阅读说明：本技术 类阿片受体拮抗剂的固体剂型用的医药剂型 (Pharmaceutical dosage forms for solid dosage forms of opioid receptor antagonists ) 是由 杨笑岚 许悦郎 石英珠 于 2019-02-01 设计创作，主要内容包括：本发明内容提供一种类阿片受体拮抗剂的缓释剂型,其特征在于,包含：包含至少一类阿片受体拮抗剂的缓释颗粒、至少一医药上可接受的载剂、以及一pH-依赖性聚合物,其中该缓释颗粒经该pH-依赖性聚合物被覆,以及该类阿片受体拮抗剂选自纳美芬、纳曲酮或其盐所组成的群组。本发明内容进一步提供一种制备类阿片受体拮抗剂的缓释剂型的方法,其特征在于,包含下列步骤：将至少一类阿片受体拮抗剂与至少一医药上可接受的载剂混合,形成混合物；以一pH-依赖性聚合物对该混合物进形湿式制粒,形成缓释颗粒；令该缓释颗粒通过网筛进行筛选,得到过筛的缓释颗粒；以及压缩该过筛的缓释颗粒,得到缓释(SR)剂型。(The present invention provides an opioid receptor antagonist sustained release dosage form comprising: comprises sustained-release particles of at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer, wherein the sustained-release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof. The present disclosure further provides a method of preparing a sustained release dosage form of an opioid receptor antagonist, comprising the steps of: mixing at least one type of opioid receptor antagonist with at least one pharmaceutically acceptable carrier to form a mixture; subjecting the mixture to wet granulation with a pH-dependent polymer to form sustained release granules; screening the sustained-release granules through a mesh screen to obtain screened sustained-release granules; and compressing the sieved sustained release granules to obtain a Sustained Release (SR) dosage form.)

1. An extended release dosage form of an opioid receptor antagonist, comprising: comprises sustained-release particles of at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer,

wherein the sustained release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

2. The sustained release dosage form of claim 1, wherein the opioid receptor antagonist is in the form of an anhydrous salt, a mono-, di-, or poly-hydrated salt, or a mixture thereof.

3. The sustained-release dosage form of claim 1, wherein the pH-dependent polymer is soluble beyond pH 6.0.

4. The sustained-release formulation of claim 1, wherein the pH-dependent polymer is selected from the group consisting of acrylic and methacrylic acid copolymers, methacrylate ester copolymers, ethoxyethyl methacrylate copolymers, methacrylic acid-acrylic acid copolymers, aminoalkyl methacrylate copolymers, and ammonioalkyl methacrylate copolymers.

5. The sustained-release dosage form of claim 1, wherein the ratio of free carboxyl groups to free ester groups of the pH-dependent polymer is between about 1: 1 to about 1: 2, in the above range.

6. The sustained release dosage form of claim 1, wherein the pharmaceutically acceptable carrier is selected from the group consisting of binders, lubricants, anti-agglomerants, and disintegrants.

7. The sustained release dosage form of claim 1, further comprising an outer coating surrounding the sustained release dosage form.

8. The sustained-release dosage form of claim 7, wherein the outer coating layer comprises a pH-dependent polymer.

9. The sustained-release dosage form of claim 1, wherein the sustained-release dosage form is in the form of a lozenge, a capsule or a caplet.

10. An extended release solid form of an opioid receptor antagonist comprising:

sustained release particles comprising at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer; and

an outer coating layer comprising a pH-dependent polymer,

wherein the sustained release particles are coated with the pH-dependent polymer and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof; and the extended release solid form is surrounded by the outer coating.

11. The extended release solid form of claim 10, wherein the opioid receptor antagonist is in the form of an anhydrous salt, a mono-, di-, or poly-hydrated salt, or a mixture thereof.

12. The extended release solid form of claim 10, wherein the pH-dependent polymer is dissociable above pH 6.0.

13. The extended release solid form of claim 10, wherein the ratio of free carboxyl groups to free ester groups of the pH-dependent polymer is between about 1: 1 to about 1: 2, in the above range.

