CN106176639A - A kind of method preparing Roflumilast tablet - Google Patents

Abstract

The invention provides a kind of method preparing Roflumilast tablet, it comprises the steps: a, the raw material weighing each weight proportion and adjuvant: roflumilast 1 part, lactose 20-450 part, corn starch 10-250 part, 30 POVIDONE K 30 BP/USP 90 3-25 part, magnesium stearate 0.5-25 part；B, roflumilast and 30 POVIDONE K 30 BP/USP 90 are dissolved in 50-95% ethanol, are prepared as pastille binding agent；C, take lactose and sieve with corn starch, mixing；D, the pastille binding agent of b step is joined in the mixture of lactose and corn starch, pelletize, be dried, granulate, always mix, tabletting, be prepared as tablet.Roflumilast piece preparation method of the present invention ensure that the medicament contg uniformity, and raw material controls particle diameter without micronization, and this invention can increase the dissolution of insoluble drug, and common dissolving reduces technological operation step, saves the energy, and reduces cost.

Description

A kind of method preparing Roflumilast tablet

Technical field

The present invention relates to a kind of method preparing Roflumilast tablet, belong to field of pharmaceutical preparations.

Background technology

Roflumilast, was completed by the research and development of AnDa Co., Ltd of Germany in 1993 for 2009 by Metrizamide company of Switzerland III clinical trial phase, in July, 2010 European Union's approval listing, is to obtain European Union's approval first New class COPD medicine, in state's list marketings such as Germany, Britain, Denmark.In December, 2010 In Canada, approval lists, in March, 2011 U.S. FDA approval input Clinical practice (trade name: “Daliresp^TM", specification: 0.5mg, dosage form: tablet) thus become ten the most in the world It is approved first new oral medicine for chronic obstructive pulmonary disease treatment.

Number of patent application CN201210261940.7, denomination of invention: roflumilast tablet preparation and preparation side thereof Method, disclose by roflumilast and lactose with certain proportion micropowder after, add adjuvant in other and mix in prescription Close and pelletize with PVPK90 aqueous solution again.Though the method improves the dissolution of insoluble drug roflumilast, But being pulverized by roflumilast and need special micronization equipment when commercial production, input cost is higher and easy Loss raw material, increases operational process of craft and difficult control, is unfavorable for operator's labor protection.

Number of patent application CN201210266920.9, denomination of invention: a kind of roflumilast oral formulations and Preparation method, discloses employing solid dispersion technology by material dissolution in appropriate ethanol solution, addition Appropriate amount of auxiliary materials mix homogeneously, is dried, and volatilize ethanol.Take this mixture and add binding agent soft material, pelletize, Being dried, granulate, adds appropriate fluidizer or lubricant always mixes, tabletting, coating, packaging, obtains sieve fluorine The special sheet of department.Though the method does not uses micronization but raw material is dissolved in ethanol, adds adjuvant mix homogeneously and is dried, powder Pelletize with binding agent again after broken, be dried；Two step mixings, two steps are dried, and loaded down with trivial details being unfavorable for produces greatly process, And the easy consumption energy increases cost.

Summary of the invention

In order to solve above-mentioned technical problem, technical scheme provides the system of a kind of Roflumilast tablet Preparation Method.

The invention provides a kind of method preparing Roflumilast tablet, it comprises the steps:

A, the raw material weighing each weight proportion and adjuvant: roflumilast 1 part, lactose 20-450 part, jade Rice starch 10-250 part, 30 POVIDONE K 30 BP/USP 903-25 part, magnesium stearate 0.5-25 part；

B, roflumilast and 30 POVIDONE K 30 BP/USP 90 are dissolved in 50-95% ethanol, are prepared as pastille binding agent；

C, take lactose and sieve with corn starch, mixing；

D, the pastille binding agent of b step is joined in the mixture of lactose and corn starch, pelletize, dry Dry, granulate, total mixed, tabletting, be prepared as tablet.

