CN110585153A - Pregabalin sustained-release composition and preparation method thereof - Google Patents
Pregabalin sustained-release composition and preparation method thereof Download PDFInfo
- Publication number
- CN110585153A CN110585153A CN201810608326.0A CN201810608326A CN110585153A CN 110585153 A CN110585153 A CN 110585153A CN 201810608326 A CN201810608326 A CN 201810608326A CN 110585153 A CN110585153 A CN 110585153A
- Authority
- CN
- China
- Prior art keywords
- pregabalin
- release composition
- sustained release
- agent
- swelling agent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Abstract
The invention provides a pregabalin sustained release composition, which comprises: (a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt, or hydrate thereof; (b) a matrix forming agent; (c) a swelling agent; and (d) a gelling agent; wherein the swelling agent is selected from one or the combination of at least two of croscarmellose sodium, low-substituted hydroxypropyl cellulose and polyoxyethylene. The pregabalin sustained-release composition provided by the invention can be rapidly expanded in volume when contacting an aqueous medium, and exceeds the pylorus diameter (13mm) of a human stomach, so that the gastric emptying time can be prolonged to prolong the detention time of the pregabalin in the stomach, and the absorption of the pregabalin in the small intestine and ascending colon is improved; meanwhile, the pregabalin sustained release composition provided by the invention realizes 24-hour slow release, can realize QD (once a day) administration, reduces the administration times and improves the compliance of patients.
Description
Technical Field
The invention relates to the technical field of pregabalin preparations, in particular to a pregabalin slow-release composition and a preparation method thereof.
Background
Pregabalin is used for the treatment of neuropathic pain and post-herpetic neuralgia (PHN) associated with Diabetic Peripheral Neuropathy (DPN). The medicine can be used as calcium ion channel regulator for inhibiting central nervous system voltage dependent calcium channel alpha 2-delta subunit. Reducing calcium ion inflow, and reducing release of excitatory neurotransmitter such as glutamate, norepinephrine, and substance P, thereby effectively controlling neuropathic pain, and having anxiolytic and anticonvulsant effects.
Clinical studies have shown that pregabalin is not uniformly absorbed in the gastrointestinal tract, which is well absorbed in the small intestine and ascending colon of humans, but rarely in segments of the intestine outside the hepatic flexure of the colon. This means that the average absorption window of pregabalin is about 6 hours or less, and thus if pregabalin is prepared into a conventional sustained-release formulation, the formulation passes through the colonic hepatic flexure after more than 6 hours, and the released drug is not effectively absorbed, resulting in a waste of the drug. Therefore, how to improve the absorption of pregabalin in the small intestine and ascending colon becomes a technical problem to be solved urgently by those skilled in the art.
Disclosure of Invention
An object of an embodiment of the present invention is to provide a sustained-release composition of pregabalin to improve the absorption of pregabalin in the small intestine and ascending colon. Meanwhile, the invention also provides a preparation method of the pregabalin sustained-release composition. The specific technical scheme is as follows:
the invention firstly provides a pregabalin sustained-release composition, which comprises:
(a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt, or hydrate thereof;
(b) a matrix forming agent;
(c) a swelling agent; and
(d) gelling agent;
wherein the swelling agent comprises one or a combination of at least two of croscarmellose sodium, low-substituted hydroxypropyl cellulose and polyoxyethylene; preferably, the swelling agent comprises sodium cross-linked carboxymethyl starch and at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene; more preferably, the swelling agent comprises sodium cross-linked carboxymethyl starch and polyoxyethylene.
Pregabalin, chemical name: (S) -3-aminomethyl-5-methylhexanoic acid having the following chemical structure:
in the present invention, pregabalin can be prepared by known methods as a raw material drug, or can be obtained commercially, and any method can be easily implemented by those skilled in the art, so that the present invention is not described herein. In some embodiments of the invention, pregabalin is commercially available as a drug substance.
In the present invention, pharmaceutically acceptable salts of pregabalin refer to pharmaceutically acceptable acids and basesAn addition salt of (a); such pharmaceutically acceptable salts include salts of acids such as: hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acids (such as acetic acid, HOOC- (CH)2) n-COOH (wherein n 0 to 4)), and the like. Such pharmaceutically acceptable salts also include salts of bases such as: sodium, potassium, calcium, ammonium, and the like. The person skilled in the art is aware of a number of non-toxic pharmaceutically acceptable addition salts.
