CN101491523A - Combination containing micronized gliquidone - Google Patents

Abstract

The invention relates to a pharmaceutical composition taking gliquidone which contains micronization as an active component and a method for preparing the composition. Micronized gliquidone is mixed with a surfactant and a proper excipient, palletized and tabletted to obtain the pharmaceutical composition taking the gliquidone which contains the micronization as the active component. The pharmaceutical composition greatly improves the water solubility of the gliquidone, thereby ensuring that the gliquidone is almost completely dissolved out from the composition.

Description

The compositions that contains the micronization gliquidone

Affiliated technical field

The gliquidone (gliquidone) that the present invention relates to contain the micronizing solid form is for the pharmaceutical composition of active ingredient and prepare described method for compositions.

Background technology

Pharmaceutical composition of the present invention is solid or semi-solid medicament compositions.Significant solid composite medicament, for example powder, pill, capsule and tablet etc., term " semi-solid medicament compositions " refers to mainly be dispersed in the pharmaceutical composition of forming in (height) viscosity formulated by solid active agent.Significant semi-solid medicament compositions, for example suppository, Emulsion, gellant and ointment etc.

Preferred solid dosage forms is a tablet in the scope of the invention.This area professional and technical personnel must consider the characteristics of tablet when seminar's compound.The concrete characteristics of tablet are shape, dissolution and particularly hardness.

Oral is the general optimization approach of medicament administration, accepts into the patient because this approach makes things convenient for especially and is easy to.For the professional and technical personnel in pharmaceutical compositions field, prepare a kind of solid oral dosage form and also constitute a series of challenge sometimes with all perfect characteristics.For producing drug effect, medicine must reach suitable concentration in blood samples of patients in taking the back acceptable time.In other words, medicine must have acceptable bioavailability.A very important factor that influences the bioavailability behind the drug oral is dissolving, the i.e. dissolution rate of medicine, the especially dissolution rate in gastric juice.It is reported that under 37 ℃, solid chemicals of the present invention dissolves 85% in 45 minutes at least in 0.1N HCl.Described dissolving is to measure according to hereinafter testing the method for testing of describing in the example.The professional and technical personnel of developing drugs compositions field faces preparation and is suitable for oral solid dosage forms, can accept dissolution rate so that chemical compound has.And described this area professional is subjected to the constraint of other restrictive condition.To be prepared and must meet inherent and external quality is controlled requirement with commercial scale by the pharmaceutical composition of its exploitation.

When gliquidone is common crystal form, its oral because very poor dissolubility and stripping is hindered.In the research process that improves the gliquidone bioavailability, this product is micronized.Unfortunately, the rate of dissolution of micronization gliquidone even poorer than its common crystal form.

Summary of the invention

Yet that the present inventor is surprised to find that is as mentioned below when micronized gliquidone is allocated into, with preparation composition prepared known in the art in the time, it has favorable dissolution properties and reaches inherent and external quality is controlled requirement.

Therefore, the invention provides a kind of useful especially gliquidone compositions compound method.The invention provides a kind of suitable deliquescent pharmaceutical composition that has, a kind of solid chemicals combination of oral medication that comprises the micronization gliquidone more particularly is provided.Micronized gliquidone can adopt methods known in the art to be prepared, and for example, grinds on suitable grinder and pass through suitable sieve.

According to the present invention, the characteristic of micronization gliquidone is as follows: it has at least 60% particle diameter to be not more than 20 μ m.Preferably, be 18 μ m; Having at least 90% particle diameter to be not more than 30 μ m, preferably, is 28 μ m.