14. The extended release solid form of claim 10, wherein the pH-dependent polymer is selected from the group consisting of acrylic and methacrylic acid copolymers, methacrylate ester copolymers, ethoxyethyl methacrylate copolymers, methacrylic acid-acrylic acid copolymers, aminoalkyl methacrylate copolymers, and ammonioalkyl methacrylate copolymers.

15. A method of preparing a Sustained Release (SR) dosage form of an opioid receptor antagonist comprising the steps of:

mixing at least one type of opioid receptor antagonist with at least one pharmaceutically acceptable carrier to form a mixture;

wet granulating the mixture with a pH-dependent polymer to form sustained release granules;

screening the sustained-release granules through a mesh screen to obtain screened sustained-release granules; and

compressing the sieved sustained release particles to obtain a Sustained Release (SR) dosage form,

wherein the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

16. The method of claim 15, wherein the method further comprises: coating the Sustained Release (SR) dosage form with a pH-dependent polymer.

17. The method of claim 15, wherein the opioid receptor antagonist is in the form of an anhydrous salt, a mono-, di-, or poly-hydrated salt, or a mixture thereof.

18. The method of claim 15, wherein the pH-dependent polymer is soluble beyond pH 6.0.

19. The method of claim 15, wherein the ratio of free carboxyl groups to free ester groups of the pH-dependent polymer is between about 1: 1 to about 1: 2, in the above range.

20. The method of claim 15, wherein the pH-dependent polymer is selected from the group consisting of acrylic and methacrylic acid copolymers, methacrylate ester copolymers, ethoxyethyl methacrylate copolymers, methacrylic acid-acrylic acid copolymers, aminoalkyl methacrylate copolymers, and ammonioalkyl methacrylate copolymers.

Technical Field

Background

Opioid receptor antagonists are also known as opioid antagonists, a receptor antagonist that acts at opioid receptors.

Naltrexone (Naltrexone) and Nalmefene (Nalmefene) are commonly used opioid antagonist drugs. Naltrexone is a drug used primarily to treat alcohol dependence and opioid dependence, while nalmefene is a newer opioid antagonist, similar in structure to naltrexone, but with potential pharmacological advantages in treating alcohol dependence. Naltrexone and nalmefene are competitive antagonists that bind with high affinity to opioid receptors, but do not activate the receptor. Blockade of this receptor prevents the body from responding to opioids and endorphins (endorphins).

Both naltrexone and nalmefene are characterized by rapid absorption following oral administration. Since opioid receptors have been shown to be present in the chemical receptor trigger zone (CTZ) that interacts with the Vomiting Center (VC) in the brain, compounds that are not difficult to interpret as what opioids cause Central Nervous System (CNS) -related adverse effects such as nausea and vomiting. In other words, oral administration of naltrexone or nalmefene may be uncomfortable for the patient due to rapid absorption.

For long-term disease or pain management involving alcohol dependence, medical treatments including single or combination drug therapy are still required to alleviate the above-mentioned CNS-related adverse effects to improve the quality of life of the patient.

Thus, there is a need for novel pharmaceutical dosage forms of opioid receptor antagonists.

Disclosure of Invention

The object of the present invention is to provide an opioid receptor antagonist sustained-release dosage form, comprising: sustained release particles comprising at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer, wherein the sustained release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

It is another object of the present invention to provide a sustained release solid dosage form of an opioid receptor antagonist, comprising: sustained release particles comprising at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer; and an outer coating comprising a pH-dependent polymer, wherein the sustained release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof; and the extended release solid dosage form is surrounded by the outer coating.

