CN101926785A - Medicinal controlled release preparation for treating parkinsonism and preparation method thereof - Google Patents
Medicinal controlled release preparation for treating parkinsonism and preparation method thereof Download PDFInfo
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- CN101926785A CN101926785A CN2009100869105A CN200910086910A CN101926785A CN 101926785 A CN101926785 A CN 101926785A CN 2009100869105 A CN2009100869105 A CN 2009100869105A CN 200910086910 A CN200910086910 A CN 200910086910A CN 101926785 A CN101926785 A CN 101926785A
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Abstract
The invention relates to a medicinal controlled release preparation for treating parkinsonism and a preparation method thereof, in particular to controlled release tablets which take carbidopa and levodopa as a main medicament and a preparation method thereof. The invention aims to provide carbidopa-levedopa controlled release tablets which can release medicaments at constant speed and have the high stability of medicament releasing and medicinal safety. The tablets consist of tablet cores and film coats, wherein the tablet cores take the carbidopa and the levodopa as the main medicament, and contain a controlled release material, a filler, a binding agent, an antioxidant, a lubricating agent and a wetting agent, and the film coats consist of a film-forming material and the wetting agent. The carbidopa-levedopa controlled release tablets are characterized in that the medicaments in different release media can be released at the constant speed, and have the characteristics of convenient administration, lasting effect, stable curative effect, small toxic and side effect and the like.
Description
Technical field
The present invention relates to Parkinsonian pharmaceutical controlled release formulation of a kind of treatment and preparation method thereof, specifically, relate to a kind of with Carbidopa as controlled release tablet of principal agent and preparation method thereof.Belong to field of medicaments.
Technical background
(Parkinsonism disease PD) claims " Parkinsonism " again to parkinson disease, is one of modal nervous system disease, mainly because of the degeneration of the black substance in the brain-striatum system, causes the shortage of DOPAMINE CONTENT IN RABBIT, thereby causes the extrapyramidal system functional disorder.According to the statistics of the United Nations, the whole world has 4,000,000 people at least, suffers from this disease; In the North America, the Parkinsonian is estimated as 50～1,000,000, and 50,000 patients that newly make a definite diagnosis are arranged every year.Along with the increase of global aging population quantity, these data to the year two thousand forty with double.In fact, parkinson disease and other common old neurodegenerative diseases replace cancer just gradually becomes dead first cause.But it is not to be a kind of Senile disease fully; 50% patient was 60 years old sequela, and second half patient then fell ill before 60 years old.In addition, more advanced diagnostic techniques has made brainstrust pursue new knowledge also may to suffer from this disease to those people below 40 years old.Parkinson disease belong to dyskinetic disorder and since the moving midbrain partial nerve cell of domination body gradually degeneration cause, clinical cardinal symptom be nature static tremble, stiff, be slow in action, the difficulty of walking etc.Along with the prolongation of time, the state of an illness is carrying out property and increases the weight of, and trembles at last to increase the weight of and spread all over whole body, and muscle is stiff gradually, and the balance and the coordination ability will worsen.Have a strong impact on patient's quality of life.Along with the arrival of aging society, the parkinson disease sickness rate is ascendant trend year by year, has brought serious negative effect for society and family.
Levodopa is the dopamine precursor, enters the central nervous system by blood-cerebrospinal fluid barrier, changes into dopamine through decarboxylation, thereby improves Parkinsonian tetanic, bradykinesia, disequilibrium and symptom such as tremble; Carbidopa is the periphery decarboxylase inhibitor, can suppress the outer L-dopadecarboxylase of brain, reduces the metabolism of levodopa in periphery, and its amount that enters the central nervous system is increased.After the two share, can reduce the consumption of levodopa.Make low dose of levodopa can reach effective dopamine brain concentration, and can alleviate untoward reaction, the especially gastrointestinal symptom on every side of levodopa.
