CN112741813A - Naltrexone binary subcutaneous implant and preparation method thereof - Google Patents
Naltrexone binary subcutaneous implant and preparation method thereof Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
Abstract
The invention relates to a naltrexone binary subcutaneous implant and a preparation method thereof. The naltrexone binary subcutaneous implant comprises a component A and a component B, wherein the component A is a naltrexone dispersant and comprises a naltrexone active ingredient, a dispersant and an adhesive; the component B is naltrexone sustained release preparation, which comprises naltrexone active ingredients and pharmaceutically acceptable sustained release carriers. The active ingredient of naltrexone is naltrexone compound superfine powder and/or pharmaceutically acceptable salt superfine powder thereof. The naltrexone binary subcutaneous implant not only has quick response, but also has a release period as long as 9 months (more than 270 days), has complete release degree, effectively solves the problem of poor compliance of a patient caused by drug addiction attack within a drug addiction stopping time window due to slow response of the naltrexone slow-release implant, and obviously improves the treatment effect.
Description
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a naltrexone binary subcutaneous implant and a preparation method thereof.
Background
Naltrexone, alias naltrexone, naltrexone (free base) or 17- (cyclopropylmethyl) -4, 5-epoxy-3, 14-dihydroxymorphinan-6-one; the molecular formula is C20H23NO4, the molecular weight is 341.4, and the structural formula is as follows:
naltrexone is an opioid receptor antagonist, which, like naloxone, significantly attenuates or completely blocks opioid receptors, even reversing the effects produced by intravenous opioid administration. Naltrexone hydrochloride is mainly used for the adjuvant treatment of patients with opioid drug addiction in the rehabilitation period, so that the patients with opioid drug addiction can maintain normal life and prevent or reduce relapse. Naltrexone has very few side effects and is therefore a very potent and effective drug; however, it is not ideal in clinical use, mainly because the drug taken by the addicted patient every day results in poor compliance.
Chinese patent document CN200610152903.7 discloses a long-acting sustained-release preparation of naltrexone, which is prepared by tabletting and coating microspheres composed of naltrexone and polylactic acid, the average molecular weight of the polylactic acid used is 15-35 ten thousand daltons, and the microspheres composed of naltrexone and polylactic acid are coated with polylactic acid on the outer layer, thereby avoiding the occurrence of drug burst release phenomenon and obtaining the effect of slow release.
Chinese patent document CN201110457641.6 discloses a naltrexone long-acting implant, which contains polylactic acid and naltrexone, and is a particle tabletting and coating structure, the particles are prepared into slow-release pellets by tabletting, the slow-release pellets contain polylactic acid and naltrexone, the weight ratio of polylactic acid to naltrexone in the slow-release pellets is 1:1-2, and the coating layer is DL-polylactic acid.
Preparation and quality control of triptorelin microspheres (Longradium et al, proceedings of Hubei national academy of sciences 2011, 2:28) disclose preparation process research of triptorelin microspheres, which comprises the steps of adopting a mixed solution of gelatin aqueous solution and triptorelin as an internal water phase, injecting a PVA (polyvinyl alcohol) solution with a certain concentration, stirring at a high speed for emulsification, and drying to obtain the slow-release microspheres.
A Master research paper, namely preparation and research of polylactic acid microspheres (manting, northwest university, 2007), researches the preparation of urapidil hydrochloride PLLA (levorotatory polylactic acid) sustained-release microspheres and screens and investigates parameters in a preparation process, wherein the method for coating an outer membrane with urapidil hydrochloride PLLA microspheres solves the problem of burst release of a medicament, namely, a chitosan outer membrane and a chitosan and sodium alginate outer membrane are respectively coated on medicament-carrying microspheres to obtain two microspheres A and B; the A and B microspheres and the medicine carrying microsphere C without the outer membrane are tested for in vitro release performance under the same condition, so that the medicine release is mild, and the problem of 'burst release' of the medicine is solved.
In the research process of the naltrexone long-acting implant, the naltrexone long-acting implant is found to have the problems of slow effect and incapability of quickly reaching the blood-drug concentration required by drug treatment, so that the drug addiction of a patient within a drug rehabilitation time window is caused, and the acceptance and treatment effect of the patient are further influenced. However, increasing the dose will not only solve the above problems, but also bring about a series of side effects.
Disclosure of Invention
In order to solve the problems that the existing naltrexone sustained release preparation has slow effect and can not quickly reach the blood concentration of a treatment window, the invention provides a naltrexone binary subcutaneous implant and a preparation method thereof.
