CN102885804B - Dopamine prodrug composition and preparation method thereof - Google Patents
Dopamine prodrug composition and preparation method thereof Download PDFInfo
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Abstract
Dopamine prodrug composition and preparation method thereof.Provide a kind of pharmaceutical composition of dopamine precursor medicine, described compositions comprises dopamine precursor medicine, Ro-4-4602., binding agent, stabilizing agent and pharmaceutically acceptable carrier., can not variable color be there is, effectively can ensure that in the storage life, product quality meets quality criteria requirements in the pharmaceutical composition excellent in stability containing dopamine precursor medicine provided by the invention; Drug regimen composition formula containing dopamine precursor medicine provided by the invention is simple, and supplementary product consumption is few and cheap and easy to get; The present invention preparation technology used is simple and easy to control, and device therefor is the most conventional Workshop Production equipment, with low cost, is applicable to technology and produces.
Description
Technical field
The present invention relates to medical art, be specifically related to a kind of pharmaceutical composition and preparation method thereof containing dopamine precursor medicine being used for the treatment of parkinson disease, symptomatic parkinsonism.
Background technology
Parkinson disease are central nervous system degenerative diseases of a kind of serious harm middle-aged and elderly people health, and the reason of its morbidity lacks dopamine in the ganglion basal of patient.The Parkinsonian medicine of current treatment is roughly divided into the five large classes such as dopamine precursor medicine, dopamine agonist, levodopa synergist, cholinoceptor blocking agent, short dopamine D_2 receptors medicine.Dopamine precursor medicine (levodopa class medicine, as levodopa, according to for levodopa) has been the Parkinsonian most essential drug for the treatment of since the sixties in last century always.Dopamine can not enter maincenter through brain barrier, but dopamine precursor medicine (as levodopa) can enter maincenter through blood brain barrier, and as the direct metabolism predecessor of dopamine, it makes Dopaminesubstitutive therapies become feasible., dopamine precursor medicine is transformed into dopamine in the outer decarboxylation rapidly of brain, and this just causes a large amount of waste of dopamine precursor medicine and the frequent generation of untoward reaction.Therefore, the decarboxylation of dopamine precursor medicine outside brain is suppressed to be very useful.This object can be reached by taking the outer decarboxylase inhibitor of dopamine precursor medicine and brain simultaneously.
Ro-4-4602. is the outer decarboxylase inhibitor of a kind of brain, not easily enters maincenter, only suppresses periphery dopamine precursor medicine to be converted into dopamine, and make dopamine precursor medicine content in circulation increase 5-10 doubly, the amount thus entering the dopamine precursor medicine of maincenter also increases.Dopamine precursor medicine is converted into dopamine through DOPA decarboxylase effect and plays pharmacological action in brain, improves Parkinsonian symptoms.Ro-4-4602. and dopamine precursor medicine share the untoward reaction of the periphery property cardiovascular system that both can reduce dopamine precursor medicine, can reduce again the consumption of dopamine precursor medicine.The application levodopa that such as clinical practice is verified and Ro-4-4602. (in benserazide) are in the compound formulation (compound formulation that is that prepare in this ratio and Ro-4-4602. is called " Benserazide ") of 4: 1 ratios, good curative effect can be obtained, the same with the levodopa effect of heavy dose, and toleration is far better.
But, due to Ro-4-4602. character extremely unstable, meet light, heat, wet all can variable color, medicament contg also can decline simultaneously, if do not solve product stability problems from the source such as prescription, technique at the beginning of product design, be easy to that end product quality in storage occurs and can not meet the situation of quality standard.
CN101623278A discloses Ro-4-4602. and is dispersed in after in specific carrier and is mixed with the method for levodopa and benserazide hydrochloride pharmaceutical composition with levodopa and pharmaceutically acceptable carrier again, this invention title can said composition have good stability, but said composition composition and preparation method are all more complicated.
The madopar of Roche Holding Ag of the Yuan Yan producer exploitation listing of Benserazide
(Benserazide sheet) is leading products in the market, but due to this product be similar redness color chips, may have the variable color equistability problem of product and necessarily cover up effect.
Therefore, solve the stability problem of Ro-4-4602. from source, exploitation prescription rationally simple, cost is low, it is extremely urgent to be applicable to the compound formulation of dopamine precursor medicine that technology produces and Ro-4-4602..