In the present invention, hydrate means a molecular complex of a drug (e.g., pregabalin) and a stoichiometric or non-stoichiometric amount of water.
In some embodiments of the present invention, the weight percentage of the active ingredient may be 5% to 55%, 10% to 40%, 20% to 30%, or 25% to 30%, etc., based on the total weight of the pregabalin sustained release composition.
In some embodiments of the present invention, the active ingredient may optionally include at least one additional compound having a synergistic therapeutic effect with pregabalin, in addition to pregabalin or a pharmaceutically acceptable salt, or hydrate thereof.
In the present invention, matrix forming agents are used to provide structural integrity to the composition and help control or prolong the rate of drug release and other functions. Those skilled in the art can select an appropriate matrix-forming agent based on the description of the invention herein for its role. In some embodiments of the present invention, the weight percentage of the matrix forming agent is 5% -45%, 15% -35%, or 15% -30%, etc., based on the total weight of the pregabalin sustained release composition.
In some embodiments of the invention, the matrix forming agent may be selected from a mixture of polyvinyl acetate and polyvinylpyrrolidone. Polyvinylpyrrolidone (PVP) is a homopolymer of 1-vinyl-pyrrolidin-2-one, typically having a molecular weight Mw of about 1X 103To about 1X 107About 2.5X 103To about 3X 106Or about 1X 104To about 1X 105. Polyvinylpyrrolidone is available from BASF under the trade nameAvailable from ISP under the trade name ofPolyvinyl acetate (PVAc) is a homopolymer of vinyl acetate, typically having a molecular weight Mw of about 1X 105To about 1X 106. The matrix forming agent may comprise, in weight percent based on the total weight of PVAc and PVP: 0% -90%, 20% -90%, 60% -90% and 70% -85% of PVAc. In some embodiments of the invention, the matrix forming agent is obtained from BSAF, under the trade name BSAFSR, nominally an 80/19(w/w) mixture of PVAc and PVP.
In the present invention, the swelling agent can absorb water from the gastric juice, thereby causing the size of the pregabalin sustained-release composition to expand, and possibly also can affect the drug release rate by, for example, creating channels or by forming a hydrocolloid. The swelling agent is soluble or insoluble in water. In some embodiments of the present invention, the weight percentage of the swelling agent may be 5% to 70%, 20% to 60%, or 20% to 30%, etc., based on the total weight of the pregabalin sustained release composition. Patent CN101330907A states that the swelling agent necessarily comprises cross-linked polyvinylpyrrolidone (also known as crospovidone); the inventor surprisingly found through a lot of experiments that the sustained-release pregabalin composition can rapidly expand in volume when contacting with an aqueous medium, and the expansion size can reach or even be better than the above patent, without using crospovidone, and using one or a combination of at least two of croscarmellose sodium, low substituted hydroxypropyl cellulose and polyoxyethylene as the expanding agent. Further, the inventors have surprisingly found that when the swelling agent comprises sodium crosslinked carboxymethyl starch and comprises at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene, the pregabalin sustained-release composition prepared based on the swelling agent has a faster volume expansion rate, and especially when the swelling agent comprises or consists of sodium crosslinked carboxymethyl starch and polyoxyethylene, the pregabalin sustained-release composition prepared based on the swelling agent expands to a size of more than 13mm, even more than 13.5mm after contacting an aqueous medium for 2 hours, and this result is very surprising and also very useful; as known to those skilled in the art, the earlier the size of the composition expands to 13mm, the more beneficial the pregabalin sustained release composition stays in the stomach, thereby improving the absorption of pregabalin; and in short 2h, the size of the composition reaches 13mm, so that the pregabalin sustained-release composition can be more ensured to be retained in the stomach. In the present invention, the composition "size" corresponds to the longest linear dimension of the cross-section of the dosage form having the smallest area.