In the research process, the naltrexone dispersible implant is found to rapidly increase the blood-drug concentration of naltrexone in animals (or humans) and can be maintained for about one week. Based on the research, we find that the long-acting implant (slow release agent) and the dispersed implant are prepared into a composite agent (namely a binary implant), the defects of the two agents are overcome, the advantages are obvious, and the binary implant not only can enable the medicine to take effect quickly, but also can maintain the effective blood-medicine concentration for a long time.
In order to achieve the purpose, the invention is realized by the following technical scheme:
in a first aspect, the invention provides a naltrexone binary subcutaneous implant, which comprises a component A and a component B, wherein the component A is a naltrexone dispersant and comprises a naltrexone active ingredient, a dispersant and a binder; the mass ratio of the naltrexone active ingredient to the dispersant to the binder is 1:0.4-0.9:0.2-0.8, preferably 1:0.5-0.9:0.3-0.7, more preferably 1:0.6-0.75:0.4-0.6, for example 1: 0.65: 0.5 or 1: 0.7: 0.4;
the component B is naltrexone sustained release preparation which comprises naltrexone active ingredients and pharmaceutically acceptable sustained release carriers, wherein the mass ratio of the naltrexone active ingredients to the sustained release carriers is 1:0.5-2, preferably 1:0.6-1.5, more preferably 1:0.9-1.1, such as 1:0.8, 1: 1.2 or 1: 1.8;
the mass ratio of the component A to the component B is 1:3-6, preferably 1:4-5, for example 1: 3.5, 1: 4.5 or 1: 5;
the active ingredient of the naltrexone is naltrexone compound superfine powder and/or pharmaceutically acceptable salt superfine powder thereof.
In the naltrexone binary subcutaneous implant of the present invention, the sustained release carrier comprises chitosan and polylactic acid, and the mass ratio of chitosan to polylactic acid is 1:0.2-1.0, preferably 1:0.3-0.8, more preferably 1:0.4-0.6, for example 1:0.7 or 1: 0.9;
preferably, the molecular weight of the polylactic acid is 1.8 to 40 ten thousand, preferably 2 to 10 ten thousand, for example 4, 6, 9, 15, 26, 31 or 38 ten thousand; and/or the chitosan has a molecular weight of 1 to 60 ten thousand, preferably 10 to 30 ten thousand, for example 5, 8, 16, 23, 36, 45 or 55 ten thousand.
In the naltrexone binary subcutaneous implant, the dispersing agent is compressible starch CS (or pregelatinized starch); and/or the binder is polyvinylpyrrolidone (PVP) (or crospovidone PVPP), preferably a 5-10 wt%, e.g. 6 wt% or 8 wt% polyvinylpyrrolidone (PVP) ethanolic solution.
In the naltrexone binary subcutaneous implant, the naltrexone binary subcutaneous implant further comprises a lubricant, the lubricant has a mass of 0.05-2 wt%, preferably 0.08-1.2 wt%, such as 0.06 wt%, 0.1 wt%, 0.3 wt%, 0.6 wt%, 0.8 wt% or 1.1 wt%, relative to the sum of the masses of the a component and the B component, and the lubricant is preferably magnesium stearate.
In the naltrexone binary subcutaneous implant, the average particle size of the naltrexone superfine powder is less than or equal to 15 μm, such as the particle size of 100-800nm, preferably 300-500nm, such as 200nm, 350nm or 450nm, and is more preferred; the naltrexone pharmaceutically acceptable salt comprises an inorganic salt and an organic salt, wherein the inorganic salt is at least one selected from the group consisting of sulfate, hydrochloride, hydrobromide, nitrate and phosphate; the organic salt is at least one selected from acetate, propionate, malonate, hydroxyacetate, 2-hydroxypropionate, pamoate, 2-oxopropionate, 2-butenedioate, oxalate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate; preferably, the particle size of the naltrexone pharmaceutically acceptable salt submicron powder is 100-800nm, and more preferably 300-500 nm.
In a second aspect, the present invention provides a preparation method of the naltrexone binary subcutaneous implant, comprising the following steps:
A. preparing naltrexone active ingredient superfine powder: preparing naltrexone into naltrexone active ingredient micropowder, for example, using a ball mill;
B. preparation of naltrexone dispersant: mixing naltrexone micropowder and dispersant (preferably compressible starch CS) thoroughly, adding binder (preferably 5-10 wt% (such as 6 wt% or 8 wt%) ethanol solution of polyvinylpyrrolidone PVP, and using ethanol solution to make binder amount based on polyvinylpyrrolidone), mixing thoroughly, making into soft mass, sieving to make into granule, and grading to obtain naltrexone dispersant;
C. preparing naltrexone sustained release microspheres: dissolving the naltrexone active ingredient superfine powder prepared in the step A and a pharmaceutically acceptable slow release carrier (preferably, the slow release carrier comprises chitosan CTS and polylactic acid PLA) in an organic solvent (preferably, the organic solvent comprises dichloromethane and/or chloroform), stirring to form microspheres, filtering, and drying to obtain naltrexone slow release microspheres;
D. tabletting: fully mixing and tabletting the naltrexone dispersing agent prepared in the step B and the naltrexone sustained-release microspheres prepared in the step C to obtain a naltrexone binary implant bare chip (each bare chip has the weight of, for example, 200-1000mg, and further, for example, 300mg or 400 mg);
E. coating: and D, coating the bare chip of the naltrexone binary implant prepared in the step D, and drying to obtain the naltrexone binary subcutaneous implant.