Summary of the invention
The object of this invention is to provide a kind of pharmaceutical composition containing dopamine precursor medicine and preparation method thereof, the pharmaceutical composition containing dopamine precursor medicine had good stability can be obtained.Said composition prescription is simple, and preparation method is simple and easy to do, is applicable to suitability for industrialized production.
One aspect of the present invention provides a kind of pharmaceutical composition containing dopamine precursor medicine, and described compositions comprises dopaminergic agent, Ro-4-4602., binding agent, anhydrous citric acid and pharmaceutically acceptable carrier.
In a preferred embodiment of the present invention, described dopamine precursor medicine is levodopa.
In a preferred embodiment of the present invention, described binding agent be selected from hypromellose, polyvidone, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose one or more.
In a preferred embodiment of the present invention, described stabilizing agent be selected from anhydrous citric acid, vitamin C, alpha-tocopherol, BHA, tartaric acid one or more.
In a preferred embodiment of the present invention, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 10: 1 to 1: 1, preferably 8: 1 to 2: 1, more preferably 6: 1 to 3: 1, and be preferably 4: 1, Ro-4-4602. is with the weighing scale of benserazide.
In a preferred embodiment of the present invention, the consumption of described binding agent is preferably 0.1-5.0 weight portion, more preferably 1.0-4.0 weight portion, is 100 parts by weight with described Ro-4-4602..
In a preferred embodiment of the present invention, the preferred 0.01-5 weight portion of consumption of described stabilizing agent, more preferably 0.015-4 weight portion is 100 parts by weight with described Ro-4-4602..
In a preferred embodiment of the present invention, described pharmaceutical composition also comprises antioxidant, flavouring agent, odor mask, pigment, filler, fluidizer, lubricant or diluent.
The present invention provides a kind of method preparing the pharmaceutical composition containing dopamine precursor medicine of the present invention on the other hand, said method comprising the steps of:
A binding agent adds in water by (), abundant stirring and dissolving, then adds anhydrous citric acid, is stirred to dissolve completely to obtain slurry;
B dopaminergic agent, Ro-4-4602. and pharmaceutically acceptable carrier mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mix and form the described pharmaceutical composition containing dopamine precursor medicine.
In a preferred embodiment of the present invention, said method comprising the steps of:
A binding agent adds in purified water by (), abundant stirring and dissolving, then adds stabilizing agent, is stirred to dissolve completely to obtain serosity;
B dopamine precursor medicine, Ro-4-4602. and filler mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mixing;
D mixture that step (c) obtains by () and mix lubricant obtain described pharmaceutical composition.
Major advantage of the present invention is:
(1), can not there is variable color, effectively can ensure that in the storage life, product quality meets quality criteria requirements in the pharmaceutical composition excellent in stability containing dopamine precursor medicine provided by the invention;
(2) the drug regimen composition formula containing dopamine precursor medicine provided by the invention is simple, and supplementary product consumption is few and cheap and easy to get;
(3) the present invention preparation technology used is simple and easy to control, and device therefor is the most conventional Workshop Production equipment, with low cost, is applicable to technology and produces.
Detailed description of the invention
" scope " disclosed herein is with the form of lower limit and the upper limit.One or more lower limit can be respectively, and one or more upper limit.Given range is limited by a selected lower limit and a upper limit.Selected lower limit and the upper limit define the border of special scope.All scopes that can carry out by this way limiting comprise and may be combined with, and namely any lower limit can be combined to form a scope with any upper limit.Such as, list the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects.In addition, if the minimum zone value listed 1 and 2, and if list maximum magnitude value 3,4 and 5, then the scope below can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5.
In the present invention, unless otherwise indicated, new technical scheme can be mutually combined to form between the content range of each component of compositions and its preferable range.
In the present invention, unless otherwise indicated, " its combination " represents the multicomponent mixture of described each element, such as two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
In the present invention, unless otherwise indicated, all " part " and percent (%) all refer to percetage by weight.
In the present invention, unless otherwise indicated, in all compositionss, the percent sum of each component is 100%.
In the present invention, unless otherwise indicated, the breviary of any real combinings that numerical range " a-b " represents between a to b represents, wherein a and b is real number.Such as numerical range " 0-5 " represents the whole real numbers all listed between " 0-5 " herein, and the breviary of " 0-5 " just these combinations of values represents.