It should be noted that the swelling agents croscarmellose sodium, low-substituted hydroxypropyl cellulose and polyoxyethylene used in the present invention are all commonly used pharmaceutical excipients, and the structures, properties and obtaining ways of the swelling agents, croscarmellose sodium, low-substituted hydroxypropyl cellulose and polyoxyethylene are well known to those skilled in the art, and are finally used for implementing the technical scheme of the present invention.
In the present invention, a gelling agent may modify (e.g., prolong) the drug release characteristics of the composition. Gelling agents include synthetic and/or natural polymers that generally have low water solubility (e.g., slightly to poorly soluble). When contacted with water, the gel forms a viscous mixture (having a viscosity greater than water) that extends the time over which the drug, e.g., pregabalin, is released from the composition. In some embodiments of the present invention, the weight percentage of the gelling agent may be 1% to 30%, 1% to 20%, or 3% to 10%, etc., based on the total weight of the pregabalin sustained release composition.
In some embodiments of the present invention, the gelling agent is selected from one or a combination of carbomer, polysaccharide, preferably the gelling agent is carbomer.
Carbomer is a high molecular polymer of acrylic acid bonded allyl sucrose or pentaerythritol allyl ether. The number of carboxylic acid groups (-COOH) is typically 56.0-68.0% based on the dry product. The average molecular weight of carbomer number is about 1 × 105To about 1X 1010Or about 7X 105To about 4X 109。
Polysaccharides (polysaccharides) are polymeric carbohydrate macromolecules consisting of sugar chains with glycosidic linkages, at least more than 10 monosaccharides; in the present invention, representative polysaccharides employed may include one or a combination of raw gum, inulin, guar gum, chitosan, carob gum, carrageenan.
Xanthan gum, also known as corn gum, has a molecular weight Mw of about 2X 106The polysaccharide of (4). Inulin, also known as oligofructose and polyfructose, is a class of natural polysaccharides, typically having a number of D-fructose fragments in the range of from 2 to about 140, usually from about 25 to about 30. Guar gum having a molecular weight Mw of about 2X 105The hydrophilic colloidal polysaccharide of (1). Chitosan is a poorly water-soluble polysaccharide consisting of a copolymer of beta-D-glucosamine and N-acetyl-beta-D-glucosamine, typically having a number average molecular weight of about 1X 104To about 1X 106. The carob gum is a natural polysaccharide, similar to guar gum, and is galactomannan with a molecular weight Mw of about 5 × 104To about 3X 106Within the range of (1). Carrageenan, commonly known as carrageenan, has the chemical structure of calcium, potassium, sodium, and ammonium salts of polysaccharide sulfate esters composed of galactose and anhydrogalactose. Due to the different binding forms of the sulfate, the method can be divided into: kappa-type, iota-type, lambda-type, and the like. Carrageenans may be selected in a variety of grades based on the type of gel, aqueous solubility and viscosity when mixed with water. It should be noted that the above polysaccharides are all commercial products, and are easily available to those skilled in the art and used for implementing the present invention.
In some embodiments of the present invention, the pregabalin sustained release composition may further comprise a filler, and the filler may change (e.g., increase) the volume and weight of the pregabalin sustained release composition, thereby facilitating subsequent molding of the composition, such as tableting or the like. In the technical solution of the present invention, a filler commonly used in the art may be selected, including but not limited to one or a combination of at least two of microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate dihydrate, and anhydrous calcium hydrogen phosphate. In some embodiments of the present invention, the weight percentage of the filler may be 1% to 15% or 3% to 8% or the like, based on the total weight of the pregabalin sustained release composition.
In some embodiments of the present invention, the pregabalin sustained release composition may further comprise a lubricant, which helps to include various processing steps such as component mixing, tableting, and the like; for example, lubricants can make the pressure distribution uniform during tableting and make the tablet density uniform; the force required to push the tablet out of the die hole is reduced. Another possible effect of the lubricant is to improve the appearance of the tablet, making the tablet surface shiny and smooth. In the technical solution of the present invention, a lubricant commonly used in the art may be selected, including but not limited to one or a combination of at least two of magnesium stearate, talc, aerosil, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol, and more preferably magnesium stearate. In some embodiments of the present invention, the lubricant may be in a weight percentage of 0.1% to 1.5% or 0.5% to 1% or the like, based on the total weight of the pregabalin sustained release composition.