In the preparation method, in the step A, the particle size of the naltrexone active ingredient submicron powder can be 100-; and/or the presence of a gas in the gas,
in the step B, naltrexone active ingredients: dispersing agent: the mass ratio of the three adhesives is 1:0.4-0.9:0.2-0.8, preferably 1:0.5-0.9:0.3-0.7, more preferably 1:0.6-0.75:0.4-0.6, for example 1: 0.65: 0.5 or 1: 0.7: 0.4; the particle size of the naltrexone dispersant may be 200-800 μm, for example 250 μm, 400 μm, 500 μm or 750 μm; and/or the presence of a gas in the gas,
in the step C, the mass ratio of the chitosan to the polylactic acid is 1:0.2-1.0, preferably 1:0.3-0.8, more preferably 1:0.4-0.6, for example, 1:0.7 or 1: 0.9; preferably, the molecular weight of the polylactic acid is 1.8 to 40 ten thousand, preferably 2 to 10 ten thousand, for example 4, 6, 9, 15, 26, 31 or 38 ten thousand; and/or the chitosan has a molecular weight of 1 to 60 ten thousand, preferably 10 to 30 ten thousand, for example 5, 8, 16, 23, 36, 45 or 55 ten thousand; in the case of mixtures of dichloromethane and chloroform, the volume ratio of dichloromethane to chloroform is (1-4):1, for example 1.5: 1. 2: 1 or 3.5: 1; preferably, the microspheres are formed by stirring at 30-45 ℃, e.g. 35 ℃ or 43 ℃, and have a particle size of 20-100 μm, e.g. 35 μm, 50 μm, 60 μm or 85 μm; and/or the presence of a gas in the gas,
in the step D, the mass ratio of the naltrexone dispersing agent to the naltrexone sustained release microspheres may be 1:3-6, preferably 1:4-5, for example, 1: 3.5, 1: 4.5 or 1: 5; preferably, the conditions for tableting are tableting at a temperature of 40-50 ℃, e.g. 42 ℃ or 49 ℃, and a pressure of 8-15KN, e.g. 9KN or 13 KN; and/or the presence of a gas in the gas,
in the step E, the drying condition is that the mixture is firstly dried in air at 15-25 ℃, such as 17 ℃ or 24 ℃ for 30-60s, such as 40s or 55s, and then dried in vacuum at 30-55 ℃, such as 35 ℃, 45 ℃ or 52 ℃ for less than 48h (such as 1-24 h, preferably 5-24 h); preferably, the coating comprises coating with a solution of polylactic acid, PLA, in ethyl acetate at a concentration of 5-10 wt%, such as 5.5 wt% or 9 wt%, preferably 8 wt%.
In the above preparation method, in the step D, the following steps are further included between the step of sufficiently mixing and the step of tabletting: adding a lubricant and fully mixing uniformly; the mass of the lubricant is 0.05-2 wt.%, preferably 0.08-1.2 wt.%, for example 0.06 wt.%, 0.1 wt.%, 0.3 wt.%, 0.6 wt.%, 0.8 wt.% or 1.1 wt.%, relative to the sum of the masses of the a-and B-components, the lubricant preferably being magnesium stearate.
The invention also provides the naltrexone binary subcutaneous implant prepared by the preparation method.
In the invention, the compressible starch CS is pregelatinized starch, and the polyvinylpyrrolidone PVP is crospovidone.
The technical scheme of the invention has the following advantages:
(1) the invention designs a naltrexone binary subcutaneous implant consisting of a component A and a component B, wherein the component A is a naltrexone dispersant which can take effect quickly, and the component B is a naltrexone sustained-release agent which can take effect for a long time. The component A and the component B are prepared into the complexing agent, so that the defects of slow effect taking and short maintenance time of the naltrexone long-acting preparation are effectively overcome, and the drug compliance and the practicability are greatly improved. Clinical drug rehabilitation practice shows that the naltrexone binary subcutaneous implant prepared by the invention not only can rapidly reach the blood-drug concentration required by treatment of patients, but also can maintain the blood-drug concentration for a long time (can maintain 9 months and more than 270 days). A large body of clinical data indicates that patient compliance (with good therapeutic compliance) and prevention of drug relapse are good after the use of the binary subcutaneous implant.