Summary of the invention
The purpose of this invention is to provide a kind of can constant release medicine and the stability of medicine release and the higher Parkinsonian carbidopa/levodopa controlled release tablet of treatment of safety of medication, form by label and film-coat, wherein: label is as principal agent with Carbidopa, comprise controlled-release material, filler, binding agent, antioxidant, lubricant, wetting agent, film-coat is made up of filmogen and wetting agent.It is characterized in that can constant release at different release medium Chinese medicines.Characteristics such as controlled release tablet of the present invention has that convenient drug administration, effect are lasting, stable curative effect, toxic and side effects are little.
Carbidopa/levodopa controlled release tablet of the present invention is characterized in that: contain carbidopa 10-200mg in each dosage unit, levodopa 50-400mg.
Carbidopa/levodopa controlled release tablet of the present invention is characterized in that: contain carbidopa 30-100mg in each dosage unit, levodopa 100-300mg.
Carbidopa/levodopa controlled release tablet of the present invention is characterized in that:
Described controlled-release material can select for use in hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, cellulose acetate, sodium alginate, cellulose diacetate, Triafol T, glyceryl monostearate, the hydroxy methocel one or more to make, preferred hydroxypropyl methylcellulose.
Described filler can select for use in microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, poly-phthalic acid vinyl acetate, Polyethylene Glycol, chitosan, sucrose, lactose, starch, dextrin, Icing Sugar, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, the titanium dioxide one or more to make preferably microcrystalline cellulose.
In the optional water of described binding agent, ethanol, dehydrated alcohol, starch slurry, copolyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more are made, preferred copolyvidone.
Described antioxidant can select for use in L-cysteine hydrochloride, citric acid, citric acid, gallic acid, the sodium sulfite one or more to make optimization citric acid.
Described lubricant can be selected one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols, month pure magnesium sulfate of extension, preferred magnesium stearate for use.
In the optional water of described wetting agent, ethanol, dehydrated alcohol, starch slurry, chloroform, acetone, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Described filmogen can select for use in ethyl cellulose, starch, Aquacoat, methylcellulose, cellulose acetate, acrylic resin, Opadry, the Sulisi one or more to make, preferred Opadry.
Carbidopa/levodopa controlled release tablet of the present invention is characterized in that counting by weight percentage, and it consists of:
The preparation method of carbidopa/levodopa controlled release tablet of the present invention, it comprises following steps:
1. prepare binding agent will write out a prescription in 20～30% amounts of binding agent add ethanol and be configured to 10% (w/v) solution in right amount, as binding agent, standby;
2. granulate 70～80% amount mix homogeneously of binding agent in carbidopa, levodopa, controlled-release material, filler, antioxidant and the prescription of recipe quantity, add the solution that 1. makes and carry out wet granulation, the 24 mesh sieves granulate that wets, 45 ℃ of dryings 2 hours, take out, 20 mesh sieve granulate, standby;
3. the tabletting granule that will 2. make and the lubricant of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, scrobicula 10mm stamping.
The art for coating of carbidopa/levodopa controlled release tablet of the present invention, it comprises following steps:
The recipe quantity filmogen is added in an amount of wetting agent, stirred 45 minutes, whole dissolvings are disperseed, standby.The plain sheet that makes is put in the high-efficiency coating pot, at the uniform velocity sprayed into the coating solution coating, the sheet bed tempertaure remains on 35～45 ℃, and until evenly wrapping the thin film clothing, it is about 3% that coating increases weight, promptly.
Carbidopa/levodopa controlled release tablet of the present invention, it is characterized in that, described controlled release tablet is according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt dissolution determination first subtraction unit, with water 900ml is release medium, rotating speed is that per minute 100 changes, operation in 1 hour, 3 hours, 5 hours, is respectively got solution 5ml in accordance with the law, filter, and the release medium of replenishing equivalent temperature, suitable volume simultaneously, according to the chromatographic condition under the assay item, precision is measured subsequent filtrate 20 μ l, inject chromatograph of liquid, the record chromatogram; It is an amount of that other gets the Carbidopa reference substance, and precision claims fixed, adds the also quantitative dilution of mobile phase dissolving and make the mixing reference substance solution that every 1ml contains carbidopa 0.06mg, contains levodopa 0.23mg, measures with method.Calculate every burst size respectively at different time.Every of this product should be respectively more than 15～35%, 35～75% and 75% of labelled amount in the burst size of 1 hour, 3 hours and 5 hours.