In some embodiments of the present invention, the pregabalin sustained release composition may further comprise a coating powder, and in the technical solution of the present invention, a coating powder commonly used in the art may be selected, including but not limited to at least one of polyvinyl alcohol and polyethylene glycol, at least one of silicon dioxide and talc, and/or a flavoring agent; in some embodiments of the present invention, the weight percentage of the coating powder may be 2% to 6%, 3% to 4%, etc. based on the total weight of the pregabalin sustained release composition.
The invention also provides a preparation method of the pregabalin sustained release composition, which comprises the following steps:
mixing the active ingredient, matrix forming agent, swelling agent, gelling agent and optional filler, and molding. In particular embodiments, the forming process may include the steps of granulating, optionally pelletizing, and tableting. The invention uses the particle diameter D of the pregabalin raw material medicine50The control is as follows: 50-175 μm and selective flowThe matrix forming agent, the swelling agent and the gelling agent with better performance realize that the sustained-release tablet can be prepared by adopting a direct tabletting mode in the process. The mixing and the subsequent molding steps are conventional steps and operations in the art, and the present invention is not limited to these steps.
In addition, the inventor examines the influence of the mixing time on the content uniformity of the mixed materials in the process of preparing the pregabalin slow-release composition; it was surprisingly found that the longer the mixing time, the better the content uniformity within 20 minutes, and that over 20 minutes there is little change in the content uniformity; after more than 25 minutes, the content uniformity tends to be even worse, and the specific test results are detailed in table 1. Based on this, in some embodiments of the invention, the mixing time in the mixing process is preferably 10 to 25 minutes, most preferably 15 minutes. It is noted that the mixture as described herein comprises the active ingredient, the matrix forming agent, the swelling agent, the gelling agent and optionally the filler.
TABLE 1
In some embodiments of the present invention, when the pregabalin sustained release composition contains a lubricant, the active ingredient, the matrix forming agent, the swelling agent, the gelling agent, and optionally the filler may be mixed and then the mixture may be subjected to a mixing step
Mixing with all the lubricant, and then carrying out a forming process;
or
And B, mixing with part of the lubricant, granulating, optionally grading, adding the rest of the lubricant, and performing other molding processes such as tabletting.
In some embodiments of the present invention, when the pregabalin sustained release composition contains a coating powder, the preparation method further comprises: after forming, a film coating premix is adopted for coating. Wherein the film coating premix can comprise at least one of polyvinyl alcohol and polyethylene glycol, at least one of silicon dioxide and talcum powder, and/or a flavoring agent; the solid content of the film coating premix can be 10-15%. The coating process is also a conventional process and operation in the art, and the present invention is not limited thereto.
The pregabalin slow release composition provided by the invention can be prepared into a tablet form, and based on the pregabalin slow release tablet, the pregabalin slow release tablet comprises the pregabalin slow release composition.
The pregabalin sustained-release composition provided by the invention can be rapidly expanded in volume when contacting an aqueous medium, and exceeds the pylorus diameter (13mm) of a human stomach, so that the gastric emptying time can be prolonged to prolong the detention time of the pregabalin in the stomach, and the absorption of the pregabalin in the small intestine and ascending colon is improved; meanwhile, the pregabalin sustained release composition provided by the invention realizes 24-hour slow release, can realize QD (once a day) administration, reduces the administration times and improves the compliance of patients.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a dissolution profile of pregabalin sustained release tablets prepared in examples 1 to 8 of the present invention and comparative example 1.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Preparation example of Pregabalin sustained-release tablet (oval tablet)
The english abbreviations appearing in the following examples are shown in table 2 below:
TABLE 2
Example 1
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, CMS-Na and carbomer 974P are sieved together with a 40 mesh sieve, added with PEO, mixed by a mixer for 15min, added with magnesium stearate for 5min, and tabletted.
Example 2
Prescription:
note: the amount of feed was calculated as anhydride
The preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR and carbomer 974P are sieved by a 40-mesh sieve together, then PEO is added, the mixture is mixed for 10min by a mixer, half of magnesium stearate in the prescription amount is added and mixed for 5min, dry granulation is carried out, after 20-mesh sieving and size stabilization, half of magnesium stearate in the prescription amount is added and mixed for 10min, and tabletting is carried out.