(2) The naltrexone binary subcutaneous implant disclosed by the invention is composed of a dispersant unit and a sustained-release agent unit, wherein the dispersant unit can quickly take effect to reach a drug treatment window, and the sustained-release agent unit can be effective for a long time, so that a patient can keep a high-level blood concentration for a long time, the defect that the naltrexone sustained-release implant cannot quickly reach the blood-drug concentration (treatment window) of the patient is effectively overcome, the compliance of the patient to the drug is remarkably improved, the clinical defect that the sustained-release dosage form drug is released for a long time (more than 180 days) and takes effect slowly (after 7 days) is effectively overcome, the drug-loading amount is increased, the retention time of the drug in a human body can be effectively prolonged, the drug effect is enhanced, and the toxic. The binary subcutaneous implant can be stably released in a drug release period of nine months (more than 270 days), obviously improves the clinical treatment effect of the naltrexone implant and reduces the side effect of the naltrexone implant.
(3) According to the preparation method of the naltrexone binary subcutaneous implant, naltrexone dispersant particles and naltrexone microspheres are fully and uniformly mixed to form a skeleton structure, so that the occurrence of microsphere fragmentation during tabletting is avoided, and the occurrence of a drug burst release phenomenon is avoided. The preparation method has mature process and good stability, and provides technical support for the commercial application of the naltrexone binary subcutaneous implant.
Drawings
In order that the present disclosure may be more readily and clearly understood, reference is now made to the following detailed description of the present disclosure taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a graph of blood levels in rats 10 days after implantation of the naltrexone dispersion implant of Experimental example 1;
FIG. 2 is a graph of blood concentration in rats 10 days after implantation of the naltrexone sustained release implant in Experimental example 2;
FIGS. 3 and 4 are graphs of plasma levels of rats 10 days and 180 days after implantation of the naltrexone binary subcutaneous implant in Experimental example 3, respectively;
fig. 5 and 6 are graphs of blood concentrations in humans 10 days and 180 days after implantation of the naltrexone binary subcutaneous implant in Experimental example 4, respectively.
Detailed Description
Before the present embodiments are described in detail, it is to be understood that the invention is not limited in scope to the specific embodiments; the terminology used in the examples herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated.
Comparative example 1 preparation of naltrexone dispersible implant
The raw materials of the naltrexone dispersion implant of this comparative example included: 1000g of naltrexone, 667g of dispersant Compressible Starch (CS), 750g of binder polyvinylpyrrolidone (PVP), 5 wt% ethanol solution and 10g of lubricant magnesium stearate.
The preparation method comprises the following steps:
(1) preparing naltrexone superfine powder: preparing naltrexone into naltrexone superfine powder with the particle size of 300-500nm by using a ball mill;
(2) and (3) granulating: mixing naltrexone superfine powder with dispersant Compressible Starch (CS), adding 5 wt% ethanol solution of binder polyvinylpyrrolidone (PVP), mixing, making into soft material, sieving with 60 mesh sieve, granulating, and oven drying at 50 deg.C for 24 hr to obtain naltrexone dispersant granule;
(3) tabletting: fully mixing the particles of the naltrexone dispersant with a lubricant magnesium stearate, and tabletting under the pressure of 15KN to obtain a naltrexone dispersant bare chip;
(4) coating: naltrexone dispersion implants were obtained by coating the naltrexone dispersion bare tablets with an 8% solution of polylactic acid (PLA) ethyl acetate.
Comparative example 2 preparation of naltrexone sustained release implant
The raw materials of the naltrexone sustained release implant of the comparative example comprise: 1000g of naltrexone, 667g of slow release carrier Chitosan (CTS) (molecular weight is 20 ten thousand), 333g of slow release carrier polylactic acid (PLA) (molecular weight is 2 ten thousand) and 20g of lubricant magnesium stearate.
