrochloride saturated aqueous solution 8g
Oxycodone hydrochloride saturated alcohol solution 30g
Nano-mesh structure cellulose alcohol solution 3.75g
4.1.2 tableting formula
4.2 preparation Process
(1) Adding oxycodone hydrochloride saturated aqueous solution, oxycodone hydrochloride saturated alcohol solution and cellulose alcohol solution with a mesh structure into a reaction kettle, mixing, recovering ethanol, and dispersing precipitate with tert-butyl alcohol.
(2) Freeze-drying: starting a freeze dryer to pre-freeze the product, reducing the temperature of the product to below 50 ℃ below zero at a speed of 2 ℃/min, and preserving the heat for 450 min. And after the product is completely frozen and solid, starting a condenser to reduce the temperature to below-50 ℃, starting vacuum freeze-drying, gradually increasing the temperature to-15 ℃, keeping for 480min, continuously gradually increasing the temperature to-10 ℃, and keeping for 300min to basically freeze-dry the water and the tert-butyl alcohol in the sample. And continuously heating to 20 ℃, keeping the temperature for 300min, and finishing freeze-drying to obtain the cellulose loaded oxycodone hydrochloride with the nano-mesh structure.
(3) Preparing 11 percent ethanol solution of the modified ammonium polymethacrylate I solution for later use.
(4) The prescribed amount of sodium carboxymethylcellulose (CMC-Na) was mixed with 11% ethanol solution of ammonium polymethacrylate I solution, and oven-dried at 50 ℃ for 1 h.
(5) Uniformly mixing the prescription dose of the mixture of the oxycodone hydrochloride nano-net structure cellulose, the vinyl acetate, the PVP K30 and the mixture in the step (3), and tabletting.
Example 5
The dissolution property of the oxycodone hydrochloride sustained release tablets prepared according to the preparation processes in the following method example 4: enzyme-free gastric juice dissolution conditions:
dissolution conditions in water
| Method for preparing dissolving-out medium | Degassed purified water |
| Volume of medium/ml | 900 |
| Temperature/. degree.C | 37 |
| Rotational speed/r/min | 100rpm ( |
| Sample volume/ |
5 |
| Sampling time point (min) | 30,60,120,240,360,480,600,720,900,1080,1440 |
Dissolution conditions in phosphate buffer pH7.5
Dissolution conditions in acetate buffer of pH4.5
The dissolution curve of the oxycodone hydrochloride sustained release tablets prepared by the method 2.2 in the example 4 in the enzyme-free gastric juice is shown in figure 12A; 3.2 the dissolution curves of the oxycodone hydrochloride sustained release tablets prepared by the method in an acetic acid medium and water with the pH value of 4.5 are shown in a figure 12B and a figure 12C; 4.2 the dissolution curve of the oxycodone hydrochloride sustained release tablets prepared by the method in phosphate medium with pH7.5 is shown in figure 12D. In-vitro dissolution experiments show that the abuse-proof drug-loaded delivery system for oxycodone hydrochloride only hinders the extraction of drugs from human bodies, and the in-vivo abuse-proof drug-loaded delivery system can be slowly released in gastric juice and intestinal juice when patients normally take the drugs.
Claims (10)
1. An abuse-resistant oxycodone sustained release tablet characterized by comprising at least:
1) 1-7 parts by weight of oxycodone-loaded mesh nanocellulose;
2) 4-10 parts by weight of polymer with swelling property in water;
3) 8-24 parts of polyvinyl acetate;
wherein, oxycodone active components are distributed on the surface and in the pore channels of the mesh nanocellulose, wherein the polymer with swelling performance in water is selected from one or more of polyalkylene oxide, acrylic acid, acrylate polymer and modified ammonium polymethacrylate I; the preparation method of the modified ammonium polymethacrylate I is the same as that of ammonium polymethacrylate I in 'Chinese pharmacopoeia 2015 edition', but the feeding ratio of three monomers is as follows: MMA: BMA: DMAEMA = 60: 30: 10 to MMA: BMA: DMAEMA = 55: 30: 15.