Compositions of the present invention preferably contains pharmaceutically suitable carrier and excipient, and filler for example is as lactose, sucrose, mannitol, corn starch, microcrystalline Cellulose or calcium hydrogen phosphate; Lubricant is as stearic acid, Polyethylene Glycol, magnesium stearate, Pulvis Talci or micropowder silica gel; Disintegrating agent, as rice, Rhizoma Solani tuber osi or corn starch, carboxymethylstach sodium or cross-linking sodium carboxymethyl cellulose; Binding agent adjoins pyrrolidone or hydroxypropyl methylcellulose and wetting agent as pre-gelatinization corn starch, polyethylene, as sodium lauryl sulphate and polysorbate.Significant filler is lactose, sucrose, starch or microcrystalline Cellulose; Preferred lactose, starch and microcrystalline Cellulose.Significant lubricant is stearic acid, Polyethylene Glycol, hydrogenated vegetable oil, sodium stearyl fumarate or magnesium stearate, preferred magnesium stearate.Significant disintegrating agent is rice, Rhizoma Solani tuber osi and corn starch, carboxymethyl starch sodium, preferred carboxymethyl starch sodium.Preferred adhesive is at 30 POVIDONE K 30 BP/USP 30.Find that also can select polysorbate is wetting agent.Significant wetting agent is polysorbate20 (polysorbas20), polysorbate40 (polysorbate40), polysorbate60 (polysorbate60), polysorbate80 (Tween 80), polysorbate65 (polysorbate65), polysorbate85 (polysorbate85).More meaningful wetting agent is polysorbate20, polysorbate40, polysorbate60, polysorbate80.Preferred wetting agent is a polysorbate80.

Reasonably compositions contains (to account for the weight of compositions gross weight):

Gliquidone: 4%-35%

Filler: 60%-90%

Disintegrating agent: 2%-8%

Binding agent: 0.5%-5%

Wetting agent: 0.1%-1.5%

More rational compositions contains (to account for the weight of compositions gross weight):

Gliquidone: 6%-20%

Filler: 75%-85%

Disintegrating agent: 3%-6%

Binding agent: 1%-3%

Lubricant: 0.4%-0.8%

Wetting agent: 0.5%-1.2%

Preferred compositions contains (to account for the weight of compositions gross weight): gliquidone: 12.1%; Lactose: 52.4%; Corn starch: 20%; Microcrystalline Cellulose 8%; Carboxymethyl starch sodium: 4%; 30 POVIDONE K 30 BP/USP 30:2%; Polysorbate: 0.8%; Micropowder silica gel 0.3%; Magnesium stearate 0.5%.

For preparing compositions of the present invention, the micronization gliquidone is mixed with proper excipient and granulate.

The ratio of wetting agent/gliquidone (w/w) is a key factor.For obtaining fine solubility, fully moistening of active ingredient.When the content of wetting agent in compositions was too high on the other hand, the hardness of gained tablet was inappropriate, and the result is unsuitable for commercial production.

Wetting agent/gliquidone ratio can change between about 0.02 and 0.2.Described ratio preferable range is about 0.025～0.12.Be more preferably about 0.05～0.08.Most preferably be about 0.065.

Tablet of the present invention can be circle or special-shaped tablets, its basal surface can be level or convex and its edge smooth.Described tablet can have line or disconnect labelling, also can have symbol or other labelling.

Another aspect of the present invention is to have the patient of related disorders that a kind of Therapeutic Method is provided to suffering from diabetes, and it comprises the oral pharmaceutical composition as solid dosage form that contains the micronization gliquidone.

The specific embodiment

The present invention now further describes as follows with embodiment, but the scope of the invention is not limited to these embodiment certainly.

Embodiment 1

Tablet is formed:

Form weight (%)

Gliquidone 12.1

Lactose 52.3

Microcrystalline Cellulose 8

Carboxymethyl starch sodium 4

30 POVIDONE K 30 BP/USP 30 2

Micropowder silica gel 0.3

Magnesium stearate 0.5

Polysorbate80 0.8

Starch 20

Amount to 100.0

(1) micronization of gliquidone

Use the gliquidone micronization of vibration type super micron mill with the 1kg amount.When granule is small enough to be taken away by air flow, when forming pneumatic jig, their collections are obtained micronized chemical compound.

(2) preparation of binder solution

Under magnetic agitation, 30 POVIDONE K 30 BP/USP 30 and polysorbate80 are dissolved in an amount of purified water.