Preferably, the weight proportion of raw material described in step a and adjuvant is:

Roflumilast 1 part, lactose 50-450 part, corn starch 10-200 part, 30 POVIDONE K 30 BP/USP 903-15 Part, magnesium stearate 0.5-10 part.

Preferably, the weight proportion of raw material described in step a and adjuvant is:

Roflumilast 1 part, lactose 50-400 part, corn starch 12.5-150 part, 30 POVIDONE K 30 BP/USP 903-10 Part, magnesium stearate 0.5-10 part.

Preferably, the weight proportion of raw material described in step a and adjuvant is:

Roflumilast 1 part, lactose 400 parts, corn starch 100 parts, 30 POVIDONE K 30 BP/USP 904 parts, tristearin 8 parts of magnesium of acid.

Wherein, the concentration of alcohol described in step b is 50% ethanol.

Wherein, the method for granulating described in step d is: pastille binding agent b step prepared and step c The lactose of preparation and the mixture of corn starch set high in effect wet granulator, arrange mixing speed 400rpm, shear rate 1000rpm, pelletize 30s～60s, until material is the soft of uniform wet state Material, 20 mesh sieve of the granule after pelletize.

Wherein, the drying means described in step d is: fluid bed airpillow-dry, temperature of charge control 45 DEG C～ 55 DEG C, controlling moisture is 1.0%～3.0%.

Wherein, the total mixing method of granulate described in step d is: cross 24 mesh sieve granulate, magnesium stearate is added Granule is put mix homogeneously in Mixers with Multi-direction Movement and is obtained midbody particle.

Wherein, the tableting pressure described in step d is 40～80N.It is further preferred that described in step d Tableting pressure be 50～70N.

Owing to Roflumilast tablet specification is minimum and the difficult soluble substance of raw material, uniformity of dosage units, dissolution are The index of the major control of Roflumilast tablet, inventor is used principal agent, bonding by the discovery that studies for a long period of time Agent is jointly dissolved in dispersed in certain density ethanol solution or dissolves, as the binding agent containing principal agent, Add soft material processed in the adjuvant of mix homogeneously, pelletize, be dried, granulate, add appropriate fluidizer or lubrication Agent always mixes, tabletting, packaging, obtains Roflumilast tablet.Roflumilast tablet of the present invention ensures that medicament contg is equal Evenness, reduces principal agent particle diameter simultaneously, and raw material, without micronization, increases the dissolution of insoluble drug, improves Bioavailability, and common minimizing technological operation step of dissolving, the saving energy reduces input cost.

Accompanying drawing explanation

Fig. 1 lab scale of the present invention sample and the former stripping curve (0.01M hydrochloric acid) grinding medicine；

Fig. 2 lab scale of the present invention sample and the former stripping curve (water) grinding medicine；

Fig. 3 lab scale of the present invention sample and the former stripping curve (pH4.5 acetate buffer) grinding medicine；

Fig. 4 lab scale of the present invention sample and the former stripping curve (pH6.8 phosphate buffer) grinding medicine；

In Fig. 5 present invention, test agent compares (water-0.02%SDS) with the former medicine stripping curve that grinds；

In Fig. 6 present invention, test agent compares (0.1MHCL-0.02%SDS) with the former medicine stripping curve that grinds；

In Fig. 7 present invention, test agent compares (pH4.5 acetate-0.02%SDS) with the former medicine stripping curve that grinds；

In Fig. 8 present invention, test agent compares (pH6.8 phosphate-0.02%SDS) with the former medicine stripping curve that grinds.

Detailed description of the invention

Following embodiment is used for further illustrating but is not limited to the present invention.

The Selection experiment of embodiment 1 principal agent dissolution solvent

In taking raw material respectively about 0.5g putting beaker, it is gradually added into variable concentrations (50%, 75%, 95%) Ethanol solution, shaking limit, limit is observed, until solution clarification, weighs added quantity of solvent.According to different second The consumption of determining alcohol, the mixed accessories to 250g carries out soft material processed respectively, observes the humidity condition of soft material, And carry out, with 20 mesh sieves, investigation of sieving, the results are shown in Table 1.