2. the oxycodone sustained-release tablet according to claim 1, characterized in that the oxycodone is selected from oxycodone or pharmaceutically acceptable salts thereof.
3. The oxycodone sustained-release tablet according to claim 1, characterized in that the oxycodone is oxycodone hydrochloride.
4. The oxycodone sustained release tablet of any one of claims 1 to 3, wherein the oxycodone-loaded mesh nanocellulose is prepared by the following method:
Taking a certain amount of mesh nano-cellulose and absolute ethyl alcohol, fully mixing and dispersing to prepare a mesh nano-cellulose-ethyl alcohol mixed solution with the solid content of 5-30%;
mixing oxycodone active ingredient saturated aqueous solution and meshed nano-cellulose alcoholic solution at the ratio of oxycodone: mixing the cellulose with the nano-mesh structure in a mass ratio of 1: 1-1: 5, and then performing spray drying, rotary evaporation or freeze drying to obtain the oxycodone-loaded mesh nano-cellulose.
5. The oxycodone sustained release tablet of claim 1, wherein the abuse-resistant oxycodone sustained release tablet further comprises a binder and a disintegrant.
6. The oxycodone sustained release tablet of claim 5, wherein the abuse-resistant oxycodone oral sustained release tablet further comprises one or more of povidone, sodium carboxymethyl cellulose, and sodium carboxymethyl starch.
7. The oxycodone sustained release tablet according to claim 6, characterized in that the abuse-resistant oxycodone oral sustained release tablet further comprises 1-6 parts by weight of povidone and 4-12 parts by weight of sodium carboxymethylcellulose.
8. The oxycodone sustained release tablet of any one of claims 1-6, wherein the oxycodone oral sustained release tablet is formulated as follows:
1) 1-7 parts by weight of oxycodone hydrochloride-loaded mesh nanocellulose;
2) 4-10 parts of modified ammonium polymethacrylate I;
3) 8-24 parts of polyvinyl acetate;
4) povidone K301-8 weight parts;
5) 4-12 parts of sodium carboxymethylcellulose.
9. The oxycodone sustained release tablet of claim 8, wherein the oxycodone oral sustained release tablet is formulated as follows:
1) 2-6 parts by weight of oxycodone hydrochloride-loaded mesh nanocellulose, wherein the oxycodone hydrochloride loading amount is 20% -50%;
2) 7-10 parts of modified ammonium polymethacrylate I;
3) 12-20 parts of polyvinyl acetate;
4) povidone K302-6 weight parts;
5) 5-11 parts of sodium carboxymethylcellulose.
10. The method for preparing oxycodone sustained release tablets according to claim 1, wherein the oxycodone sustained release tablets are obtained by mixing the components in the prescription, granulating and tabletting.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101304752A (en) * | 2005-11-10 | 2008-11-12 | 弗拉梅技术公司 | Anti-misuse microparticulate oral pharmaceutical form |
| CN101394839A (en) * | 2006-03-01 | 2009-03-25 | 爱的发制药有限公司 | Crush-resistant oxycodone tablets intended for preventing accidental misuse and unlawful diversion |
| CN110452305A (en) * | 2019-08-14 | 2019-11-15 | 安徽安生生物化工科技有限责任公司 | It is a kind of with mesh-structured microcrystalline cellulose and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050074493A1 (en) * | 2003-10-03 | 2005-04-07 | Mehta Atul M. | Extended release formulations of opioids and method of use thereof |
| US9492444B2 (en) * | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
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| CN101304752A (en) * | 2005-11-10 | 2008-11-12 | 弗拉梅技术公司 | Anti-misuse microparticulate oral pharmaceutical form |
| CN101394839A (en) * | 2006-03-01 | 2009-03-25 | 爱的发制药有限公司 | Crush-resistant oxycodone tablets intended for preventing accidental misuse and unlawful diversion |
| CN110452305A (en) * | 2019-08-14 | 2019-11-15 | 安徽安生生物化工科技有限责任公司 | It is a kind of with mesh-structured microcrystalline cellulose and preparation method thereof |
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