In the present invention, unless otherwise indicated, the breviary of the arbitrary integer combination that integer numerical range " a-b " represents between a to b represents, wherein a and b is integer.Such as integer numerical range " 1-N " represents 1,2 ... N, wherein N is integer.
If do not particularly not pointed out, this description term " one " used refers to " at least one ".
If do not particularly not pointed out, the benchmark of percent of the present invention (comprising percetage by weight) is all the gross weight of described compositions.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In the present invention, if do not illustrated especially, all embodiments mentioned in this article and preferred implementation can be combined to form new technical scheme mutually.
In the present invention, if do not illustrated especially, all technical characteristics mentioned in this article and preferred feature can be combined to form new technical scheme mutually.
The compound that the present invention that the pharmaceutical composition that the present invention relates to comprises safe and effective amount relates to and pharmaceutically acceptable carrier." safe and effective amount " means that the consumption of compound is enough to improve feelings to be cured the disease, and does not occur serious side effect during treatment in the medical science judgement category generally admitted.The safe and effective amount of certain compound should according to concrete feelings to be cured the disease, the age meeting subject patient and physiological situation, coincident with severity degree of condition, the course for the treatment of length, the factor such as pharmaceutical carrier and route of administration and determining.Now comprise the compound of about 0.1% to about 99.9% by weight in compositions.
In the present invention, except as otherwise noted, described material or compositions or compound etc. are all pharmaceutically acceptable.
In the present invention, term " DOPA " or " dopamine precursor medicine " etc. represent levodopa class dopamine precursor medicine, include but not limited to levodopa, according to replacing levodopa etc.
One aspect of the present invention provides a kind of pharmaceutical composition containing dopamine precursor medicine, and described compositions comprises dopamine precursor medicine, Ro-4-4602., binding agent, stabilizing agent and pharmaceutically acceptable carrier.
In the present invention, described dopamine precursor medicine is conventional, and it can be synthesized by methods known in the art, or is obtained by commercially available.In a preferred embodiment of the present invention, described dopamine precursor medicine is levodopa, purchased from pharmaceutical Co. Ltd of Guangxi Napo County.Usually, levodopa molecular formula is: C
9h
11nO
4
In the present invention, described Ro-4-4602. is conventional, and it can be synthesized by methods known in the art, or is obtained by commercially available.In a preferred embodiment of the present invention, described Ro-4-4602. is purchased from Zhejiang Nexchem Pharmaceutical Co., Ltd..Usually, the molecular formula of Ro-4-4602. is: C
10h
15n
3o
5hCl
In the present invention, described binding agent can be any binding agent conventional in this area.In a preferred embodiment of the present invention, described binding agent be selected from hypromellose, polyvidone, sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose one or more.In another preferred embodiment of the present invention, described binding agent is one or more in polyvidone, hypromellose, methylcellulose and ethyl cellulose.In a preferred embodiment of the present invention, described binding agent is hypromellose.
In the present invention, described stabilizing agent is conventional, and it can be stabilizing agent conventional in this area.It can be synthesized by methods known in the art, or is obtained by commercially available.In a preferred embodiment of the present invention, described stabilizing agent be selected from anhydrous citric acid, vitamin C, alpha-tocopherol, BHA, tartaric acid one or more, in another preferred embodiment of the present invention, described stabilizing agent is selected from anhydrous citric acid.
In the present invention, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is conventional, and those of ordinary skill in the art can directly obtain this weight ratio in conjunction with prior art again according to description of the invention.In a preferred embodiment of the present invention, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 10: 1 to 1: 1, preferably 8: 1 to 2: 1, more preferably 6: 1 to 3: 1, and be preferably 4: 1, Ro-4-4602. is with the weighing scale of benserazide.
In the present invention, the consumption of described binding agent can be conventional, and those of ordinary skill in the art can derive the concrete consumption of this binding agent again in conjunction with prior art according to description of the invention.But in order to reach good technique effect, the consumption of described binding agent is preferably 0.1-5.0 weight portion, more preferably 1.0-4.0 weight portion, is 100 parts by weight with described Ro-4-4602..