The selection of table 1 principal agent dissolution solvent and investigation result

Result: the ethanol solution of above-mentioned variable concentrations can dissolve 500mg raw material under a certain amount of very well (1000 tablet recipe amount), its solvent load has good profit to 1000 tablet recipe adjuvants (about 250g) Wet effect, it has good formability, determines that this product granulation solvent uses 50～95% material particles Ethanol solution.

The screening test of embodiment 2 Roflumilast tablet of the present invention binding agent

Owing to this product is small dimension medicine, crude drug ratio in the formulation is the least, and uniformity of dosage units is main One of quality control index wanted, for ensure uniformity of dosage units supplementary material directly mix need crude drug micro- Efflorescence, complex process and to control difficulty big, therefore plan that crude drug is dispersed pelletizes in a solvent, Choose respectively different types of binding agent such as hydroxypropyl cellulose (HPC), hypromellose (HPMC), PVP K30 (PVPK30), 30 POVIDONE K 30 BP/USP 90 (PVPK90), sodium carboxymethyl cellulose (CMC-Na) And starch, it is configured to the binder solution of normal concentration respectively with water and 50% ethanol, adds equal amount (0.5g) principal agent, observes dissolving situation and phenomenon.The results are shown in Table 2 and table 3:

Table 2 principal agent disperses or dissolves situation in the aqueous solution of different binding agents

Table 3 principal agent disperses or dissolves situation in 50% ethanol solution of different binding agents

Understand according to result of the test and use PVP K30 (PVPK30) and 30 POVIDONE K 30 BP/USP 90 (PVPK90) As binding agent, select 50% ethanol can be prepared as transparent pastille binding agent as solvent, due to PVPK30 large usage quantity, solvent load is the biggest, and solution is faint yellow, therefore selects consumption less PVPK90 is as binding agent.

Principal agent and the proportioning test of binding agent in embodiment 3 Roflumilast tablet of the present invention

Taking raw material respectively and join in appropriate 50% ethanol with PVPK90 by different proportion, stirring makes its point Dissipate and dissolve, observe dispersion phenomenon and the situation of dissolving, the dissolving situation of API Yu PVPK90 different proportion Investigation the results are shown in Table 4.

The dissolving situation of table 4 principal agent and PVPK90 different proportion investigates result

Result: when raw material and PVPK90 ratio 1:3 and more than, crude drug can be completely dissolved in Solution, determine in this product prescription the ratio of API Yu PVPk90 1:3 and more than.

The preparation technology of embodiment 4 Roflumilast tablet of the present invention

The prescription of Roflumilast tablet one-tenth as shown in Table 5 is grouped into.

The prescription of table 5 Roflumilast tablet

Preparation technology:

1. by the roflumilast of recipe quantity, 30 POVIDONE K 30 BP/USP 90 ultrasonic dissolution simultaneously in 75% second of about 50g In alcoholic solution, as the binding agent containing principal agent, this binding agent is water white transparency, without agglomerate and bubble.

2. the lactose taking recipe quantity mixed 100 mesh sieve 3 times with corn starch.

3. the binding agent containing principal agent is joined in the mixture of lactose and corn starch, prepare soft material 20 Mesh sieve is pelletized, and 60 DEG C of baking oven is dried (moisture 1-3%).

4. granule crosses 24 mesh sieve granulate, and additional magnesium stearate mixes as midbody particle.

5. tabletting, tablet hardness scope control is 50～70N.

The Roflumilast tablet present invention prepared grinds medicine contrast with former, and wherein, former grinding refers to that Germany's Metrizamide is public The commercially available product of departmentOr American Forest Pharma Inc.Sieve fluorine department of the present invention Special sheet and the former medicine that grinds buffer molten at 0.1 hydrochloric acid solution (see Fig. 1), aqueous solution (see Fig. 2) and pH4.5 Liquid (see Fig. 3), pH6.8 phosphate buffer (see Fig. 4) and stripping curve the results are shown in Table 6.