It is a further object of this invention to provide a method of preparing a sustained release dosage form of an opioid receptor antagonist, comprising the steps of: mixing at least an opioid receptor antagonist with at least one pharmaceutically acceptable carrier to form a mixture; wet granulating the mixture with a pH-dependent polymer to form sustained release granules; screening the sustained-release granules through a mesh screen to obtain screened sustained-release granules; and compressing the sieved sustained release granules to obtain a Sustained Release (SR) dosage form, wherein the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

Drawings

The present invention is described in detail below with reference to the attached drawing figures, wherein like numerals represent corresponding parts in the drawing figures. These figures are intended to be illustrative of various embodiments of the present disclosure in general, but are illustrative only and not intended to limit the scope of the present disclosure.

FIG. 1 shows the dissolution profiles of nalmefene immediate release tablets (NMF-IR) and nalmefene sustained release tablets (NMF-SR) (6 tablets mean) in a buffered medium at pH 6.8 in an embodiment of the present disclosure using USP apparatus two detection method (USP <711 >.

FIG. 2 shows the dissolution profiles of naltrexone immediate release tablets (NTX-IR) and naltrexone sustained release tablets (NTX-SR) (6 tablet averages) in a buffered medium at pH 6.8 in an embodiment of the present disclosure using USP apparatus two test method (USP <711 >.

Figure 3 shows the mean plasma concentration versus time profiles of nalmefene immediate release tablets (NMF-IR) and nalmefene sustained release tablets (NMF-SR) in an oral (P.O.) rat test according to an embodiment of the present disclosure.

FIG. 4 shows the dissolution profiles of naltrexone immediate release tablets (NTX-IR) and naltrexone sustained release tablets (further modified dosage forms) (NTX-SR2) (6 tablet averages) in a buffered medium at pH 6.8 in an embodiment of the present disclosure using USP apparatus two test method (USP <711 >).

Figure 5 shows the mean plasma concentration versus time profiles of an immediate release naltrexone (NTX-IR) and a sustained release naltrexone (further modified dosage form) (NTX-SR2) in an oral dog (P.O.) trial according to one embodiment of the present disclosure.

FIG. 6 shows the dissolution profiles of nalmefene sustained release tablets SR3S (NMF-SR3S) and SR3L (NMF-SR3L) in a buffer medium at pH 6.8 in an embodiment of the present disclosure using USP apparatus two test method (USP <711 >).

FIG. 7 shows the dissolution profiles in buffer medium at pH 6.8 of naltrexone sustained release lozenge SR3S (NTX-SR3S) and naltrexone sustained release lozenge SR3L (NTX-SR3L) in an embodiment of the present disclosure using USP apparatus two test method (USP <711 >).

Detailed Description

These and other aspects of the present disclosure will now be described in more detail with reference to other specific embodiments thereof as described herein. It is to be understood that this disclosure may be embodied in different forms and should not be construed as limited to the specific embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and will fully convey the scope of the disclosure to those skilled in the art.

The terminology used in the description of the present disclosure is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure. 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 disclosure belongs. As used in the description of the present disclosure and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

Unless otherwise indicated, the term "opioid" as used herein refers to compounds that exhibit properties similar to those of opiates or morphine (including the agonistic , antagonist activity), wherein such compounds can interact with binding sites in the brain and other tissues that are stereogenic -and saturable. The term "opioid-like" as used herein means similar in structure and/or pharmacological properties to known opioid compounds.

As used herein, unless otherwise indicated, the term "pharmaceutically acceptable" component (such as a salt, carrier, excipient, or diluent) refers to a compound or composition that is suitable for administration to a subject for treatment as described herein, and that does not cause undue adverse side effects, given the severity of the disease and the desirability of the treatment.

As used herein, unless otherwise indicated, the term "therapeutically effective amount" means an amount necessary to prevent, delay or reduce the severity of the condition in question, and also includes an amount necessary to increase normal physiological function.