The present invention finds in the development test process, kind/model, the consumption of controlled-release material and filler have a significant impact releasing effect, kind/the model of binding agent, consumption have a significant impact technology and releasing effect, kind, the consumption of antioxidant have a significant impact antioxidant effect, for this reason, the inventor has carried out a series of tests, to prove effect of the present invention.
1. controlled-release material and filler are to the influence test of releasing effect
1.1HPMC to the influence that discharges
By prescription 1,4 and 5 as can be seen, reduce HPMC (K4M) consumption separately, perhaps use HPMC (E5) to replace section H PMC (K4M), rate of release is accelerated, and HPMC reduces by 1%, 5 hour release and increases by 10%.The analysis of causes: HPMC (K4M) can form gel layer as controlled-release material at medical surfaces behind the chance water, and the dissolving of blocking medicine discharges, the speed that how much directly has influence on drug release of its consumption.
By prescription 1,2 and 3 as can be seen, constant at HPMC (K4M) and MCC101, change separately under the situation of HPMC (E5) consumption, 1,2 and 3 hours release and its consumption are inverse ratio, and consumption to be discharged slowly, and consumption discharges soon less, but at 4 hours and 5 hours, discharging did not have difference substantially.The analysis of causes: discharge early stage because the suction of HPMC (K4M) is fast than HPMC (E5), form hydrogel layer rapidly and controlled drug release, HPMC (E5) is when gel layer forms, also aquation becomes the glutinous medicine dissolution release of having controlled gradually, discharge the later stage because hydrogel layer forms, HPMC (K4M) is not very big to the influence that discharges.
By prescription 6,7 and 8 as can be seen, from the release result as can be seen, with the increase of hypromellose K100LV consumption, release obviously slows down.Through the prescription contrast, when hypromellose is 100mg in prescription, could guarantee that sample meets the requirements in release, so can determine tentatively that also the consumption of hypromellose K100LV is every 100mg.
1.2MCC (101) influence to discharging
By the release data as can be seen, increase MCC (101) the consumption rate of release that can obviously slow down separately, increase by 1% consumption, the each point release reduces nearly one percentage point.The analysis of causes: because MCC (101) itself is water insoluble, can not be as controlled-release material, but can absorb water, can promote HPMC (K4M) to form hydrogel layer like this, the dissolving of blocking medicine discharges, and increases its consumption, has accelerated the formation of hydrogel layer accordingly, thereby slowed down the speed that discharges, each point release value reduces.
1.3 the influence of lactose to discharging
By prescription 1 and 10 as can be seen, behind the adding lactose, prescription discharged at 1,2 hour to be accelerated, but release does not obviously change in the later stage, almost consistent.The analysis of causes: discharge early stage,, make that the speed of HPMC (K4M) aquation formation gel layer is slack-off because lactose is soluble in water, the speed that medicine dissolution discharges is very fast relatively, discharge the later stage, because gel layer forms, lactose is less relatively to the dissolving diffusion influence of medicine.