(3) particulate preparation

Mix gliquidone micropowder, lactose, microcrystalline Cellulose, starch, carboxymethyl starch sodium,, cross 20 mesh sieves and granulate with binder solution system soft material, 20 mesh sieve granulate are crossed in 60 degree forced air dryings, add micropowder silica gel, behind the mix homogeneously, add magnesium stearate, mix homogeneously promptly.

(4) preparation of tablet

Use tablet machine that the said mixture compression is prepared into tablet.

Embodiment 2

Employing is pressed the flow preparation tablet of embodiment 1 (2)～(4) without micronized gliquidone.

The test example

Precision is got the about 30mg of gliquidone reference substance in the 500ml volumetric flask, adds dimethyl formamide 10ml and makes dissolving, adds the dissolution medium dilution of 300ml, shakes up, and adds the blank sheet, and this solution was heated to 37 ℃ and mechanical oscillation 30 minutes.Be settled to scale with dissolution medium.Afterwards, use the 0.45um membrane filtration, in contrast product solution.

The tablet of preparation described in embodiment 1 and the embodiment 2 is put into the stripping rotor (as described in 2005 editions appendix XC second methods of Chinese Pharmacopoeia) of slurry subtraction unit respectively, rotating speed is arranged on 75 ± 2 rev/mins, dissolve medium is the phosphate buffer 500ml of pH8.5, and temperature is fixed in 37 ℃ ± 0.5 ℃.After 45 minutes, from stripping rotor, take out the 6ml sample and, get subsequent filtrate as sample solution through the 0.45um membrane filtration.

Get contrast solution and sample solution,, measure absorbance, calculate stripping quantity at the wavelength place of 314nm according to ultraviolet visible spectrophotometry (appendix IV A).

Computing formula

Dissolution %=A45*Ws/As/30*100%

Wherein: A45 is the trap of 45 minutes samples of mensuration.

Ws is the amount of the gliquidone reference substance of weighing with mg.

As: the trap of the reference solution of mensuration.

The result shows as the dissolution of tablet after 45 minutes of preparation among the embodiment 1 is 95%, and promptly 95% dissolves, and the dissolution that contains the tablet (embodiment 2) of crystallization gliquidone is about 50%.

Gliquidone sheet of the present invention in the gliquidone micronization, adopts rational adjuvant combination to make this product have goodish dissolution, can guarantee its release in gastrointestinal tract.

Claims (8)

1. one kind comprises pharmaceutically suitable carrier and gliquidone is the pharmaceutical composition of active ingredient, it is characterized in that this active ingredient is the micronizing solid form, its weight ratio that has at least 60% particle diameter to be not more than 20 μ m and wetting agent and active ingredient is 0.02～0.2.

2. pharmaceutical composition as claimed in claim 1, wherein pharmaceutical composition is a solid composite medicament.

3. as the pharmaceutical composition of claim 1 or 2, wherein active component is the gliquidone of micronization form.

4. pharmaceutical composition as claimed in claim 3, wherein said pharmaceutical composition comprise the micronization gliquidone of 3-30%.

5. it is wetting agent that pharmaceutical composition as claimed in claim 3, wherein said pharmaceutical composition also comprise polysorbate, and wherein the ratio ranges of polysorbate and gliquidone is 0.02～0.2.

6. pharmaceutical composition as claimed in claim 2, wherein said pharmaceutical composition is a tablet.

7. pharmaceutical composition as claimed in claim 3, wherein said pharmaceutical composition are the following tablets of basic composition:

Form weight (%)

Gliquidone 12.1

Lactose 52.3

Microcrystalline Cellulose 8

Carboxymethyl starch sodium 4

30 POVIDONE K 30 BP/USP 30 2

Micropowder silica gel 0.3

Magnesium stearate 0.5

Polysorbate80 0.8

Starch 20

Amount to 100.0.

8. tablet as claimed in claim 6 is characterized in that its dissolution rate is greater than 90% after 30 minutes.