The term "pharmaceutically acceptable carrier" as used herein, unless otherwise indicated, refers to a carrier, whether diluent or excipient, that is compatible with the other ingredients of the medicament and not deleterious to the recipient thereof. Pharmaceutically acceptable carriers that can be used are disclosed in various references, including Raymond C Rowe, Paul J Sheskey, and Handbook of Pharmaceuticals Excipients published by Marrian E Quinn. In a non-limiting embodiment, the pharmaceutically acceptable carrier is selected from the group consisting of inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binders, preservatives, buffering agents, lubricants, and/or oils. The composition may optionally further comprise at least one additional biologically active compound or agent.

The term "pH-dependent polymer" as used herein, unless otherwise indicated, refers to a broad class of polymers that substantially dissolve only above a particular induced pH and which enable the pharmaceutical dosage form to target a particular region of the intestinal tract. The pH-dependent polymers are particularly useful for therapy relying on targeted drug release in the high-pH colonic region, i.e. for topical treatment of Crohn's disease, ulcerative colitis, or intestinal cancer.

It is an object of the present invention to provide a class of sustained release dosage forms of opioid receptor antagonists comprising: sustained release particles comprising at least one type of opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer, wherein the sustained release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

In some embodiments, opioid receptor antagonists useful in the present disclosure include: for example, but not by way of limitation, naltrexone (naltrexone), nalmefene (nalmefene), naloxone (naloxone), naltrendole (naltrindole), nalorphine (nalorphine), nalbuphine (nalbuphine), normorphine (normorphine), nopiperone (norlipanone), derivatives thereof, and the like. In some embodiments, the opioid receptor antagonists of the present disclosure comprise naltrexone or nalmefene.

In some embodiments, nalmefene or naltrexone in salt form in the context of the present invention may be in the form of their anhydrous salts, mono-, di-or poly-hydrated salts or mixtures thereof, but are not limited to these. In some embodiments, nalmefene or naltrexone in salt form in the context of the present invention may include, but are not limited to, inorganic acid salts of nalmefene or naltrexone, organic acid salts of nalmefene or naltrexone, and the like. As the inorganic acid salt, examples of the inorganic acid may include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, phosphorous acid and nitric acid, but are not limited thereto. Further, as the organic acid salt, examples of the organic acid may include acetic acid, malic acid, tartaric acid, formic acid, oxalic acid, lactic acid, citric acid, fumaric acid, cinnamic acid, salicylic acid, propionic acid, methanesulfonic acid, p-toluenesulfonic acid, ascorbic acid, gluconic acid, and benzoic acid, but are not limited thereto.

In some embodiments, nalmefene or naltrexone in the form of a salt according to the present disclosure may be nalmefene or naltrexone in the form of a hydrochloride salt, a hydrochloride dihydrate, or a mixture thereof. In the pharmaceutical dosage forms of the present disclosure, nalmefene or naltrexone in the form of a hydrochloride salt, a hydrochloride salt dihydrate or a mixture thereof may be present in an amount of about 1-75% by weight. In a particular embodiment, in the pharmaceutical dosage forms of the present disclosure described above, the nalmefene or naltrexone in salt form may be nalmefene hydrochloride and may comprise an amount of about 1-75% by weight, such as 5-35% by weight or 10-29.5% by weight. In another particular embodiment, in the pharmaceutical dosage forms of the present disclosure, nalmefene or naltrexone in salt form may be naltrexone hydrochloride and/or hydrochloride dihydrate and may comprise an amount of about 1-75% by weight, such as 5-35% by weight or 10-29.5% by weight.

In some embodiments, the pH-dependent polymer of the present disclosure may comprise at least one acrylic polymer. The acrylic polymer may be a cationic, anionic or non-ionic polymer and may be based on acrylate monomers and/or methacrylate monomers, such as polymers formed from methacrylic acid or methacrylate esters. In one embodiment, the acrylic polymer is an anionic polymer. In some embodiments, the pH-dependent polymer of the present disclosure is selected from the group consisting of acrylic and methacrylic acid copolymers, methacrylate ester copolymers, ethoxyethyl methacrylate copolymers, methacrylic-acrylic acid copolymers, aminoalkyl methacrylate copolymers, and aminoalkyl methacrylate copolymers, but is not limited thereto. In some embodiments, the pH-dependent polymer of the present disclosure may be an anionic copolymer based on methacrylic acid and methyl methacrylate. In a preferred embodiment, the pH-dependent polymer is a methacrylate copolymer.