Table 6 is made lab scale sample by oneself and is ground commercially available product stripping curve measurement result with former

Interpretation of result:

Being compared with the former stripping curve ground by lab scale sample, Roflumilast tablet of the present invention and the former product that grind exist During dissolution 15 minutes, accumulative dissolution all not up to 85%, need to use f2 similar factors to be evaluated, meter Calculation formula is:

$f_2=50\log \{{[1+\frac{1}{n}\underset{t-1}{\overset{n}{\mathrm{\Σ}}}{(\mathrm{Rt}-\mathrm{Tt})}^1]}^{-0.5}\×100\}$

(Rt Yu Tt represents reference and the average accumulated release by test preparation t time point respectively, and n is Number of test points, generally 4～5 points, stripping quantity time point more than 85% only chooses 1)

Judgment basis: the f2 factor >=50, it is determined that for similar；The f2 factor < 50, it is determined that for dissmilarity.

Roflumilast tablet of the present invention is with former to grind product dissolved corrosion consistent: 50 ＜ f2 values ＜ 100.Above-mentioned four kinds Medium does not all add SDS, more can embody product in vitro correlation.

The following is and Tablets lab scale is determined to the big technological parameter produced.

Embodiment 5 is pelletized and finishing technique parameter determination

Carrying out the optimization of granulating process according to the formulation and technology drafted, studied by lab scale, manual mode is examined Examine soft material to pelletize with different sieve meshes (20 mesh, 24 mesh, 30 mesh, 40 mesh) respectively, observe technique Feasibility, result of the test is shown in Table 7.

Table 7 pelletization phenomenon

After 20 mesh sieves are pelletized, bulky grain is the most, can cause granule lamination, by above-mentioned phenomenon analysis Show that 20 mesh sieves and 24 mesh sieves are the most feasible, but 20 mesh sieves possess advantage faster of sieving, analyze graininess Can, contrast early stage 20 mesh sieve granulation granulate effect, primarily determine that 20 mesh sieves are pelletized and 24 mesh sieve granulate, Result of the test is shown in Table 8.

Table 8 20 mesh sieve is pelletized and 24 mesh sieve granulate investigate result

Efficient wet granulator is used to prepare soft material, swing mechanical particle in pilot process checking research Equipment, its intensity is more than the craft granulation of lab scale, and 16 mesh sieve granulation granules are too big, final employing 24 mesh Sieve series grain and granulate, its shaping particles is good, and velocity through screen is fast, and particle size distribution equalizes, good fluidity, Compressibility is good, and hardness is moderate, and pilot process proof procedure is smooth, is suitable for mechanization production.

Test result indicate that: according to pilot scale research situation, be suitable for granulation and the granulate condition of mechanization production, Therefore 20 mesh sieves are selected to pelletize, 24 mesh sieve granulate.

Embodiment 6 baking temperature and the selection of drying mode

Supplementary material compatibility test illustrates, roflumilast is fully able to bear the temperature of 60 DEG C and is dried, lab scale The sample of research all can possess identical prescription with reference preparation, and the wetting agent in conjunction with this product is 50～the ethanol solution of 95%, possess good volatility, pilot scale research sample is under 60 DEG C of drying regimes Can effectively control moisture in 3h 1.0%～3.0%, this moisture adapts to industrialized production, and tabletting shapes Property is good, and all adjuvants of this prescription can keep original characteristic at such a temperature.

Binding tests and production equipment practical situation, lab scale conceptual phase uses the hot air circulation static state side of being dried Formula, for providing production efficiency, the enlarged experiment stage uses the airpillow-dry mode of fluid bed, and by 3 Criticize scale up test and checking.

Product quality, energy consumption and time are considered, finally according to testing result and large-scale production The baking temperature of Roflumilast tablet wet granular uses 45～55 DEG C to be carried out, and mode is fluid bed airpillow-dry, When moisture is that the 1.0-3.0% time is as dry terminal.

Embodiment 7 tablet hardness determines

According to former triturate pressure between 50N～70N, in prescription screening is studied, sample is all by reference system The hardness range of agent carry out debug tabletting, the sample formation obtained is good, friability all below 0.3%, Without fracture be full of cracks and fragment phenomenon.Also designing and investigated pressure simultaneously is 40N, 50N, 60N and 80N Time impact on prescription dissolved corrosion.The results are shown in Table 9.