Each adjuvant shows the result that influences who discharges: 1. HPMC (K4M) is the principal element of this medicine release of control, and it can form certain gel layer in dispose procedure, the dissolving of blocking medicine discharges, increase consumption release and slow down, reduce consumption and discharge increase, influence is obvious; 2. the collaborative HPMC (K4M) of MCC (101) plays the effect of sustained release, and it is water insoluble, but can imbibition, can accelerate the speed that HPMC (K4M) forms gel layer like this, thus the release of the medicine that slowed down, the same HPMC of trend (K4M) that influence discharges; 3. HPMC (E5) viscosity is little a lot of than HPMC (K4M), and its hydration rate is slower, same HPMC (K4M) the medicine release in early stage of can slowing down when share, but the later stage gel layer forms, and influence is not very big; 4. lactose is soluble in water, add in the prescription an amount of after, discharge early stage because lactose is fast than HPMC (K4M) suction, the formation of gel layer of having slowed down, thus accelerated the rate of release of medicine, the later stage influence is less.
By the preliminary test prescription screening, because HPMC (E5) and lactose slow down respectively and improve the rate of release in early stage, little for the later stage influence, and HPMC (K4M) and microcrystalline Cellulose are consistent to the influence of drug release, all can play the effect of sustained release, therefore test employing HPMC (K4M) is main controlled-release material, is used in combination microcrystalline Cellulose, not only prescription is simple, and has reduced the factor that influence discharges.By the prescription drug release determination, determine that prescription 4,7 is more excellent test recipe, each point discharges approaching with commercially available kind.
2. kind/the model of binding agent, consumption are tested the influence of technology and releasing effect
Test has been carried out the technology scale-up with different binding agents, and the result is as follows:
From the result of the test tabulation as can be seen: 1. the carr index is all smaller, shows the mobile relatively good of material, can carry out the continuous tabletting of technology; 2. particle size distribution is reasonable is PVP (K90D) and PVP (S630), and with the two particle size distribution equilibrium that makes respectively, 200 fine powder is few now, and the granule and the fine powder of granule below 100 orders that makes with PVP (K30) is more, is unfavorable for continuous tabletting; 3. the granule made of each adhesive is all less angle of repose, shows better mobile.
The above granule that makes is carried out continuous tabletting test respectively, and the result is as follows:
The result shows the granule that makes with PVP (K30) and PVP (K90D), has occurred " falling lid ", phenomenon that hardness is little in continuous tabletting process, is not then occurring this situation as the granule that binding agent makes with PVP (S630) in continuous tabletting process.The analysis of causes: because the principal agent levodopa occupies sizable ratio in this prescription, and levodopa is to be the acicular crystal material, the independent visible multilamellar slabbing of tabletting, almost there is not compressibility, when prescription being carried out pelletize with PVP (K30) and PVP (K90D), though particle diameter increases, had certain compression stroke, can still can't reach the needed plastic deformation of continuous tabletting, caused " falling lid ", the appearance of phenomenons such as hardness is low, and with PVP (S630) as binding agent, because its vitrification point is low than PVP (K30) and PVP (K90D), more is easy to generate plastic deformation, the granule that makes thus not only particle diameter improves, and have bigger plasticity, can reach the requirement of continuous tabletting.
Process choice PVP (S630) is as binding agent.
Select by binding agent, determine PVP (S630), in the technical process its consumption has been carried out single factor and investigated, the results are shown in following table as binding agent:
By the result as can be known, the PVP of different proportion consumption (S630) has certain influence to release, and showing as increases its consumption, and release is slowed down, and reduces consumption, discharges and accelerates.Simultaneously in the process of the test to having carried out corresponding investigation firmly, to being in 8.4% the prescription at PVP (S630) consumption, having suppressed hardness respectively is the slice, thin piece of 9.16KG and 7.21KG, and carried out drug release determination, the result sees the above table, the slice, thin piece that makes under two kinds of pressure discharges basically identical, does not have notable difference, and it is little to show that pressure discharges influence to this medicine.
3. the kind of antioxidant, consumption are tested the antioxygen influential effect
By investigation to Carbidopa stability, find that levodopa and carbidopa all can be oxidized, especially carbidopa is very easily oxidized, and identical report is also arranged in the document.Event reaches the stability in the longer-term storage process for guaranteeing preparation in mensuration, consider to add in prescription antioxidant, simultaneously the kind of antioxidant is investigated with each factor that influences oxidation rate.