In some embodiments, the pH-dependent polymers of the present disclosure may dissolve only when a particular induced pH is exceeded. For example, the pH-dependent polymer of the present disclosure may dissolve above pH5.0, pH6.0, or pH 7.0. In one embodiment, the pH-dependent polymer of the present disclosure is soluble above pH 6.0. In a preferred embodiment, the pH-dependent polymer of the present disclosure is soluble above pH 7.0.

In some embodiments, the pH-dependent polymers of the present disclosure have a ratio of free carboxyl groups to free ester groups in a range of about 1: 1 to about 1: 2, in the above range. In a particular embodiment, the pH-dependent polymer of the present disclosure has a ratio of free carboxyl groups to free ester groups of about 1: 1. in a preferred embodiment, the pH-dependent polymer of the present disclosure has a ratio of free carboxyl groups to free ester groups of about 1: 2.

in some embodiments, the pH-dependent polymer of the present disclosure is preferably a methacrylic acid copolymer, which is commercially availableA polymer.

The polymers are useful in a wide range of different concentrations and physical forms; such physical forms include aqueous solutions, aqueous dispersions, organic solutions and solid substances. The medical properties of the polymer are determined by the chemical nature of the functional groups. For example,l, S, FS and E polymers have pH-dependent acidic or basic groups.The enteric coating prevents release of the GCC stimulus in the stomach and can be controlled to release in the intestine. In some embodiments, the anionic group will contain a carboxyl groupThe grades are mixed with each other to allow pH-dependent release of GCRA peptide and/or its analogues. In some embodiments, use is made ofThe L and S grades are used as sausage casings. In a specific embodiment, the

L, the ratio of free carboxyl groups to free ester groups is about 1: 1. in a specific embodiment, theS, the ratio of free carboxyl groups to free ester groups is about 1: 2. various kinds of

The polymers are further described in international pharmacopoeias such as ph. Such polymers are prepared byL 100-55、L 30D-55、L orS100 (commercially available from Rohm Pharma GmbH, Weiterstat, Germany).

In some embodiments, the pH-dependent polymer is selected from the group consisting of methacrylic acid copolymers, toS is preferably selected fromS100 is most preferred. The preferred concentration is 10% by weight, preferably 4-7% by weight, of the total weight of the dosage form.

In some embodiments, sustained release particles of the present disclosure may comprise a wide variety of pharmaceutically acceptable carriers including binders, lubricants, anti-agglomerants, disintegrants, dispersants and/or granulating agents, surfactants and/or emulsifiers, preservatives, buffers, lubricants, and/or oils. In some embodiments, the pharmaceutically acceptable carrier of the present disclosure is selected from the group consisting of binders, lubricants, anti-agglomerants, and disintegrants.

In some embodiments, for example, the binder of the present disclosure may include, but is not limited to, one or more sugars, such as glucose, lactose, sucrose; sugar alcohols such as xylitol, sorbitol or mannitol; polysaccharides such as starch, cellulose or cellulose derivatives such as hydroxypropyl cellulose (HPC) or modified celluloses such as microcrystalline cellulose; synthetic polymers such as polyvinylpyrrolidone (PVP) or polyethylene glycol (PEG). In a preferred embodiment, the binder of the present disclosure comprises hydroxypropyl cellulose (HPC), mannitol, microcrystalline cellulose, or polyvinylpyrrolidone (PVP).

In some embodiments, the derivatives of cellulose of the present disclosure may include, but are not limited to, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), Methylcellulose (MC), cellulose acetate, sodium carboxymethyl cellulose, calcium salts of carboxymethyl cellulose, ethyl cellulose, and the like. In a preferred embodiment, the cellulose derivative of the present disclosure may be hydroxypropyl cellulose (HPC). The amount of hydroxypropyl cellulose (HPC) may be 2-50 wt%, such as 5-15 wt% or 10.5-14.5 wt%, by weight of the dosage form.