Example 3
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, CMS-Na and carbomer 974P are sieved together with a 40 mesh sieve, added with PEO, mixed by a mixer for 15min, added with magnesium stearate for 5min, and tabletted.
Example 4
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, CMS-Na and carbomer 974P are sieved together with a 40 mesh sieve, added with PEO, mixed by a mixer for 15min, added with magnesium stearate for 5min, and tabletted.
Example 5
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, CC-Na and carbomer 974P are sieved by a 40-mesh sieve together, then PEO is added, a mixer is used for mixing for 15min, magnesium stearate is added, mixing is carried out for 5min, and tabletting is carried out.
Example 6
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, L-HPC and carbomer 974P are sieved together with a 40 mesh sieve, PEO is added, the mixture is mixed for 15min by a mixer, magnesium stearate is added, the mixture is mixed for 5min, and tabletting is carried out.
Example 7
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, L-HPC and chitosan are sieved by a 40-mesh sieve together, then PEO is added, a mixer is used for mixing for 15min, magnesium stearate is added, mixing is carried out for 5min, and tabletting is carried out.
Example 8
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, CMS-Na and carbomer 974P are sieved together with a 40 mesh sieve, added with PEO, mixed by a mixer for 15min, added with magnesium stearate for 5min, and tabletted. And coating with a film coating premix with 12% (w/w) solid content, wherein the coating weight is increased to 3%. The film coating premix contains polyvinyl alcohol, silicon dioxide, talcum powder, polyethylene glycol and flavoring agent; is prepared by dissolving the above materials in purified water and sieving with 80 mesh sieve.
Example 9
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,SR, microcrystalline cellulose and carbomer 974P are sieved by a 40-mesh sieve together, then PEO is added, a mixer is used for mixing for 15min, magnesium stearate is added for mixing for 5min, and tabletting is carried out.
Examples 10 to 18
Examples 10-18 were completed with reference to the preparation of example 8, and the recipe in table 3 below.
TABLE 3
Comparative example 1
Example 30 in patent CN101330907A
Comparative example 2
Prescription:
the preparation method comprises the following steps: weighing the prescribed amount of pregabalin andSR sieving with 40 mesh sieve, adding PEO, mixing for 15min, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 3
Prescription:
the preparation method comprises the following steps: weighing the pregabalin and PEO according to the prescription amount, mixing for 15min by a mixer, adding magnesium stearate, mixing for 5min, and tabletting.
Comparative example 4
Prescription:
the preparation method comprises the following steps: weighing pregabalin with a prescription amount,And (3) sieving SR and carbomer 974P together by a 40-mesh sieve, mixing for 10min by a mixer, adding half of magnesium stearate according to the prescription amount, mixing for 5min, performing dry granulation, sieving by a 20-mesh sieve, granulating, adding half of magnesium stearate according to the prescription amount, mixing for 10min, and tabletting.
Drug dissolution and swelling test
Tablet dissolution test of examples 1-8 and comparative example 1
1. The dissolution method comprises the following steps:
1) the method comprises the following steps: dissolution test (the second method (paddle method), with the addition of a settling basket) of "0931 dissolution and release test" in the fourth general rule of the chinese pharmacopoeia 2015 edition.
2) Dissolution medium: 0.06mol/L HCl, 900ml
3) Rotating speed: 50 revolutions per minute
4) Sampling time: 1h, 2h, 4h, 6h, 9h, 12h, 16h and 24h
5) The detection method comprises the following steps: high performance liquid chromatography, detection wavelength: 210nm
6) Preparing a test solution: 10ml of the solution was taken at each time point and filtered.
7) Preparing a reference substance solution: a pregabalin control was taken and formulated with 0.06mol/L HCl to a control solution concentration of about 360. mu.g/ml.
2. The instrument model is as follows:
intelligent dissolution tester (model: DT820, manufacturer: Germany Eveka Co., Ltd.)