3.1 the selection of antioxidant kind
Each preliminary election antioxidant is measured under fixed chromatographic condition, investigated the interference that it is measured main peak.The results are shown in following table:
According to last table measurement result, select for use main peak is measured glitch-free L-cysteine hydrochloride and citric acid, further investigate the relation of antioxidant consumption and antioxidant effect.
3.2 the relation of antioxidant consumption and antioxidant effect
The L-cysteine hydrochloride of getting same amount prepares different samples respectively with citric acid, investigates its aqueous solution is placed 6 hours peak areas in 50 ℃ water-bath situation of change, and measurement result sees the following form:
The amount of L-cysteine hydrochloride is to the influence of carbidopa stability
| Time | Every 10mg | Every 15mg | Every 20mg | Every |
| 0 | 721523 | 675779 | 717502 | 830734 |
| 6 | 374600 | 433866 | 436531 | 701438 |
| (A 0-A 6)/A 0(％) | 48.1 | 35.8 | 39.2 | 15.6 |
| The solution pH value | 6.09 | 5.98 | 4.99 | 3.88 |
The amount of L-cysteine hydrochloride is to the influence of levodopa stability
| Time | Every 10mg | Every 15mg | Every 20mg | Every |
| 0 | 3449477 | 3182985 | 3449127 | 3980553 |
| 6 | 3370353 | 3128372 | 3379093 | 3880840 |
| (A 0-A 6)/A 0(％) | 2.3 | 1.7 | 2.0 | 2.5 |
| The solution pH value | 6.09 | 5.98 | 4.99 | 3.88 |
(annotate: the amount with the L-cysteine hydrochloride that adds in the prescription is carried out labelling; Recipe quantity is that the sample of 20mg failed to measure in 6 hours, and the result who adds up in the table at room temperature places 13 hours result again after water-bath is placed 6 hours for sample)
The amount of citric acid is to the influence of carbidopa stability
The amount of citric acid is to the influence of levodopa stability
| Time | Every | Every | Every | Every | Every | Every 36mg |
| 5mg | 10mg | 15mg | 20mg | 26mg | ||
| 0 | 3493045 | 5115652 | 4444050 | 3555148 | 4192720 | 3720921 |
| 6 | 3376107 | 5060431 | 4380615 | 3508067 | 4163842 | 3696152 |
| (A 0-A 6)/A 0(％) | 3.3 | 1.1 | 1.4 | 1.3 | 0.7 | 0.7 |
| The solution pH value | 6.04 | 4.55 | 4.43 | 4.20 | 3.88 | 3.91 |
(annotating: carry out labelling) with the amount that adds citric acid in the prescription
By measurement result as can be seen: with the increase of antioxidant consumption, the degradation rate of main peak peak area is in obvious decline; 6 hours main peak peak areas of citric acid degradation rate of identical recipe quantity is lower than the L-cysteine hydrochloride, illustrates that the antioxidant effect of citric acid is better than the L-cysteine hydrochloride.The synergism of L-cysteine hydrochloride and citric acid is investigated in test simultaneously, and the result shows and unites the no synergy of use.So determine that antioxidant is citric acid, consumption is defined as 15mg according to main peak peak area degradation rate.Binding isotherm: citric acid is as antioxidant, can effectively guarantee the hydrogen ion concentration in the solution, thereby stoped the formation of free radical, and then effectively reduced the generation of oxidation reaction, from the Changing Pattern of the pH value of measuring different amounts antioxidant solution, this point has been described also.
3.3 temperature is to the influence of oxidation rate
Sample with technology is amplified is mixed with aqueous solution, investigates it places 6 hours peak areas under 50 ℃, 45 ℃, 37 ℃, 25 ℃ condition situation of change.The results are shown in following table:
| Temperature | The carbidopa degradation rate | The |
| 25℃ | 3.95％ | 0.1％ |
| 37℃ | 3.3％ | 0.2％ |
| 45℃ | 20.5％ | 1.6％ |
| 50℃ | 16.5％ | 1.4％ |
By measurement result as can be known: raise with temperature, the degradation rate of principal agent is increasing; Illustrate that temperature has certain influence to the stability of this product, sample is answered low temperature storage.