The preparation method comprises the following steps:
(1) preparing naltrexone superfine powder: preparing naltrexone into naltrexone superfine powder with the particle size of 300-500nm by using a ball mill;
(2) preparing naltrexone sustained release microspheres: weighing naltrexone superfine powder, sustained-release carrier Chitosan (CTS) and polylactic acid (PLA) according to the selected weight, fully and uniformly mixing, dissolving in dichloromethane to serve as a dispersion phase, taking water as a continuous phase, slowly adding the dispersion phase into the continuous phase under the conditions of stirring at 1200rpm/min and 40 ℃ to form microspheres, filtering and drying to obtain naltrexone sustained-release microspheres with the particle size of 20 mu m;
(3) tabletting: uniformly mixing the prepared naltrexone sustained-release microspheres and magnesium stearate with the selected weight, heating to 40 ℃, tabletting, and obtaining naltrexone sustained-release implant bare chips under the tabletting pressure of 15 KN;
(4) coating: coating the naltrexone sustained-release implant bare chip with 8% of polylactic acid (PLA) ethyl acetate solution, then suspending and drying for 60s at 25 ℃, and then drying for 24h at 50 ℃ in vacuum to obtain the naltrexone sustained-release implant.
EXAMPLE 1 preparation of a binary subcutaneous naltrexone implant
The naltrexone binary subcutaneous implant of the embodiment comprises the following raw materials:
the component A comprises: 1000g of naltrexone, 667g of dispersant Compressible Starch (CS), 750g of adhesive polyvinylpyrrolidone (PVP) and 5% ethanol solution;
and B component: 4834g of naltrexone, 3224g of slow release carrier Chitosan (CTS) (molecular weight is 20 ten thousand), 1610g of slow release carrier polylactic acid (PLA) (molecular weight is 2 ten thousand);
and 121g of lubricant magnesium stearate.
The preparation method comprises the following steps:
A. preparing naltrexone superfine powder: preparing naltrexone into naltrexone superfine powder with the particle size of 300-500nm by using a ball mill;
B. preparation of naltrexone dispersant: fully and uniformly mixing 1000g of naltrexone superfine powder and selected weight of dispersant Compressible Starch (CS) (the mass ratio of the naltrexone superfine powder to the dispersant Compressible Starch (CS) is 1: 0.67), then adding 5 wt% of ethanol solution of binding agent polyvinylpyrrolidone (PVP) (the mass ratio of the naltrexone superfine powder to the ethanol solution of polyvinylpyrrolidone is 1: 0.75), fully mixing, making into soft material, then sieving with a 60-mesh sieve, making into granules, and finishing granules to obtain the naltrexone dispersant with the particle size of 500 mu m;
C. preparing naltrexone sustained release microspheres: weighing 4834g of naltrexone superfine powder, and selected weight of sustained release carrier Chitosan (CTS) and polylactic acid (PLA) (the mass of naltrexone and the mass of sustained release carrier chitosan and polylactic acid and the mass ratio of the two are 1:1, and the mass ratio of chitosan and polylactic acid is 1: 0.5), fully mixing, dissolving in dichloromethane solvent to obtain a disperse phase, and using water as a continuous phase. Slowly adding the dispersed phase into the continuous phase under the conditions of stirring at 1200rpm/min and 40 ℃ to form microspheres, filtering and drying to obtain naltrexone sustained-release microspheres with the particle size of 20 mu m;
D. tabletting: fully mixing a naltrexone dispersing agent and naltrexone sustained-release microspheres (the mass ratio of the naltrexone dispersing agent to the naltrexone sustained-release microspheres is 1: 4), then adding a lubricant magnesium stearate with a selected weight (the mass ratio of the naltrexone dispersing agent to the naltrexone sustained-release microspheres to the lubricant magnesium stearate is 1: 0.01), fully and uniformly mixing, and then pressing tablets at 40 ℃ and 8KN to obtain a naltrexone binary implant bare chip;
E. coating: coating the naltrexone binary implant bare chip with 8% of polylactic acid (PLA) ethyl acetate solution, then suspending and drying for 60s at 25 ℃, and then drying for 24h at 50 ℃ in vacuum to obtain the naltrexone binary subcutaneous implant.
Example 2
Similar to example 1, except that the mass ratio of the naltrexone active ingredient to the dispersant to the binder was adjusted to 1:0.5: 0.4; the mass ratio of the naltrexone active ingredient to the sustained-release carrier is 1:0.7, the mass ratio of the chitosan to the polylactic acid in the sustained-release carrier is 1:0.7, and the adhesive is 10% ethanol solution of polyvinylpyrrolidone (PVP).
Example 3
Similar to example 1, except that the mass ratio of the naltrexone active ingredient to the dispersant to the binder was adjusted to 1:0.8: 0.6; the mass ratio of the naltrexone active ingredient to the sustained-release carrier is 1:1.5, the mass ratio of the chitosan to the polylactic acid in the sustained-release carrier is 1:0.4, and the adhesive is 10% ethanol solution of polyvinylpyrrolidone (PVP).