3. Dissolution results
The dissolution results of examples 1-8 and comparative example 1 in 0.06mol/L HCl medium are shown in Table 4 and FIG. 1:
TABLE 4
| Batch number | 1h | 2h | 4h | 6h | 9h | 12h | 16h | 24h | f2 |
| Comparative example 1 | 18.4 | 28.6 | 44.0 | 55.8 | 69.1 | 79.6 | 90.2 | 100.4 | NA |
| Example 1 | 17.3 | 27.1 | 41.3 | 52.4 | 64.8 | 74.3 | 83.5 | 96.5 | 69 |
| Example 2 | 18.0 | 27.2 | 39.7 | 48.9 | 59.2 | 67.4 | 77.5 | 90.9 | 54 |
| Example 3 | 17.8 | 27.1 | 40.9 | 51.7 | 64.1 | 73.7 | 83.4 | 95.8 | 67 |
| Example 4 | 16.2 | 25.7 | 39.8 | 51.4 | 65.1 | 75.7 | 86.1 | 97.1 | 69 |
| Example 5 | 19.8 | 29.8 | 41.1 | 53.4 | 65.2 | 76.4 | 86 | 99.7 | 74 |
| Example 6 | 15.7 | 25.8 | 38.1 | 51.0 | 63.1 | 72.4 | 84.1 | 97.1 | 64 |
| Example 7 | 15.9 | 25.8 | 36.5 | 48.5 | 61.1 | 73.1 | 81.4 | 94.2 | 58 |
| Example 8 | 16.4 | 28.1 | 37.4 | 51.2 | 63.4 | 75.7 | 85.1 | 100.7 | 65 |
Note: the dissolution results in the table are all in percent.
As can be seen from Table 4 and FIG. 1, the pregabalin sustained release tablets prepared in the embodiments 1-8 of the present invention release slowly in 24h, the release in 2h is less than 30%, the release in 12h is 80%, and the release in 24h is 100%; the dissolution characteristics thereof were substantially identical to those of the sustained-release tablet (comparative example 1) described in patent CN101330907A, and QD administration could be achieved.
Swelling size determination of tablets of examples 1 to 8 and comparative examples 1 to 4:
the tablets prepared in the above examples were subjected to dissolution test according to the second method (paddle method) of "0931 dissolution and release determination method" of the fourth regulation of the chinese pharmacopoeia 2015 edition. 900ml of 0.06N HCl solution was used as dissolution medium, rotating at 50 rpm. The drug product was removed from the dissolution media at 1h, 2h and 6h of dissolution experiments and measured for size with an electronic vernier caliper compared to the 0h tablet (tablet before experiment) and the results are shown in table 5 below:
TABLE 5
Note: comparative example 2 the sample swelled first larger, then with the swelling time extension, the sheet became soft, the mechanical strength was poor, the sheet thickness became lower, and the sheet was taken out and paralyzed on a laboratory bench; the sample of comparative example 3 did not form after swelling for 6h and the sheet length, width and thickness could not be measured.
As can be seen from Table 5, the tablets prepared in examples 1, 3, 4, 8 according to the invention, which have reached a swelling size of more than 13mm after 2h (which corresponds to the longest linear dimension of the cross-section of the dosage form with the smallest area), are clearly superior to those of comparative example 1; in other examples, after 6 hours, the swelling size of the polymer also reaches more than 13 mm; the size can effectively delay the retention time of the sustained-release tablet in the stomach through mechanical blockage, and the pharmaceutical composition can continuously release the pregabalin when the sustained-release tablet is retained in the stomach, effectively widen the absorption window of the pregabalin, improve the absorption of the pregabalin in the small intestine and ascending colon and allow QD (quantum dot dose) administration. Furthermore, it can be seen from comparison with comparative examples 2 to 4 that the swelling size is smaller than in examples 1 to 8 in the absence of at least one of the matrix former, the swelling agent and the gelling agent.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention shall fall within the protection scope of the present invention.
Claims (10)
1. A pregabalin sustained release composition comprising:
(a) an active ingredient comprising pregabalin or a pharmaceutically acceptable salt, or hydrate thereof;
(b) a matrix forming agent;
(c) a swelling agent; and
(d) gelling agent;
wherein the swelling agent comprises one or a combination of at least two of croscarmellose sodium, low-substituted hydroxypropyl cellulose and polyoxyethylene; preferably, the swelling agent comprises sodium cross-linked carboxymethyl starch and at least one of low-substituted hydroxypropyl cellulose and polyoxyethylene; more preferably, the swelling agent comprises sodium cross-linked carboxymethyl starch and polyoxyethylene.