3.4 light is to the influence of oxidation rate
Sample with technology is amplified is mixed with aqueous solution, investigates it places 6 hours peak areas under 254nm, 365nm and sun exposure situation of change.The results are shown in following table:
| Wavelength | The carbidopa degradation rate | The levodopa degradation rate |
| 254nm | 56.4％ | 1.4％ |
| 365nm | 11.1％ | 0.3％ |
| More than 400 | 3.9％ | 0.1％ |
By measurement result as can be known: increase with wavelength, the degradation rate of principal agent is obviously reducing.Binding isotherm, light and heat is the same, luminous energy can provide the necessary activation energy that reacts, make molecule activation, suitable and the enough radiation (photon) of energy of essential adsorption frequency, photon in molecule absorption light (or weighing), to cause photochemical reaction, irrelevant with reaction temperature, the wavelength of light is different to promote that the ability of chemical reaction is also different, and the energy of photon successively decreases with light wavelength, (wavelength 50～400nm) promotes that the ability of chemical reaction is the strongest to ultraviolet light, (400～750nm) take second place visible light, and (750～10000nm) effect is the most weak, and light is by producing effectively catalysis and excite oxidation reaction of free radical for infrared light.
In view of the said determination result: this product should be preserved under the condition of illumination avoiding.
Description of drawings
Fig. 1 is the influence curve figure of citric acid consumption to carbidopa, levodopa stability.
Fig. 2 is the influence curve figure of L-cysteine hydrochloride consumption to carbidopa, levodopa stability.
Fig. 3 is the carbidopa/levodopa controlled release tablet releasing curve diagram of two embodiment preparations.
Beneficial effect
Levodopa, carbidopa are prepared into the hydrophilic gel controlled release tablet, have compared following advantage with conventional formulation:
1, compare with conventional formulation, the controlled release preparation rate of releasing drug is steady, near the Zero order rate process, can overcome the peak valley phenomenon that produces behind the ordinary preparation multiple dose administration. After the conventional release administration of medication, drug concentration rises to rapidly maximum, because metabolism is drained and degradation, rapid decrease will be controlled at drug concentration between MEC and the maximum safe concentration relatively more difficult again then;
2, can make in the body effective blood drug concentration length of holding time, and steadily, utilization ratio of drug can reach 80～90%, the utilization rate of conventional medicine only is 40～60%;
3, can reduce medicine to GI side effect. Ordinary preparation is made controlled release preparation and can be reduced side effect because rapidly disintegration stripping in enteron aisle after oral is big to GI irritation;
4, the medicine little for therapeutic index, that the half-life is short makes that controlled release preparation can be avoided frequent medication and the danger that causes poisoning;
5, obviously prolonged the medicine constant release time, therefore reduced medicining times, improve patient's compliance, abirritate and bad reaction are specially adapted to the medicine that the half-life weak point need frequently be taken.
Specific embodiment
Embodiment 1
Plain tablet recipe:
Levodopa 200g
Carbidopa 50g
Hypromellose (K100) 100g
Copolyvidone (S630) 23g
Microcrystalline Cellulose (101) 10g
Citric acid 15g
Magnesium stearate 4g
Ethanol 54g
Make 1000
The film-coat prescription:
Opadry II 12g
Purified water is an amount of
Preparation process
1. the 6g copolyvidone adds ethanol and is configured to 10% (w/v) solution in right amount in will writing out a prescription, and is as binding agent, standby;
2. with 17g copolyvidone mix homogeneously in carbidopa, levodopa, hydroxypropyl emthylcellulose, microcrystalline Cellulose, citric acid and the prescription of recipe quantity, add binding agent and carry out wet granulation, the 24 mesh sieves granulate that wets, 45 ℃ of dryings 2 hours, take out, 20 mesh sieve granulate, standby;
3. the outer magnesium stearate that adds recipe quantity, mix homogeneously, scrobicula 10mm stamping.
