CN102688211B - A kind of levocarnitine osmotic pumps is slow, controlled release tablet and preparation method thereof - Google Patents

Abstract

The present invention relates to a kind of levocarnitine osmotic pump controlled release tablet and preparation method thereof, belong to pharmaceutical formulating art, its active component is levocarnitine and salt thereof or derivant.This controlled release tablet and preparation method thereof solves the easy moisture absorption of levocarnitine raw material, is unfit to do into the Technology problem of tablet, compared with conventional tablet, controlled release tablet overcome levocarnitine ordinary preparation oral time to problems such as the zests of gastrointestinal.

Description

A kind of levocarnitine osmotic pumps is slow, controlled release tablet and preparation method thereof

Technical field

The present invention relates to a kind of levocarnitine osmotic pump controlled release tablet and preparation method thereof.

Technical background

Levocarnitine (Levocarnitine), another name levocarnitine, DL-carnitine chloride, L-carnitine etc., it is a kind of special acid be extensively present in body tissue, main promotion lipid metabolism, carry out beta oxidation, produce ATP energy supply, the clinical auxiliary treatment lacking the disease such as related complication, cardiovascular disease, diabetes caused for maintenance hemodialysis carnitine, there is important clinical value, in recent years along with people are to the growing interest of diet products, levocarnitine is in fat-reducing and regulate the health-care effects such as body function should have increasingly extensive.

By the end of in January, 2011, the whole nation has the production Xu Kou that 37 enterprises obtain levocarnitine preparation, in addition carrying out declaring the producer producing official written reply and then having nearly 30, health product production is declared producer and is reached upper hundred especially, visible levocarnitine preparation at home demand day by day increases, researches and develops intensification, but the above-mentioned medicine overwhelming majority declaring and produce is injection imitation medicine, or simply change solvent, as levocarnitine sodium chloride injection, minority is oral formulations, and oral agents comprises conventional tablet, capsule and oral administration solution.The research of slow controlled release oral dosage formulations aspect has no report.

Injection produce and quality control cost higher, patient carries, use inconvenience; The DL-carnitine chloride sheet (capsule) of conventional tablet and capsule to be all the auxiliary specification being used for the treatment of gastroenteropathy be 0.1g, the levocarnitine sheet being used for the treatment of carntine deficiency does not also have manufacturer production to sell; Oral administration solution is the oral formulations being uniquely used for the treatment of at present carntine deficiency, but its to there is times for spraying many, and there is the side effect that GI irritation causes diarrhoea, develop levocarnitine osmotic pump controlled release tablet for above-mentioned present situation

Summary of the invention

Provide that levocarnitine osmotic pumps is delayed, the preparation method of controlled release tablet, preparation technology coordinates prescription, efficiently solves the easy moisture absorption of levocarnitine, the problem of poor fluidity, poor compressibility.

Levocarnitine osmotic pumps is slow, controlled release tablet, and be made up of the label and the foraminate semi permeability film coating of band comprising levocarnitine, wherein label is made up of levocarnitine, the adjuvant playing controlled-release function and other adjuvants; Semipermeable membrane coating is made up of cellulose acetate and part PEG4000.

Described rising adjuvant that is slow, controlled-release function mainly comprises penetrating agent and skeletal matrix, penetrating agent and osmotic pressure promoter, play the indoor osmotic pressure of regulating, one or more having in lactose, fructose, glucose, mannitol, sodium chloride, potassium chloride, potassium sulfate conventional, preferred lactose, mannitol, in addition, some water soluble drug inherently can use as osmotic pressure promoter, simplify prescription with medicine as osmotic pressure promoter, be comparatively applicable to the larger hydrophilic medicament of dosage and prepare that osmotic pumps is slow, controlled release tablet; Skeletal matrix is selected from one or more in ethyl cellulose, hyprolose, hypromellose, sodium carboxymethyl cellulose, polyvidone, copolyvidone, carbomer, acrylic resin, stearic acid, octadecanol, several in preferred hypromellose, ethyl cellulose, polyvidone, copolyvidone, wherein again using hypromellose as first-selection, hypromellose is according to the difference of viscosity, model is more, the ratio shared by hypromellose that can regulate various viscosity according to release characteristic in prescription.