2. The sustained release pregabalin composition of claim 1, wherein the matrix forming agent is selected from a mixture of polyvinyl acetate and polyvinylpyrrolidone.
3. The sustained release composition of pregabalin according to claim 1 or 2, wherein the gelling agent is selected from one of carbomer, polysaccharides or a combination thereof, preferably the gelling agent is carbomer.
4. A pregabalin sustained release composition according to any one of the claims 1 to 3, wherein the weight percentage of the active ingredient is 5% to 55%, preferably 10% to 40%, based on the total weight of the pregabalin sustained release composition; the weight percentage of the matrix forming agent is 5% -45%, preferably 15% -35%; the weight percentage of the swelling agent is 5% -70%, preferably 20% -60%; the weight percentage of the gel is 1% -30%, preferably 3% -10%.
5. The pregabalin extended release composition according to any one of claims 1 to 4, wherein the composition further comprises a filler, preferably one or a combination of at least two of microcrystalline cellulose, starch, pregelatinized starch, calcium phosphate dihydrate, anhydrous calcium hydrogen phosphate; more preferably, the weight percentage of the filler is 1% to 15%, preferably 3% to 8%, based on the total weight of the pregabalin sustained release composition.
6. The pregabalin sustained release composition according to any one of claims 1 to 5, wherein the composition further comprises a lubricant, preferably one or a combination of at least two of magnesium stearate, talc, aerosil, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol, more preferably magnesium stearate; also preferably, the lubricant is present in an amount of 0.1 to 1.5% by weight, preferably 0.5 to 1% by weight, based on the total weight of the pregabalin sustained release composition.
7. The sustained release composition of pregabalin of any one of claims 1 to 6, wherein the composition further comprises a coating powder, preferably the coating powder comprises at least one of polyvinyl alcohol and polyethylene glycol, at least one of silicon dioxide and talc, and/or a flavoring agent; more preferably, the weight percentage of the coating powder is 2% -6%, preferably 3% -4%, based on the total weight of the pregabalin sustained release composition.
8. A process for the preparation of a pregabalin extended release composition according to any of the claims 1 to 7, comprising:
the active ingredient, matrix forming agent, swelling agent, gelling agent and optional filler are mixed and then subjected to a shaping treatment.
9. The process for preparing a pregabalin extended release composition according to claim 8, wherein the mixing time is 10 to 25 minutes, preferably 15 minutes.
10. A pregabalin sustained release tablet comprising the pregabalin sustained release composition of any one of claims 1 to 7.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810608326.0A CN110585153A (en) | 2018-06-13 | 2018-06-13 | Pregabalin sustained-release composition and preparation method thereof |
| PCT/CN2019/090933 WO2019238068A1 (en) | 2018-06-13 | 2019-06-12 | Sustained-release pregabalin composition and preparation method therefor |
| CN201980014023.9A CN111741748B (en) | 2018-06-13 | 2019-06-12 | Pregabalin sustained-release composition and preparation method thereof |
| US16/618,756 US11938222B2 (en) | 2018-06-13 | 2019-06-12 | Pregabalin sustained release composition and method for preparing the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810608326.0A CN110585153A (en) | 2018-06-13 | 2018-06-13 | Pregabalin sustained-release composition and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110585153A true CN110585153A (en) | 2019-12-20 |
Family
ID=68849169
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810608326.0A Pending CN110585153A (en) | 2018-06-13 | 2018-06-13 | Pregabalin sustained-release composition and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110585153A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110974798A (en) * | 2019-12-19 | 2020-04-10 | 江苏优仿医药科技有限公司 | Pharmaceutical composition, sustained-release tablet and preparation method thereof |