4. OpadryII 12g is added in the water, and add water to 300ml, stirred 45 minutes, make whole dissolvings.The plain sheet that makes is put in the high-efficiency coating pot, at the uniform velocity sprayed into the coating solution coating, the sheet bed tempertaure remains on 35～45 ℃, and until evenly wrapping the thin film clothing, it is about 3% to increase weight, and is drying to obtain.
Plain tablet recipe:
Levodopa 200g
Carbidopa 50g
Hydroxypropyl emthylcellulose (K4M) 20g
Copolyvidone (S630) 23g
Microcrystalline Cellulose (101) 10g
Citric acid 15g
Magnesium stearate 3.5g
Ethanol is an amount of
----------------------------------
Make 1000
The film-coat prescription:
Opadry II 10g
Purified water is an amount of
Ethanol is an amount of
Preparation process:
1. the 6g copolyvidone adds ethanol and is configured to 10% (w/v) solution in right amount in will writing out a prescription, and is as binding agent, standby;
2. with 17g copolyvidone mix homogeneously in carbidopa, levodopa, hydroxypropyl emthylcellulose, microcrystalline Cellulose, citric acid and the prescription of recipe quantity, add binding agent and carry out wet granulation, the 24 mesh sieves granulate that wets, 45 ℃ of dryings 2 hours, take out, 20 mesh sieve granulate, standby;
3. the outer magnesium stearate that adds recipe quantity, mix homogeneously, scrobicula 10mm stamping.
4. OpadryII 10g is added in the water, and add water to 100ml, add ethanol 100ml again and stirred 45 minutes, make whole dissolvings.The plain sheet that makes is put in the high-efficiency coating pot, at the uniform velocity sprayed into the coating solution coating, the sheet bed tempertaure remains on 35～45 ℃, and until evenly wrapping the thin film clothing, it is about 3% to increase weight, and is drying to obtain.
In order to investigate release in vitro effect of the present invention, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt dissolution determination first subtraction unit, with water 900ml is release medium, rotating speed is that per minute 100 changes, operation in accordance with the law, in 1 hour, 3 hours, 5 hours, respectively get solution 5ml, filtration, and the release medium of replenishing equivalent temperature, suitable volume simultaneously, according to the chromatographic condition under the assay item, precision is measured subsequent filtrate 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the Carbidopa reference substance, and precision claims fixed, adds the also quantitative dilution of mobile phase dissolving and make the mixing reference substance solution that every 1ml contains carbidopa 0.06mg, contains levodopa 0.23mg, measures with method.Calculated its burst size respectively at 1 hour, 3 hours and 5 hours.
The carbidopa/levodopa controlled release tablet of two embodiment preparations, release characteristic is:
Claims (10)
1. treat Parkinsonian pharmaceutical controlled release formulation for one kind, form by label and film-coat, wherein: label be with Carbidopa as principal agent, comprise controlled-release material, filler, binding agent, antioxidant, lubricant, wetting agent, film-coat is made up of filmogen and wetting agent.
2. the described controlled release tablet of claim 1, it is characterized in that can constant release at different release medium Chinese medicines.
3. the described controlled release tablet of claim 1 is characterized in that: contain carbidopa 10-200mg in each dosage unit, levodopa 50-400mg.
4. the described controlled release tablet of claim 3 is characterized in that: contain carbidopa 30-100mg in each dosage unit, levodopa 100-300mg.
5. each described controlled release tablet among the claim 1-4 is characterized in that:
Described controlled-release material can select for use in hydroxypropyl methylcellulose, ethyl cellulose, methylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate-phthalate, hydroxypropyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, cellulose acetate, sodium alginate, cellulose diacetate, Triafol T, glyceryl monostearate, the hydroxy methocel one or more to make, preferred hydroxypropyl methylcellulose.