Other described adjuvants comprise wetting agent, binding agent, lubricant, opacifier, filler, and wherein wetting agent is selected from the ethanol-water solution of water, dehydrated alcohol, various concentration, preferred water; Described binding agent is selected from starch slurry, polyvidone, hyprolose, hypromellose, methylcellulose, gelatin, Polyethylene Glycol, preferred polyvidone; Described lubricant is selected from magnesium stearate, Pulvis Talci, micropowder silica gel, polyethylene glycols, preferred magnesium stearate, Pulvis Talci; Described opacifier is selected from titanium dioxide, Pulvis Talci, silicon dioxide, preferred titanium dioxide; Described filling machine comprises microcrystalline Cellulose, starch, dextrin, calcium carbonate, preferably microcrystalline cellulose.

The main cellulose acetate of tool foraminate semi permeability coating membrane and PEG4000 composition, wherein cellulose acetate is semipermeable membrane coating material, effect allows water enter the inner dissolved substance of slice, thin piece and osmotic pressure promoter, and other optional semipermeable membrane coating materials also have cellulose acetate, CAP, acrylic resin, hydroxypropyl cellulose phthalate ester; Wherein PEG4000 is penetrating regulator, and Main Function is the permeability regulating semipermeable membrane, and other optionally comprise polyvidone, copolyvidone, hyprolose etc.

Can also add pharmaceutically acceptable plasticizer in described semi permeability coating membrane, plasticizer is selected from Reomol.

Described levocarnitine delays, comprise in controlled release tablet: levocarnitine 10%-90%, PVPS-6301%-50%, HPMC1%-50%, ethyl cellulose 0.1%-10%, magnesium stearate 0.1%-1%, cellulose acetate 1%-30%, PEG40001%-30%, preferred levocarnitine 20%-90%, PVPS-6305%-30%, HPMC5%-30%, ethyl cellulose 0.2%-5%, magnesium stearate 0.2%-1%, cellulose acetate 1%-20%, PEG40001%-20%, most preferably levocarnitine 40%-90%, PVPS-6305%-20%, HPMC5%-20%, ethyl cellulose 0.2%-3%, magnesium stearate 0.5%-1%, cellulose acetate 1%-10%, PEG40001%-10%.

Levocarnitine osmotic pumps is delayed, the preparation method of controlled release tablet is first take by recipe quantity the levocarnitine sieved, skeletal matrix, osmotic pressure promoter and other adjuvant mix homogeneously, drip wetting agent or binding agent soft material, granulate, dry, sieve granulate, then the solution containing cellulosic material is sprayed at particle surface, spray limit, limit stirring and drying granule, weightening finish is to recipe quantity, sieve granulate, dry, finally add appropriate lubricant, tabletting, bag semipermeable membrane clothing, and to adopt laser or mechanical punching mode to make a call to a diameter in the side of coated tablet be 0.2mm-1.2mm aperture.Described cellulosic material comprises: cellulose acetate, cellulose acetate titanate esters, ethyl cellulose, methylcellulose, preferred, ethyl.

Levocarnitine be one have extremely strong draw moist in water very soluble inner salt, osmotic pressure is produced after being dissolved in water, so can be used as the use of osmotic pressure promoter, levocarnitine can very fast overflowing from aperture, so with the addition of hypromellose in label, polyvidones etc. have the macromolecular material of viscosity, and the solution of fiber film material or resin molding material is contained in granulate intermediate surface sprinkling, netted water-stop structure is formed at sheet core inner after making compression molding, reduce the speed that water enters label, also reduce the speed that levocarnitine overflows aperture, the coating weight gain that can determine the need of granule coating and fiber film material according to concrete actual release situation, slow by regulating the coating amount of the stickiness and particle surface fibrous membrane with viscosity macromolecular material to make levocarnitine sheet have, release characteristics.

Delay according to levocarnitine, the different this films of controlled release tablet specification can be prepared into the circular piece of rule and irregular caplets, the punch position of rule sheet is fixed, generally punch at the home position of slice, thin piece convex surface, and irregular caplets punch position is not fixed, punch position difference likely can have influence on the stripping of levocarnitine in label, and concrete punch position can be formulated according to stripping situation.