In some embodiments, the amount of mannitol of the present disclosure may be 2-50 wt%, such as 5-15 wt%, or 10.5-14.5 wt% of the weight of the dosage form.

In some embodiments, the polyvinylpyrrolidone (PVP) of the present disclosure may have a viscosity k value of between 5 and 180 when measured as a 1% aqueous solution, and a pH value of between 2 and 11 in a 5% solids aqueous solution. Examples of the polyvinylpyrrolidone may include, but are not limited to, polyvinylpyrrolidone of K29-32 grade, K25 grade, K30 grade, or K40 grade. In a preferred embodiment, the polyvinylpyrrolidone (PVP) of the present disclosure may be a polyvinylpyrrolidone of grade K29-32, and may be present in an amount of 1-30 wt%, such as 5-15 wt%, or 10.5-13.9 wt%, based on the weight of the dosage form.

In some embodiments, the microcrystalline cellulose of the present disclosure may be present in an amount of 3 to 60 weight percent, such as 15 to 55 weight percent, or 36.5 to 47.5 weight percent, based on the weight of the dosage form.

In some embodiments, for example, the lubricant of the present disclosure may include, but is not limited to, one or more monoglycerides that may be waxy. The monoglyceride may have a melting point between 50 ℃ and 90 ℃, such as, but not limited to, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃, 80 ℃, 83 ℃, 85 ℃, or 90 ℃ and the like. Examples of monoglycerides may include, but are not limited to, glycerol monomyristate, glycerol monopalmitolate, glycerol monocetyl-6-enoate (glycerol monolonosporanate), glycerol monooleate (glycerol monolonoleate), glycerol monolinoeladate (glycerol monolinoeladate), glycerol monoisocitrate (glycerol monoacetate), glycerol monolinolinoleate (glycerol monolinolinoleate), glycerol monolinoleate (glycerol monolinoleate), glycerol monooctanoate (glycerol monooleate), glycerol monooleate-5, 8, 11-trienoate (glycerol monooleate), glycerol monooleate (glycerol monooleate), glycerol monoolate, glycerol monoo, Glyceryl dibehenate (glycerol dibehenate), glyceryl behenate (glycerol behenate), glyceryl dipalmitostearate (glycerol dipalmitostearate), glyceryl distearate (glycerol distearate), glyceryl monolinoleate, and any combination thereof. In a preferred embodiment, the lubricant of the present disclosure may be glycerol dibehenate. Furthermore, the glycerol dibehenate of the present disclosure may have a particle size between 0.5 μm and 500 μm, but is not limited thereto. In a particular embodiment, the amount of glyceryl dibehenate may range from 0.01 to 10 weight percent, such as from 0.1 to 5 weight percent or from 0.65 to 0.9 weight percent, based on the weight of the dosage form.

In some embodiments, for example, lubricants of the present disclosure may include, but are not limited to: one or more fumed silicas (fumed silicas). The fumed silica can have a particle size of 15m²G and 300m²Specific surface area between/g, but not limited thereto. Examples of fumed silica can include, but are not limited to, hydrophobic fumed silica or hydrophilic fumed silica having water absorbing capacity. The hydrophilic fumed silica of the present disclosure can be, but is not limited to, a fumed silica treated with dimethyldichlorosilane. The hydrophobic fumed silica of the present disclosure can have between 90 and 99 wt.% SiO₂And (4) content. The hydrophilic silica having water absorption capacity of the present disclosure has between 10% and 30% by weight of SiO₂And (4) content. In a preferred embodiment, the lubricant of the present disclosure may be a hydrophilic fumed silica. Further, the amount of hydrophilic fumed silica of the present disclosure can be 0.01 to 10 weight percent, such as 0.1 to 5 weight percent, or 0.65 to 0.9 weight percent of the dosage form weight. Useful lubricants are silica materials, for example, AEROSIL, which is a commercially available colloidal silica, a submicron fumed silica (submicron fumed silica) having a particle size of about 15 nm.