In the present invention, the consumption of described stabilizing agent can be conventional, and those of ordinary skill in the art can derive the concrete consumption of this stabilizing agent again in conjunction with prior art according to description of the invention.But in order to reach good technique effect, the preferred 0.01-5 weight portion of consumption of described stabilizing agent, more preferably 0.015-4 weight portion is 100 parts by weight with described Ro-4-4602..
Except above-mentioned substance, pharmaceutical composition of the present invention, also optionally containing other additives, such as but not limited to antioxidant, flavouring agent, odor mask, pigment, filler, fluidizer, lubricant or diluent (filler) etc.These additives are all well known in the art.
Such as, also fluidizer, caking inhibiter and diluent can be added in described pharmaceutical composition.
Fluidizer in described pharmaceutical composition is selected from the combination by the arbitrary proportion of one or both in Pulvis Talci, micropowder silica gel.
Lubricant in described pharmaceutical composition is selected from stearic acid, magnesium stearate, Rikemal B 200, hexadecanol, octadecanol, starch and derivant thereof, the mixture of a kind of in microcrystalline Cellulose or wherein two kinds and two or more arbitrary proportion.
Diluent (filler) in described pharmaceutical composition is selected from glucose, sucrose, lactose, starch and derivant thereof, microcrystalline Cellulose, dextrin, mannitol, xylitol, sorbitol, pregelatinized Starch, the mixture of a kind of in sucrose or wherein two kinds and two or more arbitrary proportion.
The consumption of these additional additive is generally 0.01-100 weight portion, is more preferably 0.1-80 weight portion.By weight percentage, these extra additive components are no more than 10% usually, as accounted for 0.5%-5%.
Pharmaceutical composition of the present invention can make common pharmaceutical dosage form, the oral or non-oral administration of the form of granule, powder, tablet, capsule, syrup, suppository, injection, Emulsion, tincture, suspension, solution that includes but not limited to.
For oral administration, tablet, lozenge, capsule, pill, powder, granule, paste, suspensoid, Emulsion or solution can be used.
For parenteral administration, injection and infusion solution can be used.
For intra-articular injection, the suspensoid of corresponding configuration can be used.
For intramuscular injection, aqueous solution and oil solution or suspensoid and corresponding depots preparation can be used.
For external local application, lotion, cream and gel etc. can be used.
In preference, pharmaceutical composition of the present invention can be made into oral formulations.The solid chemicals of oral medication is described above, comprises powder, granule, tablet, pill, capsule.
The present invention provides a kind of method preparing pharmaceutical composition of the present invention on the other hand, said method comprising the steps of:
A binding agent adds in water by (), abundant stirring and dissolving, then adds stabilizing agent, is stirred to dissolve completely to obtain slurry;
B dopamine precursor medicine, Ro-4-4602. and pharmaceutically acceptable carrier mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mix and form described pharmaceutical composition.
In a preferred embodiment of the present invention, said method comprising the steps of:
A binding agent adds in purified water by (), abundant stirring and dissolving, then adds stabilizing agent, is stirred to dissolve completely to obtain serosity;
B dopamine precursor medicine, Ro-4-4602. and filler mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mixing;
D mixture that step (c) obtains by () and mix lubricant obtain pharmaceutical composition of the present invention.
In described method of the present invention, its component and consumption identical with the definition in pharmaceutical composition of the present invention.
Describe the present invention in detail by the following examples, but following examples are only exemplary, scope of the present invention is not limited thereto.