Levocarnitine osmotic pumps is delayed, the preparation method of controlled release tablet comprises the following step:

1) levocarnitine, osmotic pressure promoter, skeletal matrix and other adjuvant mix homogeneously of a part are taken by prescription;

2) spray wetting agent or binding agent soft material, cross 20 mesh sieve extrusion granulators;

3) made granule to be put in 50 DEG C of air dry ovens 1.5 hours;

4), after drying, take out, 20 mesh sieve granulate;

5) spray the solution of cellulose-containing material at particle surface, reach design flow to weight gain;

6) by 5) gained granule again crosses 20 mesh sieves, and to be put by gained granule in 50 DEG C of air dry ovens 0.5 hour;

7) after drying, appropriate lubricant is added, mix homogeneously, tabletting.

8) coating, cellulose acetate-PEG4000 (9: 1), acetone/water is solvent, reaches design flow to label weightening finish.

9) punch, adopting laser or mechanical punching mode to make a call to a diameter in the side of coated tablet is 0.2mm-1.2mm aperture.

Their Dissolution Test in vitro:

According to dissolution method first method, with 900mL water for solvent, rotating speed is 75 turns per minute, at 0.5,1,2,4,8,12 hour difference sampling and measuring levocarnitine content, obtains accumulative dissolution.

Levocarnitine content assaying method is with reference to National Drug Administration standard (trying) WS-493 (X-434)-99.

This utility model technology is equally applicable to levocarnitine salt.

Accompanying drawing explanation

Fig. 1 Core formulation 1 In Vitro Dissolution curve chart

Fig. 2 Core formulation 2 In Vitro Dissolution curve chart

Fig. 3 Core formulation 3 In Vitro Dissolution curve chart

Fig. 4 Core formulation 4 In Vitro Dissolution curve chart

Detailed description of the invention

Below in conjunction with embodiment, the present invention is described further, but be not any limitation of the invention.

Embodiment one:

Core formulation 1: by 1000 tablets

Semipermeable membrane coating solution forms:

Cellulose acetate 29.25g

PEG40003.25g

Acetone/water (20: 1) 1000mL, coating weight gain 5%

Preparation process:

1) levocarnitine, HPMC K4M, the polyvidone-S630 mix homogeneously that have sieved is taken by prescription;

2) spray distilled water soft material, cross 20 mesh sieve extrusion granulators;

3) made granule to be put in 50 DEG C of air dry ovens 1.5 hours;

4), after drying, take out, 20 mesh sieve granulate;

5) ethanol solution containing ethyl cellulose is sprayed, to weight gain 1% at particle surface;

6) by 5) gained granule again crosses 20 mesh sieves, and to be put by gained granule in 50 DEG C of air dry ovens 0.5 hour;

7) after drying, appropriate magnesium stearate is added, mix homogeneously, tabletting.

8) coating, cellulose acetate-PEG4000 (9: 1), acetone/water (20: 1) is solvent, to label weightening finish 5%.

9) punch, adopting laser boring mode to make a call to a diameter in the side of coated tablet is 0.6mm aperture.

10) Core formulation 1 In Vitro Dissolution curve chart is shown in Fig. 1.

Embodiment two:

Core formulation 2: by 1000 tablets

Semipermeable membrane coating solution forms:

Cellulose acetate 45g

PEG40005g

Acetone/water (20: 1) 2000mL, coating weight gain 6%

Preparation process:

1) by prescription take sieved levocarnitine, hypromellose E15, hypromellose E5, polyvidone-S630 mix homogeneously;

2) spray distilled water soft material, cross 20 mesh sieve extrusion granulators;

3) made granule to be put in 50 DEG C of air dry ovens 1.5 hours;

4), after drying, take out, 20 mesh sieve granulate;

5) ethanol solution containing cellulose acetate is sprayed, to weight gain 1% at particle surface;

6) by 5) gained granule again crosses 20 mesh sieves, and to be put by gained granule in 50 DEG C of air dry ovens 0.5 hour;

7) after drying, appropriate magnesium stearate is added, mix homogeneously, tabletting.

8) coating, cellulose acetate-PEG4000 (9: 1), acetone/water (20: 1) is solvent, to label weightening finish 6%.

9) punch, adopting mechanical punching mode to make a call to a diameter in the side of coated tablet is 0.8mm aperture.