Experimental example 1 measurement of blood concentration of rat 10 days after implantation of naltrexone dispersion implant
The naltrexone dispersion implant prepared in comparative example 1 was implanted in rats and blood was collected from the orbit on days 1,2,3,4,5,6,7,8,9, and 10 after implantation, and plasma was isolated by a conventional method. Taking 0.5mL of a plasma sample, adjusting the pH value to 8-9 by using 1.3mol/L sodium bicarbonate buffer solution, adding 5mL of dichloromethane each time, extracting for three times, combining extracting solutions, separating an organic phase, drying the organic phase by using nitrogen on a water bath at 50 ℃, and measuring the blood-drug concentration of a rat by using HPLC. The specific experimental results are shown in fig. 1. Wherein the abscissa is time (days) and the ordinate is blood-drug concentration (ng/mL).
Experimental example 2 measurement of blood concentration in rats 10 days after implantation of naltrexone sustained release implant
The naltrexone sustained release implant prepared in comparative example 2 was implanted in rats and blood was collected from the orbit on days 0,1,2,3,4,5,6,7,8,9, and 10 after implantation, and plasma was isolated by a conventional method. Taking 0.5mL of a plasma sample, adjusting the pH value to 8-9 by using 1.3mol/L sodium bicarbonate buffer solution, adding 5mL of dichloromethane each time, extracting for three times, combining extracting solutions, separating an organic phase, drying the organic phase by using nitrogen on a water bath at 50 ℃, and measuring the blood-drug concentration of a rat by using HPLC. The specific experimental results are shown in fig. 2. Wherein the abscissa is time (days) and the ordinate is blood-drug concentration (ng/mL).
Experimental example 3 measurement of blood concentration of rats 10 days and 180 days after implantation of naltrexone binary subcutaneous implant
The naltrexone binary subcutaneous implants prepared in example 1 were implanted in rats and blood plasma was isolated by routine methods after implantation by orbital bleeds on days 0,1,2,3,4,5,6,7,8,9,10 and 20,40,60,80,100,120,140,160, 180. Taking 0.5mL of a plasma sample, adjusting the pH value to 8-9 by using 1.3mol/L sodium bicarbonate buffer solution, adding 5mL of dichloromethane each time, extracting for three times, combining extracting solutions, separating an organic phase, drying the organic phase by using nitrogen on a water bath at 50 ℃, and measuring the blood-drug concentration of a rat by using HPLC. The results of the specific experiments are shown in fig. 3 and 4. Wherein the abscissa is time (days) and the ordinate is blood-drug concentration (ng/mL).
As can be seen from fig. 1 to 4, compared to the naltrexone dispersible implant prepared in comparative example 1 and the naltrexone sustained release implant prepared in comparative example 2, the naltrexone binary subcutaneous implant prepared in example 1 overcomes the disadvantage of short maintenance time of the naltrexone sustained release implant and the naltrexone dispersible implant, and can take effect within less than 1 day after being implanted into rats, and can stably release and maintain effective blood concentration within 180 days after being implanted.
Experimental example 4 drug-time curves of human plasma of naltrexone binary subcutaneous implants the naltrexone binary subcutaneous implants prepared in example 1 were implanted subcutaneously into the abdomen of drug-addicted patients, venous blood was taken on days 1,2,3,4,5,6,7,8,9,10 and 20,40,60,80,100,120,140,160,180, respectively, after implantation, blood plasma was isolated from the patients, 0.5mL of the plasma samples were taken, pH was adjusted to 8-9 with 1.3mol/L sodium bicarbonate buffer, 5mL of methylene chloride was added each time, extraction was carried out three times, the extracts were combined, the organic phase was separated, dried over nitrogen in a 50 ℃ water bath, and the blood-drug concentration of the human was determined by HPLC. The results of the specific experiments are shown in fig. 5 and 6. Wherein the abscissa is time (days) and the ordinate is blood-drug concentration (ng/mL).
As can be seen from fig. 5 and 6, the naltrexone binary subcutaneous implant prepared in example 1 can achieve both rapid onset of action within less than 1 day to reach the therapeutic window and stable release within 180 days after being implanted into a human body, so that a patient can maintain an effective blood concentration for a long time.