Embodiment
| Component | Manufacturer |
| Levodopa | Pharmaceutical Co. Ltd of Guangxi Napo County |
| Ro-4-4602. | Zhejiang Nexchem Pharmaceutical Co., Ltd. |
| Starch | Jiaxing Bailang Starch Products Co., Ltd. |
| Anhydrous citric acid | Xinning, Taishan City pharmaceutical Co. Ltd |
| Hypromellose | DOW Chemical |
| Magnesium stearate | Huzhou Zhanwang Pharmaceutical Co., Ltd. |
The model of device therefor and manufacturer:
| Device name, model | Manufacturer |
| PMA-25 type High Speed Stirring Machine | Germany GEA |
| YK-60 type oscillating granulator | Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai |
| FL-5 boiling granulating device | Huafa Pharmaceutical Mating Development Co., Shanghai |
| DHG-9246A type electric heating constant-temperature blowing drying box | The grand experimental facilities company limited of upper Nereid |
| V-type high efficient mixer | Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai |
| GKF-120 capsule filler | Bosch packing technique (Hangzhou) company limited |
| Agilent 1100 type high performance liquid chromatograph | Anjelen Sci. & Tech. Inc |
| Binder KBF stability test case | Binder company of Germany |
Embodiment 1
Preparation method:
Hypromellose is configured to the aqueous solution of 5%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying on FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Embodiment 2
Preparation method:
Hypromellose is configured to the aqueous solution of 4%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying on FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Embodiment 3
Preparation method:
Hypromellose is configured to the aqueous solution of 3%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying in DHG-9246A type electric heating constant-temperature blowing drying box (the upper grand experimental facilities company limited of Nereid), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Embodiment 4
Preparation method:
Hypromellose is configured to the aqueous solution of 2%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying in DHG-9246A type electric heating constant-temperature blowing drying box (the upper grand experimental facilities company limited of Nereid), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Comparative example 1
Preparation method:
Hypromellose is configured to the aqueous solution of 5%, obtains serosity, for subsequent use.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying in DHG-9246A type electric heating constant-temperature blowing drying box (the upper grand experimental facilities company limited of Nereid), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Comparative example 2
Preparation method:
Hypromellose is configured to the aqueous solution of 2%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying on FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Comparative example 3
Preparation method:
Hypromellose is configured to the aqueous solution of 2%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying on FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
Comparative example 4
Preparation method:
Hypromellose is configured to the aqueous solution of 5%, adds anhydrous citric acid and be stirred to dissolving.By levodopa, Ro-4-4602., starch pulverizes and sieves rear input PMA-25 type High Speed Stirring Machine (German GEA company), serosity soft material is added after start mixing, sieve series wet granular is crossed through YK-60 type oscillating granulator (Tianxiang Jiantai Pharmaceutical Machinery Co., Ltd., Shanghai), then wet granular is carried out drying on FL-5 type boiling granulating device (Huafa Pharmaceutical Mating Development Co., Shanghai), granulate, add magnesium stearate, after V-type high efficient mixer (Tianhe Pharmaceutical Machinery Co., Ltd. Shanghai) mixing, GKF-120 capsule filler (Bosch packing technique (Hangzhou) company limited) filled capsules and get final product.
By the Benserazide capsule produced in embodiment 1-4 and comparative example 1-4, employing plastic bottle is packed, carry out accelerated test (temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%) and long term test (temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 5%), the Character change situation of perusal capsule 's content powder, detect the content decline situation of two kinds of drug levodopa, Ro-4-4602. by Agilent 1100 type high performance liquid chromatograph (Anjelen Sci. & Tech. Inc), testing result is shown in table 1-table 4.
Accelerated test concrete grammar: after capsule is packed by plastic bottle, put in Binder KBF stability test case (German Binder company), accelerated test condition is temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5%, in 1 month, 2 months, 3 months, 6 months character of taking a sample to check, content and other indexs.
Long term test concrete grammar: after capsule is packed by plastic bottle, put in Binder KBF stability test case (German Binder company), long term test condition is temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 5%, in 3 months, 6 months, 9 months, 12 months, 18 months, 24 months character of taking a sample to check, content and other indexs.
Table 1 accelerated test result (character of capsule 's content powder)
Table 2 long-term test results (character of capsule 's content powder)
| 3 months | 6 months | 9 months | 12 months | 18 months | 24 months | |
| Embodiment 1 | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color |
| Embodiment 2 | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color |
| Embodiment 3 | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color |
| Embodiment 4 | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color | Off-white color |
| Comparative example 1 | Off-white color | Pale pink | Pale pink | Pink | Pink | Pink |
| Comparative example 2 | Off-white color is partially yellow | Faint yellow | Faint yellow | Yellow | Yellow | Yellow |
| Comparative example 3 | Off-white color | Pale pink | Pale pink | Pink | Pink | Pink |
| Comparative example 4 | Off-white color is partially yellow | Faint yellow | Faint yellow | Yellow | Yellow | Yellow |
Note :-: medicament contg declined and be no more than 3% compared with 0 day
+: medicament contg declines compared with 0 day more than 5%
++: medicament contg declines compared with 0 day more than 8%
+++: medicament contg declines compared with 0 day more than 10%
From the result of the test shown in table 1-table 4, Benserazide capsule stability of the present invention is good, accelerates and all invariant colors under long term test condition, and content is without significant change, and sundry item testing result also proves that this capsule stability is good simultaneously.