10) Core formulation 2 In Vitro Dissolution curve chart is shown in Fig. 2.

Embodiment three:

Core formulation 3: by 1000 tablets

Semipermeable membrane coating solution forms:

Cellulose acetate 45g

PEG40005g

Acetone/water (20: 1) 2000mL, coating weight gain 6%

Preparation process:

1) levocarnitine, hypromellose E5, polyvidone-S630, the microcrystalline Cellulose mix homogeneously that have sieved is taken by prescription;

2) spray 3% hypromellose cellulose solution soft material, cross 20 mesh sieve extrusion granulators;

3) made granule to be put in 50 DEG C of air dry ovens 1.5 hours;

4), after drying, take out, 20 mesh sieve granulate;

5) after drying, appropriate magnesium stearate is added, mix homogeneously, tabletting.

6) coating, cellulose acetate-PEG4000 (9: 1), acetone/water (20: 1) is solvent, to label weightening finish 6%.

9) punch, adopting laser boring mode to make a call to a diameter in the side of coated tablet is 0.4mm aperture.

10) Core formulation 3 In Vitro Dissolution curve chart is shown in Fig. 3.

Embodiment four:

Core formulation 4: by 1000 tablets

Semipermeable membrane coating solution forms:

Cellulose acetate 29.25g

PEG40003.25g

Acetone/water (20: 1) 1000mL, coating weight gain 4%

Preparation process:

1) levocarnitine, mannitol, microcrystalline Cellulose, hypromellose E15, the polyvidone mix homogeneously that have sieved is taken by prescription;

2) spray 5%PVP solution soft material, cross 20 mesh sieve extrusion granulators;

3) made granule to be put in 50 DEG C of air dry ovens 1.5 hours;

4), after drying, take out, 20 mesh sieve granulate;

5) ethanol solution containing ethyl cellulose is sprayed, to weight gain 0.8% at particle surface;

6) by 5) gained granule again crosses 20 mesh sieves, and to be put by gained granule in 50 DEG C of air dry ovens 0.5 hour;

7) after drying, appropriate magnesium stearate is added, mix homogeneously, tabletting.

8) coating, cellulose acetate-PEG4000 (9: 1), acetone/water (20: 1) is solvent, to label weightening finish 4%.

9) punch, adopting mechanical punching mode to make a call to a diameter in the side of coated tablet is 0.8mm aperture.

10) Core formulation 4 In Vitro Dissolution curve chart is shown in Fig. 4.

Claims (3)

1. a levocarnitine osmotic pump controlled release tablet, it is characterized in that this sheet is by having semi permeability coating membrane that diameter is 0.2mm-1.2mm aperture and label forms, this sheet comprises levocarnitine 10%-90%, PVPS-6301%-50%, HPMC1%-50%, ethyl cellulose 0.1%-10%, magnesium stearate 0.1%-1%, cellulose acetate 1%-30%, PEG40001%-30%, this sheet label is carried out the skeletal matrix of coating by water-insoluble macromolecular material, the hybrid particles compacting of osmotic pressure promoter forms, this sheet semi permeability coating membrane by ratio be 9: 1 cellulose acetate and PEG4000 form, wherein osmotic pressure promoter is levocarnitine, levocarnitine accounts for 100% of osmotic pressure promoter, skeletal matrix is HPMC, PVP-S630.

2. controlled release tablet according to claim 1, is characterized in that comprising in controlled release tablet: levocarnitine 20%-90%, PVPS-6301%-30%, HPMC1%-30%, ethyl cellulose 0.1%-5%, magnesium stearate 0.1%-1%, cellulose acetate 1%-20%, PEG40001%-20%.

3. levocarnitine osmotic pump controlled release tablet according to claim 1, it is characterized in that, the levocarnitine sieved first is taken by recipe quantity, skeletal matrix and other adjuvant mix homogeneously, drip wetting agent or binding agent soft material, granulate, dry, sieve granulate, then at the insoluble macromolecule material solution of particle surface spray water, spray limit, limit stirring and drying granule, weightening finish is to recipe quantity, sieve granulate, dry, finally add appropriate lubricant, tabletting, bag semipermeable membrane clothing, and to adopt laser or mechanical punching mode to make a call to a diameter in the side of coated tablet be 0.2mm-1.2mm aperture.