Claims (9)
1. A naltrexone binary subcutaneous implant is characterized by comprising a component A and a component B, wherein the component A is a naltrexone dispersant and comprises a naltrexone active ingredient, a dispersant and a binder; the mass ratio of the naltrexone active ingredient to the dispersant to the binder is 1:0.4-0.9:0.2-0.8, preferably 1:0.5-0.9:0.3-0.7, more preferably 1:0.6-0.75: 0.4-0.6;
the component B is naltrexone sustained release preparation which comprises naltrexone active ingredients and pharmaceutically acceptable sustained release carriers, wherein the mass ratio of the naltrexone active ingredients to the sustained release carriers is 1:0.5-2, preferably 1:0.6-1.5, and more preferably 1: 0.9-1.1;
the mass ratio of the component A to the component B is 1:3-6, preferably 1: 4-5;
the active ingredient of the naltrexone is naltrexone compound superfine powder and/or pharmaceutically acceptable salt superfine powder thereof.
2. The naltrexone binary subcutaneous implant according to claim 1, wherein the slow release carrier comprises chitosan and polylactic acid, the mass ratio of chitosan to polylactic acid being 1:0.2-1.0, preferably 1:0.3-0.8, more preferably 1: 0.4-0.6;
preferably, the molecular weight of the polylactic acid is 1.8 to 40 ten thousand, preferably 2 to 10 ten thousand; and/or the molecular weight of the chitosan is 1-60 ten thousand, preferably 10-30 ten thousand.
3. The naltrexone binary subcutaneous implant according to claim 1 or 2, wherein said dispersing agent is a Compressible Starch (CS); the binder is polyvinylpyrrolidone, preferably 5-10 wt% polyvinylpyrrolidone (PVP) in ethanol.
4. The naltrexone binary subcutaneous implant according to any one of claims 1-3, wherein said naltrexone binary subcutaneous implant further comprises a lubricant, the mass of said lubricant being 0.05-2 wt.%, preferably 0.08-1.2 wt.%, relative to the sum of the masses of the A-and B-components, preferably said lubricant is magnesium stearate.
5. The naltrexone binary subcutaneous implant according to any one of claims 1-4, wherein the particle size of the naltrexone submicron powder is 100-800nm, preferably 300-500 nm; and/or, the naltrexone pharmaceutically acceptable salt comprises inorganic salt and organic salt, wherein the inorganic salt is selected from at least one of sulfate, hydrochloride, hydrobromide, nitrate and phosphate; the organic salt is at least one selected from acetate, propionate, malonate, hydroxyacetate, 2-hydroxypropionate, pamoate, 2-oxopropionate, 2-butenedioate, oxalate, succinate, methanesulfonate, ethanesulfonate, benzenesulfonate and toluenesulfonate; preferably, the particle size of the naltrexone pharmaceutically acceptable salt submicron powder is 100-800 nm.
6. A method of preparing a naltrexone binary subcutaneous implant according to any one of claims 1 to 5, comprising the steps of:
A. preparing naltrexone active ingredient superfine powder: preparing naltrexone into naltrexone active ingredient micropowder, for example, using a ball mill;
B. preparation of naltrexone dispersant: mixing naltrexone active ingredient superfine powder and dispersant (preferably compressible starch CS) thoroughly, adding binder (such as polyvinylpyrrolidone, preferably ethanol solution of polyvinylpyrrolidone with concentration of 5-10 wt%), mixing thoroughly, making into soft material, sieving to make into granule, and grading to obtain naltrexone dispersant;
C. preparing naltrexone sustained release microspheres: dissolving the naltrexone active ingredient superfine powder prepared in the step A and a pharmaceutically acceptable slow release carrier (preferably, the slow release carrier comprises chitosan CTS and polylactic acid PLA) in an organic solvent (preferably, the organic solvent comprises dichloromethane and/or chloroform), stirring to form microspheres, filtering, and drying to obtain naltrexone slow release microspheres;
D. tabletting: fully mixing and tabletting the naltrexone dispersing agent prepared in the step B and the naltrexone sustained-release microspheres prepared in the step C to obtain a naltrexone binary implant bare chip;
E. coating: and D, coating the bare chip of the naltrexone binary implant prepared in the step D, and drying to obtain the naltrexone binary subcutaneous implant.