Table 9 stripping curve determination data

From experimental result: finished product dissolution can reach consistent requirement and each pressurised samples with reference preparation Label edge without abrasion, so tablet hardness controls in 50～70N scopes.

The big production of Tablets

Embodiment 8

Production technology:

1. roflumilast and 30 POVIDONE K 30 BP/USP 90 being dissolved in 95% appropriate ethanol solution, solution is colourless Bright, without agglomerate and bubble, as binding agent.

2. the lactose taking recipe quantity crosses 100 mesh sieves with corn starch, sets high in effect wet granulator and carries out Mixing.

3. the binding agent of pastille is joined in the mixture of lactose and corn starch, set high effect wet granulation In machine, mixing speed 400rpm, shear rate 1000rpm be set, pelletize 30s～60s, until thing The material soft material in uniform wet state, takes out and uses 20 mesh sieve.

4. using fluid bed airpillow-dry, temperature of charge controls 45 DEG C～55 DEG C of scopes.Moisture Control exists 1.0%～3.0%.

5. granule crosses 24 mesh sieve granulate；Magnesium stearate is added granule and puts mixing in Mixers with Multi-direction Movement Uniformly obtain midbody particle

6. midbody particle is put tabletting in rotary tablet machine (pressure control range 50～70N) and get final product Roflumilast tablet.

Embodiment 9

Production technology:

1. roflumilast and 30 POVIDONE K 30 BP/USP 90 being dissolved in 75% appropriate ethanol solution, solution is colourless Bright, without agglomerate and bubble, as binding agent.

2. the lactose taking recipe quantity crosses 100 mesh sieves with corn starch, sets high in effect wet granulator and carries out Mixing.

3. the binding agent of pastille is joined in the mixture of lactose and corn starch, set high effect wet granulation In machine, mixing speed 400rpm, shear rate 1000rpm be set, pelletize 30s～60s, until thing The material soft material in uniform wet state, takes out and pelletizes with 20 mesh.

4. using fluid bed airpillow-dry, temperature of charge controls 45 DEG C～55 DEG C of scopes.Moisture Control exists 1.0%～3.0%.

5. granule crosses 24 mesh sieve granulate；Magnesium stearate is added granule and puts mixing in Mixers with Multi-direction Movement Uniformly obtain midbody particle

6. midbody particle is put tabletting in rotary tablet machine (pressure control range 50～70N) and get final product Roflumilast tablet.

Embodiment 10

Production technology: 1. roflumilast and 30 POVIDONE K 30 BP/USP 90 are dissolved in 50% appropriate ethanol solution, molten Liquid is water white transparency, without agglomerate and bubble, as binding agent.

2. the lactose taking recipe quantity crosses 100 mesh sieves with corn starch, sets high in effect wet granulator and carries out Mixing.

3. the binding agent of pastille is joined in the mixture of lactose and corn starch, set high effect wet granulation In machine, mixing speed 400rpm, shear rate 1000rpm be set, pelletize 30s～60s, until thing The material soft material in uniform wet state, takes out and uses 20 mesh sieve.

4. using fluid bed airpillow-dry, temperature of charge controls 45 DEG C～55 DEG C of scopes.Moisture Control exists 1.0%～3.0%.

5. granule crosses 24 mesh sieve granulate；Magnesium stearate is added granule and puts mixing in Mixers with Multi-direction Movement Uniformly obtain midbody particle

6. midbody particle is put tabletting in rotary tablet machine (pressure control range 50～70N) and get final product Roflumilast tablet.

The tablet of embodiment 8,9,10 gained in producing greatly carries out stripping curve compare with the former product that grind, The results are shown in Table 10-13.