Described filler can select for use in microcrystalline Cellulose, mannitol, low-substituted hydroxypropyl cellulose, polyvinyl alcohol, poly-phthalic acid vinyl acetate, Polyethylene Glycol, chitosan, sucrose, lactose, starch, dextrin, Icing Sugar, cross linked polyvinyl pyrrolidone, cross-linking sodium carboxymethyl cellulose, pregelatinized Starch, the titanium dioxide one or more to make preferably microcrystalline cellulose.
In the optional water of described binding agent, ethanol, dehydrated alcohol, starch slurry, copolyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more are made, preferred copolyvidone.
Described antioxidant can select for use in L-cysteine hydrochloride, citric acid, citric acid, gallic acid, the sodium sulfite one or more to make optimization citric acid.
Described lubricant can be selected one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, hydrogenated vegetable oil, polyethylene glycols, month pure magnesium sulfate of extension, preferred magnesium stearate for use.
In the optional water of described wetting agent, ethanol, dehydrated alcohol, starch slurry, chloroform, acetone, polyvidone, crospolyvinylpyrrolidone, hydroxypropyl methylcellulose and/or other cellulose families one or more.
Described filmogen can select for use in ethyl cellulose, starch, Aquacoat, methylcellulose, cellulose acetate, acrylic resin, Opadry, the Sulisi one or more to make, preferred Opadry.
6. each described controlled release tablet among the claim 1-5 is characterized in that counting by weight percentage, and it consists of:
7. each described controlled release tablet among the claim 1-6 is characterized in that calculating by weight, and it consists of:
8. the preparation method of each described controlled release tablet among the claim 1-7, it comprises following steps:
1. prepare binding agent will write out a prescription in 20～30% amounts of binding agent add ethanol and be configured to 10% (w/v) solution in right amount, as binding agent, standby;
2. granulate 70～80% amount mix homogeneously of binding agent in carbidopa, levodopa, controlled-release material, filler, antioxidant and the prescription of recipe quantity, add the solution that 1. makes and carry out wet granulation, the 24 mesh sieves granulate that wets, 45 ℃ of dryings 2 hours, take out, 20 mesh sieve granulate, standby;
3. the tabletting granule that will 2. make and the lubricant of recipe quantity, behind the mix homogeneously, detection level determines that sheet is heavy, scrobicula 10mm stamping.
9. the art for coating of each described controlled release tablet among the claim 1-8, it comprises following steps:
The recipe quantity filmogen is added in an amount of wetting agent, stirred 45 minutes, whole dissolvings are disperseed, standby.The plain sheet that makes is put in the high-efficiency coating pot, at the uniform velocity sprayed into the coating solution coating, the sheet bed tempertaure remains on 35～45 ℃, and until evenly wrapping the thin film clothing, it is about 3% that coating increases weight, promptly.
10. each described controlled release tablet among the claim 1-9, it is characterized in that, according to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2005 D, first method), adopt dissolution determination first subtraction unit, with water 900ml is release medium, rotating speed is that per minute 100 changes, operation in 1 hour, 3 hours, 5 hours, is respectively got solution 5ml in accordance with the law, filter, and the release medium of replenishing equivalent temperature, suitable volume simultaneously, according to the chromatographic condition under the assay item, precision is measured subsequent filtrate 20 μ l, inject chromatograph of liquid, the record chromatogram; It is an amount of that other gets the Carbidopa reference substance, and precision claims fixed, adds the also quantitative dilution of mobile phase dissolving and make the mixing reference substance solution that every 1ml contains carbidopa 0.06mg, contains levodopa 0.23mg, measures with method.Calculate every burst size respectively at different time.Every of this product should be respectively more than 15～35%, 35～75% and 75% of labelled amount in the burst size of 1 hour, 3 hours and 5 hours.
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Application publication date: 20101229 |