In some embodiments, in the sustained release dosage form of the opioid receptor antagonist of the present disclosure, the dosage form is in a sustained release form, such as a sustained release lozenge. The sustained-release preparation of the opioid receptor antagonist can provide the sustained-release effect of nalmefene or naltrexone and reduce the absorption peak of the concentration in blood plasma.

In some embodiments, a sustained release dosage form according to the present disclosure may be in the form of any pharmaceutically acceptable dosage form comprising at least one therapeutically active agent and at least one pharmaceutically acceptable carrier. For example, the sustained release particles can be in liquid, semi-solid, and solid forms, including pills, tablets, capsules, and caplets. Preferred dosage forms of the sustained release granules of the present disclosure are lozenges or capsules.

It is another object of the present disclosure to provide a sustained release solid form of an opioid receptor antagonist characterized by comprising: sustained release particles comprising at least one opioid receptor antagonist, at least one pharmaceutically acceptable carrier, and a pH-dependent polymer; and an outer coating comprising the pH-dependent polymer, wherein the sustained release particles are coated with the pH-dependent polymer, and the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof; and the extended release solid form is surrounded by the outer coating.

In some embodiments, the sustained release dosage forms or sustained release solid forms of the opioid receptor antagonists of the present disclosure may delay drug dissolution for a longer period of time, thereby allowing greater flexibility in designing sustained release patterns and further providing improved plasma concentrations, with a maximum plasma concentration (Cmax)_max) Can be substantially reduced without simultaneously reducing AUC.

It is another object of the present disclosure to provide a method of preparing a Sustained Release (SR) dosage form of an opioid receptor antagonist. In some embodiments, a method of preparing a Sustained Release (SR) dosage form of an opioid receptor antagonist may comprise the steps of: mixing at least one opioid receptor antagonist with at least one pharmaceutically acceptable carrier to form a mixture; wet granulating the mixture with a pH-dependent polymer to form sustained release granules; screening the sustained-release granules through a mesh screen to obtain screened sustained-release granules; and compressing the sieved sustained release granules to obtain a Sustained Release (SR) dosage form, wherein the opioid receptor antagonist is selected from the group consisting of nalmefene, naltrexone, or a salt thereof.

In some embodiments, the pH-dependent polymers of the present disclosure may be dissolved in a solvent to provide a coating solution that is a clear or cloudy solution. For example, solvents of the present disclosure for dissolving the pH-dependent polymer include, but are not limited to, alcohols such as methanol, ethanol, propanol, isopropanol; ketones such as acetone; or pharmaceutical grade 2 and 3 solvents or combinations thereof. In a preferred embodiment, the solvent of the present disclosure used to dissolve the pH-dependent polymer may be acetone. In some embodiments, the amount of the pH-dependent polymer of the present disclosure may be 1 to 15 wt% of the coating solution.

In some embodiments, the step of screening the sustained release particles is performed by a screen. In some embodiments, the mesh size of the mesh of the present disclosure is between 10 mesh (1700 μm) and 40 mesh (380 μm), such as 10 mesh (1700 μm), or 30 mesh (550 μm).

In some embodiments, the step of compressing the sieved sustained release particles of the present disclosure may be performed by a compressive force of between 0.2 tons and 15 tons, such as 0.2 tons, 0.5 tons, 1 ton, 1.5 tons, 2 tons, 2.5 tons, 10 tons, or 15 tons. In a preferred embodiment, the compressive force of the present disclosure may be 2.5 tons.

In some embodiments, the method of making a Sustained Release (SR) dosage form of an opioid receptor antagonist of the present disclosure further comprises coating the Sustained Release (SR) dosage form with a pH-dependent polymer. The pH-dependent polymer is the same as described above.