Claims (10)
1. a pharmaceutical composition for dopamine precursor medicine, described compositions comprises dopamine precursor medicine, Ro-4-4602., binding agent, stabilizing agent and pharmaceutically acceptable carrier,
Described binding agent is selected from hypromellose,
Described stabilizing agent is selected from anhydrous citric acid,
The consumption of described binding agent is 0.1-5.0 weight portion, is 100 parts by weight with described Ro-4-4602.,
The consumption 0.01-5 weight portion of described stabilizing agent is 100 parts by weight with described Ro-4-4602.,
Described dopamine precursor medicine is levodopa.
2. pharmaceutical composition as claimed in claim 1, it is characterized in that, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 10:1 to 1:1, and Ro-4-4602. is with the weighing scale of benserazide.
3. pharmaceutical composition as claimed in claim 1, it is characterized in that, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 8:1 to 2:1, and Ro-4-4602. is with the weighing scale of benserazide.
4. pharmaceutical composition as claimed in claim 1, it is characterized in that, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 6:1 to 3:1, and Ro-4-4602. is with the weighing scale of benserazide.
5. pharmaceutical composition as claimed in claim 1, it is characterized in that, the weight ratio of described dopamine precursor medicine and Ro-4-4602. is 4:1, and Ro-4-4602. is with the weighing scale of benserazide.
6. pharmaceutical composition as claimed in claim 1, it is characterized in that, the consumption of described binding agent is 1.0-4.0 weight portion, is 100 parts by weight with described Ro-4-4602..
7. pharmaceutical composition as claimed in claim 1, it is characterized in that, the consumption of described stabilizing agent is 0.015-4 weight portion, is 100 parts by weight with described Ro-4-4602..
8. pharmaceutical composition as claimed in claim 1, it is characterized in that, described pharmaceutical composition also comprises antioxidant, flavouring agent, odor mask, pigment, fluidizer, lubricant or diluent.
9. prepare a method for pharmaceutical composition described in claim 1, said method comprising the steps of:
A binding agent adds in water by (), abundant stirring and dissolving, then adds stabilizing agent, is stirred to dissolve completely to obtain slurry;
B dopamine precursor medicine, Ro-4-4602. and pharmaceutically acceptable carrier mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mix and form described pharmaceutical composition,
Described binding agent is selected from hypromellose,
Described stabilizing agent is selected from anhydrous citric acid,
The consumption of described binding agent is 0.1-5.0 weight portion, is 100 parts by weight with described Ro-4-4602.,
The consumption 0.01-5 weight portion of described stabilizing agent is 100 parts by weight with described Ro-4-4602.,
Described dopamine precursor medicine is levodopa.
10. method as claimed in claim 9, is characterized in that, said method comprising the steps of:
A binding agent adds in purified water by (), abundant stirring and dissolving, then adds stabilizing agent, is stirred to dissolve completely to obtain slurry;
B dopamine precursor medicine, Ro-4-4602. and pharmaceutically acceptable carrier mix homogeneously are obtained solid mixture by ();
C slurry that step (a) obtains by () and the solid mixture that step (b) obtains mixing;
D mixture that step (c) obtains by () and mix lubricant obtain described pharmaceutical composition.
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| CN105078952A (en) * | 2015-08-10 | 2015-11-25 | 中国康复研究中心 | Levodopa preparation and application thereof |
| CN114224878B (en) * | 2021-04-20 | 2023-03-14 | 杭州泓友医药科技有限公司 | Compound medicine for treating Parkinson's disease |
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| CN101623278A (en) * | 2008-07-09 | 2010-01-13 | 北京德众万全药物技术开发有限公司 | Medicinal composition containing levodopa and benserazide hydrochloride |
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| CN101623278A (en) * | 2008-07-09 | 2010-01-13 | 北京德众万全药物技术开发有限公司 | Medicinal composition containing levodopa and benserazide hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 凌春生 等.制剂中药物化学降解途径.《实用药剂学》.中国医药科技出版社,2008,第54-55页. * |
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