In table 10 self-control, test agent compares water (0.02%SDS) (see Fig. 5) with commercially available product dissolved corrosion

In table 11 self-control, test agent compares 0.1mol/L hydrochloric acid (0.02%SDS) (Fig. 6) with commercially available product dissolved corrosion

In table 12 self-control, test agent compares pH4.5 acetate (0.02%SDS) (Fig. 7) with commercially available product dissolved corrosion

In table 13 self-control, test agent compares pH6.8 phosphate (0.02%SDS) (Fig. 8) with commercially available product dissolved corrosion

Interpretation of result: three batches of Roflumilast tablet of the present invention and two batches of former commercially available products of grinding are in 4 kinds of dissolution mediums Dissolved corrosion is basically identical: 50 ＜ f2 ＜ 100.Can speculate that self-control technological design is reasonable accordingly, dissolved corrosion Equivalent is ground with former.

Embodiment 11

Embodiment 7,8,9 sample is accelerated stability test investigation with former commercial preparation of grinding

Investigation project: character, content and have related substance, dissolution

Result of the test is shown in Table 14-17:

14 40 DEG C of accelerated test results of table (embodiment 8)

15 40 DEG C of accelerated test results of table (embodiment 9)

16 40 DEG C of accelerated test results of table (embodiment 10)

17 40 DEG C of accelerated test results of table (commercial samples A233836)

Roflumilast tablet of the present invention can produce qualified preparation by more scientific and reasonable technique, and This technological design science, easy and simple to handle, can reduce energy consumption, improve production efficiency.

Claims (10)

1. the method preparing Roflumilast tablet, it comprises the steps:

A, the raw material weighing each weight proportion and adjuvant:

Roflumilast 1 part, lactose 20-450 part, corn starch 10-250 part, 30 POVIDONE K 30 BP/USP 903-25 Part, magnesium stearate 0.5-25 part；

B, roflumilast and 30 POVIDONE K 30 BP/USP 90 are dissolved in 50-95% ethanol, are prepared as pastille binding agent；

C, take lactose and sieve with corn starch, mixing；

D, the pastille binding agent of b step is joined in the mixture of lactose and corn starch, pelletize, Dry, granulate, total mixed, tabletting, be prepared as tablet.

Preparation method the most according to claim 1, it is characterised in that: raw material described in step a and The weight proportion of adjuvant is:

Roflumilast 1 part, lactose 50-450 part, corn starch 10-200 part, 30 POVIDONE K 30 BP/USP 903-15 Part, magnesium stearate 0.5-10 part.

Preparation method the most according to claim 1, it is characterised in that: raw material described in step a and The part by weight of adjuvant is:

Roflumilast 1 part, lactose 50-400 part, corn starch 12.5-150 part, 30 POVIDONE K 30 BP/USP 903-10 Part, magnesium stearate 0.5-10 part.

Preparation method the most according to claim 1, it is characterised in that: raw material described in step a and The part by weight of adjuvant is:

Roflumilast 1 part, lactose 400 parts, corn starch 100 parts, 30 POVIDONE K 30 BP/USP 904 parts, tristearin 8 parts of magnesium of acid.

Preparation method the most according to claim 1, it is characterised in that: the ethanol described in step b It is 50% ethanol.

Preparation method the most according to claim 1, it is characterised in that: the granulation side described in step d Method is: lactose prepared by pastille binding agent b step prepared and step c and the mixture of corn starch Set high in effect wet granulator, mixing speed 400rpm, shear rate 1000rpm be set, pelletize 30s～ 60s, 20 mesh sieve of the granule after pelletize.

Preparation method the most according to claim 1, it is characterised in that: the dry side described in step d Method is: fluid bed airpillow-dry, and temperature of charge controls 45 DEG C～55 DEG C, controls moisture and is 1.0%～3.0%.

Preparation method the most according to claim 1, it is characterised in that: the granulate described in step d is total Mixing method is: by the granule after fluid bed drying with 24 mesh sieve granulate, adds magnesium stearate and puts Multidirectional motion In mixer, mix homogeneously obtains midbody particle.

Preparation method the most according to claim 1, it is characterised in that: the tabletting pressure described in step d Power is 40～80N.

Preparation method the most according to claim 9, it is characterised in that: the tabletting described in step d Pressure is 50～70N.