7. The preparation method according to claim 6, wherein in the step A, the particle size of the naltrexone active ingredient submicron powder is 100-800nm, preferably 300-500 nm; and/or the presence of a gas in the gas,
in the step B, naltrexone active ingredients: dispersing agent: the mass ratio of the adhesive to the binder is 1:0.4-0.9:0.2-0.8, preferably 1:0.5-0.9:0.3-0.7, more preferably 1:0.6-0.75: 0.4-0.6; the particle size of the naltrexone dispersant is 200-800 mu m; and/or the presence of a gas in the gas,
in the step C, the mass ratio of the chitosan to the polylactic acid is 1:0.2-1.0, preferably 1:0.3-0.8, and more preferably 1: 0.4-0.6; preferably, the molecular weight of the polylactic acid is 1.8 to 40 ten thousand, preferably 2 to 10 ten thousand; and/or the molecular weight of the chitosan is 1-60 ten thousand, preferably 10-30 ten thousand; in the case of using a mixture of dichloromethane and chloroform, the volume ratio of dichloromethane and chloroform is (1-4): 1; preferably, the microspheres are formed by stirring at the temperature of 30-45 ℃, and the particle size of the microspheres is 20-100 μm; and/or the presence of a gas in the gas,
in the step D, the mass ratio of the naltrexone dispersing agent to the naltrexone sustained-release microspheres is 1:3-6, preferably 1: 4-5; preferably, the tabletting condition is tabletting at a temperature of 40-50 ℃ and a pressure of 8-15 KN; and/or the presence of a gas in the gas,
in the step E, the drying condition is that the mixture is firstly suspended and dried for 30 to 60 seconds at the temperature of between 15 and 25 ℃ and then dried for less than 48 hours (for example, 1 to 24 hours) in vacuum at the temperature of between 30 and 55 ℃; preferably, the coating comprises coating with a solution of polylactic acid, PLA, in ethyl acetate at a concentration of 5-10 wt%, preferably 8 wt%.
8. The method according to claim 6 or 7, wherein the step D further comprises the following steps between the step of thoroughly mixing and the step of tabletting: adding a lubricant and fully mixing uniformly; the mass of the lubricant is 0.05-2 wt%, preferably 0.08-1.2 wt%, relative to the sum of the mass of the A component and the B component, and preferably the lubricant is magnesium stearate.
9. A naltrexone binary subcutaneous implant prepared by the method of any one of claims 6-8.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6194000B1 (en) * | 1995-10-19 | 2001-02-27 | F.H. Faulding & Co., Limited | Analgesic immediate and controlled release pharmaceutical composition |
| CN102512399A (en) * | 2011-12-31 | 2012-06-27 | 湖南赛沃药业股份有限公司 | Long-acting naltrexone implant and preparation method thereof |
| CN105582011A (en) * | 2014-10-24 | 2016-05-18 | 江苏国丹生物制药有限公司 | Methylnaltrexone bromide solid composition and preparation method thereof |
| CN110742872A (en) * | 2018-08-22 | 2020-02-04 | 深圳善康医疗健康产业有限公司 | Preparation method of naltrexone implant |
| CN112245434A (en) * | 2020-11-09 | 2021-01-22 | 深圳善康医疗健康产业有限公司 | Naltrexone and risperidone compound sustained-release composition |
-
2021
- 2021-02-08 CN CN202110172832.1A patent/CN112741813A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6194000B1 (en) * | 1995-10-19 | 2001-02-27 | F.H. Faulding & Co., Limited | Analgesic immediate and controlled release pharmaceutical composition |
| CN102512399A (en) * | 2011-12-31 | 2012-06-27 | 湖南赛沃药业股份有限公司 | Long-acting naltrexone implant and preparation method thereof |
| CN105582011A (en) * | 2014-10-24 | 2016-05-18 | 江苏国丹生物制药有限公司 | Methylnaltrexone bromide solid composition and preparation method thereof |
| CN110742872A (en) * | 2018-08-22 | 2020-02-04 | 深圳善康医疗健康产业有限公司 | Preparation method of naltrexone implant |
| CN112245434A (en) * | 2020-11-09 | 2021-01-22 | 深圳善康医疗健康产业有限公司 | Naltrexone and risperidone compound sustained-release composition |
Non-Patent Citations (7)
| Title |
|---|
| C. N. CHIANG等: "Kinetics of a naltrexone sustained-release preparation", 《CLIN. PHARMACOL. THER.》 * |
| LINDA OLSEN等: "Plasma concentrations during naltrexone implant treatment of opiate-dependent patients", 《BRITISH JOURNAL OF CLINICAL PHARMACOLOGY》 * |
| RICHARD J. HAMILTON等: "Complications of Ultrarapid Opioid Detoxification with Subcutaneous Naltrexone Pellets", 《ACADEMIC EMERGENCY MEDICINE》 * |
| 卫办医政发(2009)117号: "***办公厅关于立即停止开展皮下埋植盐酸纳曲酮治疗吸毒成瘾的通知", 《***公报》 * |
| 张丽梅: "《异烟肼缓释微球的制备与评价研究》", 24 December 2013, 北京协和医学院（清华大学医学部）&中国医学科学院 * |
| 谭盛男等编著: "《药物缓释载体及超微粉药物的应用研究》", 31 December 2017, 辽宁科学技术出版社 * |
| 陆新月等: "微球给药***载体材料的研究进展", 《中国药科大学学报》 * |
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