| CN112137978A (en) * | 2020-09-25 | 2020-12-29 | 山东则正医药技术有限公司 | Solid pharmaceutical composition for stomach retention and modified release, preparation method and application |
| CN113143874A (en) * | 2020-01-07 | 2021-07-23 | 华宇药品股份有限公司 | Sustained-release formulations of pregabalin |
| CN114246836A (en) * | 2022-01-21 | 2022-03-29 | 杭州新诺华医药有限公司 | Pregabalin sustained release tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101330907A (en) * | 2005-11-02 | 2008-12-24 | 辉瑞产品公司 | Solid oral pharmaceutical compositions for once daily dosing containing pregabalin, a matrix forming agent and a swelling agent |
| CN104840443A (en) * | 2015-05-27 | 2015-08-19 | 齐鲁制药有限公司 | Medicine composition containing active ingredients of pregabalin |
-
2018
- 2018-06-13 CN CN201810608326.0A patent/CN110585153A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101330907A (en) * | 2005-11-02 | 2008-12-24 | 辉瑞产品公司 | Solid oral pharmaceutical compositions for once daily dosing containing pregabalin, a matrix forming agent and a swelling agent |
| CN104840443A (en) * | 2015-05-27 | 2015-08-19 | 齐鲁制药有限公司 | Medicine composition containing active ingredients of pregabalin |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110974798A (en) * | 2019-12-19 | 2020-04-10 | 江苏优仿医药科技有限公司 | Pharmaceutical composition, sustained-release tablet and preparation method thereof |
| CN113143874A (en) * | 2020-01-07 | 2021-07-23 | 华宇药品股份有限公司 | Sustained-release formulations of pregabalin |
| CN112137978A (en) * | 2020-09-25 | 2020-12-29 | 山东则正医药技术有限公司 | Solid pharmaceutical composition for stomach retention and modified release, preparation method and application |
| CN114246836A (en) * | 2022-01-21 | 2022-03-29 | 杭州新诺华医药有限公司 | Pregabalin sustained release tablet and preparation method thereof |
| CN114246836B (en) * | 2022-01-21 | 2023-07-07 | 杭州新诺华医药有限公司 | Pregabalin sustained release tablet and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI330080B (en) | Solid pharmaceutical compositions containing pregabalin | |
| CN110585153A (en) | Pregabalin sustained-release composition and preparation method thereof | |
| CN109044981B (en) | Pregabalin gastric floating sustained release tablet and preparation method thereof | |
| JP2002541090A (en) | Pregelatinized starch in controlled release formulations | |
| CN107375945B (en) | Donepezil cyclodextrin inclusion compound and oral instant film agent containing same | |
| EP1478346A1 (en) | Fast disintegrating tablets | |
| CN104840443B (en) | The pharmaceutical composition of the Pregabalin containing active ingredient | |
| CN111741748B (en) | Pregabalin sustained-release composition and preparation method thereof | |
| EP2415460A1 (en) | Formulations of pregabalin for oral administration | |
| CN111053749B (en) | Pregabalin sustained-release composition and preparation method thereof | |
| JP2017531637A (en) | Pregabalin sustained-release preparation | |
| JP5420126B2 (en) | pH independent extended release pharmaceutical composition | |
| CN113521025A (en) | Pharmaceutical composition of pregabalin and preparation method and application thereof | |
| Malviya et al. | Formulation and optimization of sustained release tablets of diclofenac sodium using guar gum as release modifier | |
| DE60319983T2 (en) | Universal composition for controlled release of active ingredient containing chitosan | |
| CN113908153B (en) | Buvaracetam pharmaceutical composition, preparation method and application thereof | |
| US10632077B2 (en) | Pregabalin-containing, oral sustained-release triple layer tablet | |
| KR20110130382A (en) | A method for the production of bioadhesive compact matrices | |
| WO2022194198A1 (en) | Lacosamide pharmaceutical composition, preparation method for same, and applications thereof | |
| JP2016060731A (en) | Oral composition | |
| BK et al. | Role of Superdisintegrants in Rapid Dissolving Oral Films | |
| US11007153B2 (en) | Pregabalin-containing, high swellable, sustained-release triple layer tablet | |
| JP2007153882A (en) | Solid formulation to control elution of active ingredient to sustained-release | |
| WO2024028262A1 (en) | Novel formulation | |
| WO2014184663A2 (en) | Orally dispersible drug formulations |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |