CN1845728A - Pharmaceutical compositions and method of using levodopa and carbidopa - Google Patents
Pharmaceutical compositions and method of using levodopa and carbidopa Download PDFInfo
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- CN1845728A CN1845728A CN200480024879.8A CN200480024879A CN1845728A CN 1845728 A CN1845728 A CN 1845728A CN 200480024879 A CN200480024879 A CN 200480024879A CN 1845728 A CN1845728 A CN 1845728A
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Abstract
The present invention relates to stable compositions of levodopa and carbidopa, methods of treating patients with these compositions, and methods of preparing these compositions.
Description
Related application
The application requires the priority of following application: the U. S. application the 60/499th of application on August 29th, 2003, No. 256, the U.S. Provisional Application the 60/505th of JIUYUE in 2003 application on the 24th, No. 551, the U.S. Provisional Application the 60/559th of application on April 6th, 2004, No. 864, and No. the 60/586th, 442, the U.S. Provisional Application of on July 8th, 2004 application.
Invention field
The present invention relates to the stable composition of levodopa and carbidopa.
Background of invention
Parkinson is the neurodegenerative disease that sexual involution is a feature that carries out with dopaminergic path in the brain.The parkinsonian have usually bradykinesia, tetanic, tremble, the balance difference and advance the difficulty symptom.For the parkinsonian, simple motion is for example cooked breakfast or made coffee all can be very difficult.Especially, for example pill may be very difficult for the little article of operation.To one of the most common Therapeutic Method of parkinson is to give levodopa.Levodopa rises and passes blood brain barrier, changes into dopamine, the effect of low-level dopamine in replacement or the additional brain.The parkinsonian takes 200mg to 2g levodopa common every day, and late period, the parkinsonian took the rear end dosage of this scope.The monotherapy of levodopa is attended by undesirable side effect, for example nausea and vomiting usually.Levodopa and the dopa decarboxylase inhibitor for example administering drug combinations of carbidopa have reduced patient's side effect, have strengthened drug effect simultaneously.One of shortcoming of levodopa/carbidopa tablet is that the parkinsonian often experiences the incident of " weakening gradually ".During these incidents, the patient becomes stiff or moves stiff.This stiff situation has caused extremely harmful consequence to parkinsonian's quality of life.The patient through the sublingual administration levodopa/carbidopa tablet of being everlasting from stiff situation, to recover.Usually will not make the patient from stiff situation, alleviate 1 hour at patient's sublingual administration medicine.The controlled release tablet of levodopa/carbidopa (trade mark, " Sinemet CR (Sinemet CR) ") also provides to the patient.Sinemet CR does not bring better clinical effectiveness.Therefore, the patient who takes Sinemet CR still has " weakening gradually " and stiff situation.The patient has been used to avoid or has treated one of these methods that " weaken " situation gradually is to make the levodopa/carbidopa liquid preparation.Stable levodopa/carbidopa liquid preparation does not exist.Unsettled levodopa/carbidopa liquid suspension is the family therapy that the parkinsonian has adopted.When the patient feels that their levodopa level reduces, their unsettled levodopa/carbidopa liquid suspension of a bite of just sipping.Therefore, patient oneself prepares their levodopa concentration, and controls their symptoms of Parkinson's Disease.The manufacture method of unsettled levodopa/carbidopa liquid preparation is provided in the document.Typically, the patient is with levodopa/carbidopa pill grind up, and annex solution style such as orange juice or Ginger Ale.One of shortcoming of this method is the process of grinding.The patient who enters " weakening gradually " state has very big difficulty for grinding pill.In the process that weakens state gradually, grind the necessary intensity of pill and finger manipulation can lack or not enough.In addition, this unauthorized mixing can cause the incomplete or poor stability of bioavailability of levodopa or carbidopa.Carbidopa is unstable compounds for a long time in liquid, does not also have stable Carbidopa liquid preparation at present.Therefore, the liquid preparation that needs Carbidopa safer, more stable and that be easier to use than existing suspensoid.
Summary of the invention
Surprisingly, have been found that the stabilization formulations that can obtain new Carbidopa, it can be easily and liquid combination, is used for the treatment of the parkinsonian.
On the one hand, the invention provides exsiccant, the solid tablet or the powder of Carbidopa, it can with liquid mixing, form stable drug products.
On the other hand, the invention provides the method for the treatment of the parkinsonian with the liquid preparation of Carbidopa.
In a more particular embodiment, pharmaceutical composition comprises levodopa, carbidopa, acid and metal-chelate mixture.The example of metal-chelate mixture comprises EDTA and deferoxamine mesylate.EDTA can be the form of its salt or free alkali.On the one hand, the concentration of EDTA is 0.01mg/ml at least.
In another embodiment, acid can be selected from carboxylic acid, mineral acid, citric acid, tartaric acid, ascorbic acid, hydroascorbic acid, acetic acid, formic acid, formic acid, butanoic acid, acetic acid, benzoic acid, butanoic acid, malic acid, propanoic acid, Epoxysuccinic acid, muconic acid, furylacrylic acid, citramalic acid, capric acid, stearic acid, caproic acid (caprioc acid), malonic acid, succinic acid, diethacetic acid, methylbutanoic acid (methylbutryic acid), hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulphuric acid.
In one embodiment, compositions is the stable liquid of levodopa and carbidopa.On the one hand, stable liquid is 25 ℃ of carbidopa degradeds that have after following 7 days less than 10%.On the other hand, stable liquid is 25 ℃ of carbidopa degradeds that have after following 7 days less than 5%.Again on the one hand, stable liquid is 25 ℃ of carbidopa degradeds that have after following 30 days less than 10%.Another aspect, stable liquid is 25 ℃ of carbidopa degradeds that have after following 4 days less than 5%.On the other hand, stable liquid is 4 ℃ of carbidopa degradeds that have after following 30 days less than 5%.On the one hand, stable liquid is 25 ℃ of carbidopa degradeds that have after following 250 days less than 5%.On the other hand, stable liquid is 4 ℃ of carbidopa degradeds that have after following 360 days less than 5%.Another aspect, stable liquid is 25 ℃ of carbidopa degradeds that have after following 9 days less than 10%.
In another embodiment, pharmaceutical composition comprises levodopa, carbidopa and acid, wherein, the pH of described compositions less than or about 3.0.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 10%.On the other hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 5%.Again on the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 30 days less than 10%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 4 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 30 days less than 5%.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 250 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 360 days less than 5%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 9 days less than 10%.On the other hand, said composition also comprises other artificial sweetener or antiseptic.
In another embodiment, waterborne compositions comprises levodopa and carbidopa, and wherein, the concentration of levodopa is 2.5mg/ml to 9mg/ml.In another embodiment, the concentration of levodopa is about 4mg/ml.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 10%.On the other hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 5%.Again on the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 30 days less than 10%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 4 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 30 days less than 5%.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 250 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 360 days less than 5%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 9 days less than 10%.On the other hand, said composition also comprises other artificial sweetener or antiseptic.
In another embodiment, compositions comprises levodopa, carbidopa, acid and metal-chelate mixture, wherein, is degrading less than 1.2% carbidopa after through 24 hours under 25 ℃.The example of metal-chelate mixture comprises EDTA and deferoxamine mesylate.
Another embodiment comprises the compositions of levodopa, carbidopa, acid and metal-chelate mixture, wherein, has degraded less than 2.4% carbidopa after following 48 hours at 25 ℃.
Another compositions of the present invention comprises the stabilization formulations with low-level degradation product (degradant).On the one hand, the levodopa/carbidopa suspensoid that provides at present is provided the degradation product of hydrazine.On the one hand, composition of liquid medicine comprises about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein, in the level of 25 ℃ of hydrazines after following 24 hours less than 0.07 μ g/ml.On the other hand, composition of liquid medicine comprises about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein, in the level of 25 ℃ of hydrazines after following 3 days less than 0.32 μ g/ml.Another aspect, composition of liquid medicine comprise about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein, in the level of 25 ℃ of hydrazines after following 7 days less than 1.6 μ g/ml.Again on the one hand, composition of liquid medicine comprises levodopa and the carbidopa of about 0.4 to 1.5 mg/ml, wherein, in the level of 4 ℃ of hydrazines after following 7 days less than 0.06 μ g/ml.
In one embodiment, the liquid preparation of levodopa, carbidopa, acid and metal-chelate mixture is clarifying or translucent.
In another embodiment, pharmaceutical composition comprises levodopa, carbidopa, acid and sulfide compound.On the one hand, thioether works to stablize carbidopa.The example of thioether comprises methionine, cysteine, glutathion, thioglycerol, sodium thiosulfate and just-acetyl methionine.In another embodiment, compositions comprises levodopa, carbidopa, acid, thioether and metal-chelate mixture.
An embodiment comprises a kind of pharmaceutical composition, and it comprises about 2.5 to 6mg/ml levodopa, about 0.625 to 1.5mg/ml carbidopa, about 5mg/ml to 10mg/ml citric acid and greater than about 0.25mg/ml EDTA.Said composition also can comprise the aspartame of about 0.1mg/ml to about 1mg/ml in addition, or about 0.01mg/ml is to the sodium benzoate of about 1mg/ml.
In another embodiment, pharmaceutical composition comprises about 2.5 to 6mg/ml levodopa, about 0.25 to 0.6mg/ml carbidopa, about 5mg/ml to 10mg/ml citric acid and greater than about 0.25mg/ml EDTA.Said composition also can comprise water, about 0.1mg/ml in addition to about 1mg/ml aspartame or about 0.01mg/ml about 1mg/ml sodium benzoate extremely.
In one embodiment, pharmaceutical composition comprise about 500mg to about 1500mg levodopa, about 125mg to about 375mg carbidopa, about 1065mg about 3195mg citric acid and about 13mg about 41mg EDTA extremely extremely.Said composition can be the form of dispersible tablet or be powder or the particulate form that is used for liquid mixing.
In another embodiment, pharmaceutical composition comprises about 1000mg levodopa, about 250mg carbidopa, about 2130mg citric acid and about 27mg EDTA.Compositions can also comprise water, aspartame or sodium benzoate.
An embodiment comprises the pharmaceutical composition of levodopa, carbidopa, acid, metal-chelate mixture and sugar, and wherein, sugar accounts for compositions less than 1%.
An embodiment comprises the method that gives levodopa and carbidopa, wherein, the drying or the solid preparation of levodopa and carbidopa is added in the liquid; Mix preparation was used preparation less than 10 minutes to the patient.One aspect of the present invention is, the administration of preparation is dosage in first of parkinsonian in morning.
In another embodiment, fluid composition can dissolve about 2.5 to 6mg/ml levodopa and about 0.25 to 0.6mg/ml carbidopa.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 10%.On the other hand, said composition is 25 ℃ of carbidopa degradeds that have after following 7 days less than 5%.Again on the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 30 days less than 10%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 4 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 30 days less than 5%.On the one hand, said composition is 25 ℃ of carbidopa degradeds that have after following 250 days less than 5%.On the other hand, said composition is 4 ℃ of carbidopa degradeds that have after following 360 days less than 5%.Another aspect, said composition is 25 ℃ of carbidopa degradeds that have after following 9 days less than 10%.
Another embodiment of the invention is the method for the pharmaceutical composition of preparation treatment dopamine obstacle, and it comprises levodopa, carbidopa, acid, metal-chelate mixture and the blended step of water.
In one embodiment, fluid composition comprises levodopa and carbidopa, and wherein, the total concentration of metal ion is less than 1ppm.On the other hand, free metal ion concentration is less than 1ppm.On the one hand, compositions also comprises acid.An example of relevant acid is a hydrochloric acid.In other compositions, the total concentration of metal ion can be less than 0.1ppm, 0.1ppm, 0.01ppm or 1ppb.
In a method of the present invention, levodopa and Lodosyn comprise one or more adjuvants or activating agent, and these adjuvants or activating agent are carried out chromatography to remove metal ion.The example that is suitable for metal ion to be removed comprises ferrum, lead, zinc or aluminum.
Others of the present invention comprise uses compositions of the present invention to the patient.
Brief description of drawings
Fig. 1: proved that the dissolubility of levodopa in citrate buffer is the function of pH and levodopa concentration.
Detailed Description Of The Invention
The invention provides the stabilizing pharmaceutical composition that comprises Carbidopa. Previous levodopa and carbidopa composition are stable not, perhaps are not enough to the parkinsonian is worked. With respect to the levodopa of present listing and the levodopa/carbidopa liquid preparation of Lodosyn and at present family's preparation, the present composition can provide advantage.
" liquid levodopa/carbidopa " is defined as the preparation of levodopa, carbidopa and liquid, and wherein, one or more levodopa/carbidopa tablets mix mutually with liquid.
" parkinsonian " be defined as by doctor diagnosed suffer from parkinsonian anyone, perhaps be diagnosed with the dopamine obstacle, can have benefited from anyone of levodopa treatment.
Had been found that and made improving one's methods of levodopa and carbidopa composition stable. A kind of method of improving stability comprises the free metal concentration that reduces in levodopa and the carbidopa composition. The another kind of method of improving stability comprises the pH that reduces levodopa and carbidopa fluid composition. Another method of improving stability comprises to be selected for the preferred acid of the stability of levodopa and carbidopa.
The invention provides the Carbidopa preparation, it is in stability and be easy to use and have the advantage that is better than prior art. The levodopa/carbidopa liquid preparation that has had been found that family's preparation of present use has produced multiple catabolite. At least a in these catabolites is hydrazine, a kind of potential carcinogen. Take every day levodopa/carbidopa liquid form the 1g levodopa late period the parkinsonian present practice may cause the poisoning level of hydrazine. Although present levodopa/carbidopa liquid preparation to late period the parkinsonian significant benefit is provided, yet the preparation of this family preparation is exposed to the patient under the potential carcinogen. This potential carcinogen (" Toxological Profile for Hydrazines that is associated with cancer, " U.S. Department of Health and Human Services, September 1997). In addition, carbidopa is degraded into the forfeiture that hydrazine causes carbidopa to be renderd a service, thus the shelf life of having reduced product.
The preparation that needs the advantage of the liquid preparation stable, wieldy for the parkinsonian, that levodopa and carbidopa still are provided simultaneously. Make a lot of effort and created the stable liquid preparation that comprises levodopa and carbidopa. After a lot of tests, find that metal is so that carbidopa is unstable. One embodiment of the invention comprise levodopa, carbidopa and metal-chelate mixture. Be not subjected to any theoretical constraint, think that metal ion has caused carbidopa degraded (embodiment 12). The example of intercalating agent includes, but are not limited to EDTA, deferoxamine mesylate, EGTA, fumaric acid and malic acid. Be included in the free acid of the existing EDTA in the definition of EDTA, the form of its salt is arranged again. The example of the free acid of EDTA or the form of salt comprises edetic acid(EDTA), natrium adetate, EDTAP dipotassium ethylene diamine tetraacetate, CaEDTA, edetate sodium and edetate trisodium. Any edetic acid(EDTA), natrium adetate, EDTAP dipotassium ethylene diamine tetraacetate, CaEDTA, edetate sodium and edetate trisodium can be got rid of from embodiments more of the present invention. In one embodiment, EDTA concentration be at least 0.01mg/ml, at least 0.05mg/ml, 0.1mg/ml, 0.01 is to 0.5mg/ml, 0.05mg/ml to 0.3mg/ml, 0.05mg/ml to 0.2mg/ml or about 0.1mg/ml at least.
In another embodiment, the present composition comprises low-level metal or does not conform to detectable metal. Low-level metal is less than the 1ppm metal ion, less than the 0.5ppm metal ion, less than the 0.01ppm metal ion or less than the 1ppb metal ion. Can from the present composition, get rid of or make it minimized special metal ion and include, but are not limited to iron, calcium, magnesium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc, aluminium, arsenic, barium, cadmium, chromium, lead, mercury, selenium and silver. In a specific embodiment, levodopa and carbidopa composition comprise the metal ion less than 1ppm. In another embodiment, the composition of levodopa, carbidopa and acid comprises the metal ion less than 1ppm. In another embodiment, levodopa and carbidopa composition comprise the metal ion less than 0.1ppm. In a further embodiment, the composition of levodopa, carbidopa and acid comprises the metal ion less than 0.1ppm. In some embodiments, total metal concentration is lower than specified level, and in other embodiments, the free metal ion total concentration is lower than specified level. Free metal ion be not with the ion of other molecule (not comprising water) chemical bonding.
Comprise being purchased in the preparation of levodopa and carbidopa at a lot of preparations, metal ion exists with trace. In addition, metal ion be present in can the liquid for the preparation of levodopa and carbidopa liquid preparation in. For example adhesive, acid, flavor enhancement and diluent have for example been removed metal ion the water to method of the present invention from active component, excipient. In one embodiment, the present composition prepares by chromatography removal metal ion. In another embodiment, the present composition prepares by all or part excipient and activating agent are carried out chromatography. In another embodiment, the present composition be by all or part excipient and activating agent are carried out chromatography so that total concentration of metal ions of resulting composition less than 1ppm, less than 0.5ppm, less than 0.1ppm, prepare less than 0.01ppm or less than 1ppb. In a further embodiment, levodopa and carbidopa composition are carried out chromatography to remove metal ion. Metal ion can be removed from final composition, perhaps removes from each independent excipient of composition or activating agent. For example, metal ion can be removed from the preparation of levodopa, carbidopa and hydrochloric acid, perhaps removes metal ion individually from levodopa, carbidopa and hydrochloric acid.
In addition, have been found that sulfide compound makes the carbidopa molecule stable, thereby reduce the formation of degradation product. The example of thioether includes, but are not limited to methionine, cysteine, glutathione, thioglycerol, sodium thiosulfate and just-acetyl methionine.
Another embodiment of the invention had both comprised thioether, comprised again intercalating agent. The effect of having united the Degradation Level of carbidopa in the remarkable reduction Carbidopa composition of thioether and intercalating agent. Therefore, in one embodiment, the present invention comprises carbidopa, levodopa and one or more are selected from the material of metal-chelate mixture or thioether. Other side of the present invention is that carbidopa, levodopa and one or more are selected from the preparation of the material of metal-chelate mixture or thioether, wherein, has degraded less than 10% carbidopa after lower 7 days at 25 ℃.
In one embodiment, the present composition is stable. Stable composition is 25 ℃ of carbidopa degradeds that have after lower 7 days less than 10%, 25 ℃ of carbidopa degradeds that have after lower 7 days less than 5 %, 25 ℃ of carbidopa degradeds that have after lower 30 days less than 10%, 25 ℃ of carbidopa degradeds that have after lower 4 days less than 5%, 4 ℃ of carbidopa degradeds that have after lower 30 days less than 5%, 25 ℃ of carbidopa degradeds that have after lower 250 days less than 5%, 4 ℃ of carbidopa degradeds that have after lower 360 days less than 5%, or 25 ℃ of carbidopa degradeds that have after lower 9 days less than 10%. Embodiment of the present invention can make preparation at room temperature store to have later in 24 hours less than 1,000,000/(ppm), less than 0.5 ppm, less than 0.2ppm, less than 0.1ppm, less than 0.05ppm or less than the degradation product level of 0.01ppm. After embodiment of the present invention can make preparation at room temperature store 48 hours, a kind of specific degradation product for example hydrazine have less than 1,000,000/(ppm), less than 0.5 ppm, less than 0.2ppm, less than 0.1ppm, less than 0.05ppm or less than the level of 0.01ppm. Embodiment of the present invention can make preparation 4 ℃ lower store a week after, the level of hydrazine is less than 1,000,000/(ppm), less than 0.5ppm, less than 0.2ppm, less than 0.1 ppm, less than 0.05ppm or less than 0.01ppm.
In one embodiment, liquid preparation of the present invention after one day, has the carbidopa degraded less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5% or 0.25% 25 ℃ of lower storages. In another embodiment, liquid preparation of the present invention after three days, has the carbidopa degraded less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5% or 0.25% 25 ℃ of lower storages. In one embodiment, liquid preparation of the present invention has the carbidopa degraded less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5% or 0.25% after 25 ℃ of one weeks of lower storage. In one embodiment, liquid preparation of the present invention after one month, has the carbidopa degraded less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5% or 0.25% 25 ℃ of lower storages.
In another embodiment, to comprise the composition of levodopa be moderately stable for drug use in the present invention. In one embodiment, the levodopa of liquid form of the present invention, carbidopa or its preparation are stable, to such an extent as to when at room temperature storing 24 hours, any degradation product of formation is all less than 1%. The term degradation product refers to the product of the chemical reaction of single type in this article. For example, if the hydrolysis of two products has occured a molecule is cracked into, with regard to the present invention, will think single degradation product. In another embodiment, when storing a week under 4 ℃, any degradation product that forms in the composition is all less than 5%. Alternately, when at room temperature storing 24 hours, the present composition comprises less than 10%, any degradation product less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5%. Relative humidity (RH) can be appointed as environment RH, 75%RH or any single integer between 1 to 99%RH. The degradation product of a particular type is hydrazine.
In another embodiment, the present composition has improved stability than the preparation that adopts at present. In one embodiment, 25 ℃ lower store 24 hours after, the present composition has little 100 times carbidopa than the preparation (1 mg/ml) that Ginger Ale and sinemet (Sinemet) sheet are mixed with that adopts at present and degrades. In another embodiment, 25 ℃ lower store 24 hours after, the present composition has little 3 times carbidopa than the preparation (1mg/ml) that orange juice and sinemet sheet are mixed with that adopts at present and degrades. In another embodiment, 25 ℃ lower store 3 days after, the present composition has little 15 times carbidopa than the preparation (1mg/ml) that orange juice and sinemet sheet are mixed with that adopts at present and degrades. In yet another embodiment, 25 ℃ lower store 7 days after, the present composition has little 60 times carbidopa than the preparation (1mg/ml) that orange juice and sinemet sheet are mixed with that adopts at present and degrades.
In some embodiments of the present invention, composition has lower level carbidopa degraded than the preparation that adopts at present. The liquid levodopa/carbidopa that has been found that present use contains carbidopa degradation product (referring to embodiment 3 and 6) in the preparation of family's preparation. For example, the patient often is subject to encouraging the levodopa/carbidopa tablet is mixed with orange juice, and it comprises ascorbic acid with dissolving levodopa/carbidopa tablet. Ascorbic acid can cause the reaction that produces the carbidopa degradation product. These degradation products can cause negative biological impact, and reduce pharmaceutical efficacy, because the medicine of having degraded no longer includes function. Experiment with other acid is verified, and other carbidopa degradation product may exist. Two specific degradation products that can form in liquid levodopa/carbidopa preparation are hydrazine and 3,4-dihydroxyphenyl-1-propanone (DHPA). Not retrained by any special theory, think that carbidopa is degraded into DHPA and the hydrazine of equal proportion. Therefore, the existence of DHPA can be indicated the existence of hydrazine. The present composition has reduced the level of these degradation products. For example, the present composition can prevent the formation of these degradation products, or 25 ℃ lower store a week after, the formation that keeps these degradation products is less than 0.05%, less than 0.1%, less than 0.2%, less than 0.3%, less than 0.5%, less than 1%, less than 2%, less than 5% or less than 10%.
In another embodiment, to comprise the composition of levodopa be moderately stable for drug use in the present invention. Preferably, the preparation of the levodopa of solid dosage forms of the present invention, carbidopa or its solid form is stable, to such an extent as to when storing 2 years under 30 ℃, any degradation product of formation is all less than 0.2%. The term degradation product refers to the product of the chemical reaction of single type in this article. For example, if the hydrolysis of two products has occured a molecule is cracked into, with regard to the present invention, think single degradation product. More preferably, when storing 2 years under 40 ℃, any degradation product of formation is all less than 0.2%. Alternately, when under 30 ℃, storing 3 months, the any degradation product that forms is all less than 0.2% or 0.15% or 0.1%, and perhaps when storing 3 months under 40 ℃, any degradation product of formation is all less than 0.2% or 0.15% or 0.1%. More alternately, when storing for 4 week under 60 ℃, any degradation product of formation is all less than 0.2% or 0.15% or 0.1%. Relative humidity (RH) can be appointed as environment RH, 75%RH or any single integer between 1 to 99 %RH.
One embodiment of the invention comprise carbidopa, levodopa and one or more sour compositions. The example of acid includes, but are not limited to carboxylic acid, inorganic acid salt, citric acid, tartaric acid, ascorbic acid, hydroascorbic acid, acetic acid, formic acid, formic acid, butyric acid, acetic acid, benzoic acid, butyric acid, malic acid, propionic acid, Epoxysuccinic acid, muconic acid, furylacrylic acid, citramalic acid, capric acid, stearic acid, caproic acid, malonic acid, butanedioic acid, diethacetic acid, methylbutanoic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid. Can be sourer than the molar ratio adding of about 4 equimolar acids than about 3 equimolar acids or about 1 mole of levodopa than about 10 equimolar acids, about 1 mole of levodopa than about 7 equimolar acids, about 1 mole of levodopa than about 5 equimolar acids, about 1 mole of levodopa than about 2 equimolar acids, about 1 mole of levodopa than about 20 equimolar acids, about 0.5 mole of levodopa according to about 0.5 mole of levodopa. The concentration that those skilled in the art can increase acid is to improve the carbidopa can be dissolved in the liquid or the level of levodopa. What be included in the scope of the present invention is to increase ionic strength with the application of the solubility of raising carbidopa or levodopa. For example, HCl is added in the composition of levodopa, carbidopa and citric acid further solubilising levodopa, perhaps can allows the higher levels of levodopa of solubilising.
In some embodiments, any specific acid can be got rid of from the present invention. The example of the acid that can get rid of especially includes, but are not limited to carboxylic acid, citric acid, tartaric acid, ascorbic acid, hydroascorbic acid, acetic acid, formic acid, formic acid, butyric acid, acetic acid, benzoic acid, butyric acid, malic acid, propionic acid, Epoxysuccinic acid, muconic acid, furylacrylic acid, citramalic acid, capric acid, stearic acid, caproic acid, diethacetic acid, methylbutanoic acid, hydrochloric acid, malonic acid, butanedioic acid, phosphoric acid and sulfuric acid.
Can carry out the adjusting of ionic strength to affect solubility. Embodiment 7 shows that salt pair carbidopa stability has a little negative effect. Therefore, in some embodiments, regulate ionic strength to keep optimum stabilization. For example, the salinity in some composition is less than 1M, less than 0.75M, less than 0.5M, less than 0.3M, less than 0.2M or less than 0.1M.
The pH of liquid levodopa/carbidopa preparation can affect the stability of preparation. As embodiment 8 proves, reduce the stability that pH can improve preparation. The present composition can have 1 to 10,1 to 8,2 to 8,2 to 6,2 to 4,2.5 to 4.5,2.5 to 4,2.5 to 3.5,3 to 8,3 to 6,3 to 5,3 to 4,1 to 4,1.5 to 3.5,2 to 3 or less than 5, less than 4, less than 3, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1 or less than 2 pH.
Pharmaceutical composition of the present invention can comprise levodopa, carbidopa, the auxiliary material that one, two, three, four or more is other or additive. Auxiliary material or additive can be inertia, perhaps can be activated, can affect other component of composition. Auxiliary material or additive can include, but are not limited to acid, alkali, salt, surfactant, emulsifying agent, washing agent, adhesive, wetting agent, salt, polymer, solvent, antimicrobial, anticorrisive agent, filler, sugar, alcohol, colouring agent, flavor enhancement and buffer. Auxiliary material can play the effect of the degraded of stabilization formulations or reduction or elimination activity agent. As embodiment comprise in the present invention be, the composition that contains any well known auxiliaries is included in by Michael and Irene Ash and edits Gower Publishing, those disclosed auxiliary material among 1995, the Handbook of Pharmaceutical Additives.
In some embodiments, can get rid of any or multiple specific material. The example of the material that can be excluded includes, but are not limited to acid, alkali, salt, surfactant, emulsifying agent, washing agent, adhesive, wetting agent, salt, polymer, solvent, antimicrobial, anticorrisive agent, filler, sugar, alcohol or disclosed additive in Handbook of Pharmaceutical Additives.
Other auxiliary material can comprise particle binders. Specific particle binders includes, but are not limited to hydroxypropyl cellulose and HPMC, and polyvinylpyrrolidone. In one embodiment, water miscible particle binders is used for preparation of the present invention. In another embodiment, adopt by weight 3 to 10%, 4 to 6% or 4 to 5% adhesive.
In some embodiments, other material is added in the composition, to prevent the formation of degradation product. Any material that satisfies restriction, reduces or suppress the condition of the degradation product formation in the present composition all is conceivable. Specific example includes, but are not limited to ammonium bisulfite, ammonium sulfite, ATS (Ammonium thiosulphate), arsenones, orpiment, calcium hyposulfite, chromous chloride, frerrous chloride, ferrous oxalate, beta-mercaptoethanol, dithiothreitol (DTT), vitamin E, vitamin C, beta carotene, lycopene and flavone compound.
One aspect of the present invention provides the Carbidopa compositions, and it can be used for the treatment of the parkinsonian.For some parkinsonian, the liquid preparation of Carbidopa is more favourable than other dosage form.When parkinson constantly developed, the patient needed higher levodopa dosage constantly, to keep motor capacity.These high-caliber administration requirements often make the patient more responsive to stiff situation.Therefore, late period, the parkinsonian often needed high-caliber levodopa to avoid stiff situation.Embodiments more of the present invention will be specially adapted to the late period parkinsonian and avoid stiff situation, or by give levodopa that the patient provides high concentration rapidly so that the patient gets off quickly out from stiff situation.
The levodopa that the present invention relates to and the preparation of carbidopa can be made into powder, tablet or granule, with liquid mixing to prepare stable liquid preparation.Can use these formulation example as the parkinsonian is carried out administration.Pharmaceutical composition of the present invention can adopt the form of several different embodiments.In one embodiment, levodopa and carbidopa are made into exsiccant bag form, it can and liquid mixing.In another embodiment, levodopa and carbidopa are made into pill or tablet, it can and liquid mixing.In another embodiment, levodopa and carbidopa can be made into may be mixed in to any dosage form in the liquid.The example of the dosage form that is suitable for includes, but are not limited to powder, granule, tablet, capsule, dispersant, solution and gel.
The levodopa and the carbidopa drug products of listing are solid dosage forms at present.The parkinsonian may enter stiff situation, has to wait for segment length's time, makes its effect of drug products performance.This wait and stiff stage have seriously restricted parkinsonian's freedom and security.The present composition can provide and begin effect faster, thereby reduces the stiff time.In some embodiments, 80% or the more present composition can pass through stomach, in 1,2,3,4,5,10,15,20,25 or 30 minute, perhaps in 1 to 30,1 to 20,3 to 20,3 to 15,5 to 10,10 to 30,10 to 20 or 20 to 30 minutes, begin intestinal absorption, thereby quicken to absorb in the body.In another embodiment, 90% or the more present composition can pass through stomach, in 1,2,3,4,5,10,15,20,25 or 30 minute, perhaps in 1 to 30,1 to 20,3 to 20,3 to 15,5 to 10,10 to 30,10 to 20 or 20 to 30 minutes, begin intestinal absorption, thereby quicken to absorb in the body.
In addition, the present composition also can comprise the medicament that strengthens gastric motility.A side effect of parkinson or parkinson Drug therapy is to weaken gastric motility.The preparation of levodopa, the agent of carbidopa stomach function regulating power adjustment can provide the medicine of quick acting to the parkinsonian.The example of the medicine that is suitable for includes, but are not limited to dopamine antagonist for example cisapride and domperidone.One class gastric motility regulator can play lax sphincter of pylorus and allow gastric content to enter intestinal.The pharmaceutical preparation that strengthens gastric motility can allow levodopa and carbidopa with the food administration.A lot of parkinsonians avoided eating food in the time of levodopa dosage regimen near them.Known food reduces the absorption of levodopa.The preparation of levodopa and carbidopa and gastric motility agent can allow the patient to eat food when taking their essential drug dose.Therefore, an embodiment need be at table and be used the preparation of the present invention that comprises levodopa, carbidopa and gastric motility agent in preceding 1,2,3,4,5,10,20,25 or 30 minute, may be to the influence of levodopa bioavailability to reduce food.
The embodiment of the present invention that contain and do not contain the gastric motility agent can provide the absorption of faster and more expected levodopa in digestive system.Therefore, one aspect of the present invention need carry out administration with food with embodiment of the present invention, or at the time administration near the feed stage.Therefore, in some embodiments of the present invention, the absorption of levodopa may the influence of unable to take food thing.Another embodiment comprises with food administration or the compositions of administration in the time on the feed.
In some embodiments, the bioavailability of the present composition can be higher than the product of present listing.Higher bioavailability can cause working sooner.For example, the present composition can make that levodopa concentration increases to greater than 1 nanomole/milliliter, greater than 2 nanomole/milliliters, greater than 3 nanomole/milliliters, greater than 4 nanomole/milliliters, greater than 5 nanomole/milliliters, greater than 6 nanomole/milliliters or greater than 10 nanomole/milliliters in the blood plasma.The levodopa of compositions is greater than 1 nanomole/milliliter, greater than 2 nanomole/milliliters, greater than 3 nanomole/milliliters, greater than 4 nanomole/milliliters, greater than 5 nanomole/milliliters, can prevent, reduce or stop stiff situation greater than 6 nanomole/milliliters or greater than 10 nanomole/milliliters.Therefore, in some embodiments of the present invention, compositions can reduce or stop stiff situation.In another embodiment, the present composition can be in taking in 10 minutes of compositions the blood plasma levodopa reach the level of 3 nanomole/milliliters, can be in taking in 15 minutes of compositions the blood plasma levodopa reach the level of 3 nanomole/milliliters, can be in taking in 20 minutes of compositions the blood plasma levodopa reach the level of 3 nanomole/milliliters, can be in taking in 10 minutes of compositions the blood plasma levodopa reach the level of 4 nanomole/milliliters, can be in taking in 15 minutes of compositions the blood plasma levodopa reach the level of 4 nanomole/milliliters, perhaps can be in 20 minutes of absorption compositions the blood plasma levodopa reach the level of 4 nanomole/milliliters.The patient is to the trust difference of levodopa.Therefore, produce enough levodopa plasma concentration by administration, the present composition can prevent, reduces or stop stiff situation.Doctor, pharmacist or patient can regulate the dosage of preparation of the present invention according to parkinsonian's concrete condition.
The parkinsonian often has the difficulty of ingestion of pills.The liquid preparation of levodopa and carbidopa can work to reduce or eliminate the difficulty of administration.Present liquid levodopa/carbidopa family preparaton is not dissolved in the liquid as this area is described well.Therefore, whether fully the patient does not know Carbidopa dissolving.In addition, present described liquid levodopa/carbidopa preparation needs the parkinsonian to drink 1 liter or more levodopa/carbidopa liquid usually with the administration of 1mg/ml levodopa every day.The liquid of large volume may be difficult for swallowing of parkinsonian.The present composition can satisfy these demands.The present composition can comprise higher levels of levodopa or carbidopa than the liquid levodopa/carbidopa agent that the family that this area is described prepares.
In some embodiments, liquid preparation can comprise the about at the most 0.5mg/ml of concentration of levodopa, about at the most 1mg/ml, about at the most 2mg/ml, about at the most 3mg/ml, about at the most 4mg/ml, about at the most 5mg/ml, about at the most 10mg/ml, about at the most 20mg/ml, about at the most 30mg/ml, or about 0.5mg/ml to 30mg/ml, about 0.5mg/ml to 1mg/ml, about 1mg/ml to 5mg/ml, about 1mg/ml to 4mg/ml, about 1.5mg/ml to 2mg/ml, about 1.5mg/ml to 4mg/ml, about 2mg/ml to 5mg/ml, about 2mg/ml to 7mg/ml, about 3mg/ml to 8mg/ml, about 5mg/ml to 10mg/ml, about 4mg/ml to 10mg/ml, about 4.5mg/ml to 10mg/ml, about 4mg/ml to 8mg/ml, about 4mg/ml to 7mg/ml, about 4.5mg/ml to 6mg/ml, about 4.5mg/ml to 7mg/ml, about 4.5mg/ml to 8mg/ml, about 7mg/ml to 20mg/ml, about 10mg/ml to 30mg/ml, about 15mg/ml to 20mg/ml, or about 20mg/ml to 30mg/ml.In some embodiments, the liquid preparation of the present invention concentration 0.5mg/ml at the most that can comprise carbidopa, about at the most 1mg/ml, about at the most 2mg/ml, about at the most 3mg/ml, about at the most 4g/ml, about at the most 5mg/ml, about at the most 10mg/ml, about at the most 20mg/ml, about at the most 30mg/ml, or about 0.5mg/ml to 30mg/ml, about 0.5mg/ml to 1mg/ml, about 1mg/ml to 5mg/ml, about 1mg/ml to 4mg/ml, about 1.5 mg/ml to 2mg/ml, about 1.5mg/ml to 4mg/ml, about 2mg/ml to 5mg/ml, about 2mg/ml to 7mg/ml, about 3mg/ml to 8mg/ml, about 5mg/ml to 10mg/m, about 7mg/ml to 20mg/ml, about 10mg/ml to 30mg/ml, about 15mg/ml to 20mg/ml, or about 20mg/ml to 30mg/ml.
The amount of dissolved levodopa or carbidopa can be adjusted according to patient's demand.Skilled working doctor can determine the dosage of needs.In addition, carbidopa is stable with the ratio regular meeting influence of levodopa.The ratio that the present composition can change carbidopa and levodopa reduces or eliminates the degradation product in the preparation, enhanced stability (referring to embodiment 5).The ratio of carbidopa and levodopa can work to stablize carbidopa.Previous product comprised 1: 4 and the carbidopa of 1: 10 ratio: levodopa.The present composition can use other ratio, and plaing a part provides bigger stability to preparation.In some embodiments, carbidopa will be the levodopa of the carbidopa of 1 molar equivalent than 3 molar equivalents with the ratio of levodopa, the carbidopa of 1 molar equivalent is than the levodopa of 4 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 5 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 6 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 7 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 8 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 9 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 10 molar equivalents, the carbidopa of 2 molar equivalents is than the levodopa of 5 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 15 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 20 molar equivalents, the carbidopa of 1 molar equivalent is than the levodopa of 25 molar equivalents, or the carbidopa of 2 molar equivalents is than the levodopa of 9 molar equivalents.
In one embodiment, the present composition also comprises thickening agent or gellant.Thickening agent or gellant can make the parkinsonian easy-to-swallow.The example of thickening agent or gellant includes, but are not limited to dextrin, ethyl cellulose, hydroxyethyl-cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, Polyethylene Glycol, pectin, xanthan gum or zinc stearate.
The present composition makes preparation easy-to-swallow.Compositions can be with aqueous or based on the liquid mixing of water.The example of liquid includes, but are not limited to water, juice, tea, milk, carbonated beverages, saline and glucose solution.Usually the liquid that can get in the family provides and has been easy to mix and use.In addition, the present composition can require minimum administration volume.In one embodiment, liquid does not contain sugar or contains sugar less than 1%.The example of sugar comprises fructose and sucrose.In some embodiments, the patient can drink the 100mg levodopa in about 5ml to 500ml, about 5ml to 100ml, about 10ml to 75ml, about 15ml to 50ml, about 20ml to 30ml, about 10ml to 25ml, about 25ml to 50ml, about 50ml to 250ml, about 25ml to 100ml, about 50ml to 100ml, about 75ml to 200ml or about 100ml to the 400ml volume.
The present composition provides the extra stability that exceeds the liquid levodopa/ carbidopa.Embodiment 3 and 6 has shown and the previous relevant stability problem of liquid levodopa/carbidopa preparation.Stable liquid preparation do not comprise be separated, medicine or excipient separate, and has minimum drug degradation.The present composition can be at 4 ℃ of stable at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days of maintenances down, at least one week or at least one moon.In addition, some present composition at room temperature (22 ℃) stable at least 2 hours, at least 4 hours, at least 6 hours, at least 12 hours, at least 24 hours, at least 36 hours, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least one week or at least one month.
One embodiment of the invention comprise the compositions that comprises antiseptic, antibacterial, antimicrobial or antibacterial in addition.Protect compositions before antiseptic, antibacterial, antimicrobial or antibacterial can play a part to mix and after in liquid, mixing in liquid.The example of antiseptic, antibacterial, antimicrobial or antibacterial includes, but are not limited to benzyl alcohol, metabisulfite, benzoic acid, butyl p-hydroxybenzoate, chlorocresol, dimethyl sulfoxine, ethylparaben, water acetic acid, miaow urea, methyl parahydroxybenzoate and propyl p-hydroxybenzoate.One embodiment of the invention comprise preservative sodium benzoate.In one embodiment, the present composition does not contain any antibacterial or antimicrobial.
In some embodiments, can add other material to improve the taste of compositions.Artificial sweetener can be used to improve the taste of compositions.Shown in embodiment 9, sugar can reduce the stability of Carbidopa liquid preparation.Therefore, in one embodiment, the present composition uses the sugar less than 1%.Some artificial sweeteners can be used to improve the taste of preparation of the present invention and do not cause sugar stability problem.The example of artificial sweetener comprises aspartame, glucide, sucralose, neotame and acesulfame-K.An embodiment comprises the compositions that contains aspartame.
Be included within the scope of the invention is the compositions of the different physical form of levodopa and carbidopa.The example of the different physical form of Carbidopa includes, but are not limited to the free form of cocrystallization, amorphous substance and medicine of solvate, the salt of the acceptable salt of pharmacy, solvate, cocrystallization, polymorph, hydrate, salt.According to the physical form of carbidopa or levodopa, can need not adjuvant on the same group in the preparation.The present composition can comprise that the salt of levodopa or carbidopa is to improve stability of formulation.Shown in embodiment 11, salt for example HCl salt can work to reduce the pH of preparation, thereby improves stability of formulation.The example of the inorganic acid addition salt of levodopa or carbidopa comprises hydrochlorate, hydrobromate, sulfate, sulfamate, phosphate and nitrate.The example of the organic acid addition salt of levodopa or carbidopa comprises maleate, fumarate, benzoate, Ascorbate, succinate, oxalates, the dimethylene Salicylate, mesylate, ethanedisulphonate, acetate, propionate, tartrate, Salicylate, citrate, gluconate, lactate, malate, mandelate, cinnamate, citraconate, aspartate, stearate, palmitate, itaconate, glycollate, para-aminobenzoate, glutamate, Glu and benzene sulfonate.
The present composition also can comprise the third, the 4th kind, the 5th kind or more kinds of active component.Other active component can play enhancing or improvement treatment or the situation relevant with parkinson.The example of other active component comprises selegiline, the COMT inhibitor is entacapone or tolcapone for example, dopamine agonist is bromocriptine, ropinirole, pergolide, rotigotine or pramipexole for example, the dopamine decarboxylase inhibitor is benserazide for example, and gastric motility regulator for example cisapride or domperidone.
Carbidopa is as periphery dopamine decarboxylase inhibitor.Therefore, carbidopa prevents or limits the levodopa decarboxylation of the peripheral-system of health, thereby allows most of levodopa to pass blood brain barrier.Be included within the scope of the invention is the preparation that replaces carbidopa with benserazide (another kind of dopamine decarboxylase inhibitor).
In another embodiment of the invention, compositions can comprise levodopa and/or carbidopa derivant.Compositions can comprise prodrug for example levodopa and/or carbidopa ester derivant.The example of levodopa derivant includes, but are not limited to the levodopa ester, comprises LDME and ethyl levodopa etc.The example of carbidopa derivant includes, but are not limited to carbidopa methyl ester and carbidopa ethyl ester.
Another aspect of the present invention provides the compositions that does not contain the levodopa of any carbidopa.For some parkinsonian, the level of blood plasma carbidopa may be enough, and perhaps the patient may take the other medicines that contain carbidopa.Therefore, can from any present composition, remove carbidopa.The patient can take the pill of carbidopa or benserazide, and uses the liquid preparation of levodopa.Other embodiment comprises the compositions of the carbidopa that does not contain levodopa.
One embodiment of the invention comprise levodopa, carbidopa and thioether.The specific examples of this thioether includes, but are not limited to methionine or cysteine.
Another embodiment comprises levodopa, carbidopa and metal-chelate mixture.The specific examples of metal-chelate mixture can include, but are not limited to EDTA and deferoxamine mesylate.
Another embodiment comprises levodopa, carbidopa, thioether and intercalating agent.
In one embodiment, the present composition comprises levodopa, carbidopa and acid.In another embodiment, compositions comprises levodopa, carbidopa and acid, wherein, described acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid.
Another embodiment of the invention comprises levodopa, carbidopa, acid and thioether.Another embodiment comprises the compositions of levodopa, carbidopa, acid and intercalating agent.Another embodiment comprises levodopa, carbidopa, acid, thioether and intercalating agent.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid; With
B. at 25 ℃ after following 7 days, the level of the carbidopa of degraded is less than 0.05%, less than 0.1%, less than 0.2%, less than 0.3%, less than 0.5%, less than 1%, less than 2%, less than 5% or less than 10%.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid;
B. at 25 ℃ after following 7 days, the level of the carbidopa of degraded is less than 0.05%, less than 0.1%, less than 0.2%, less than 0.3%, less than 0.5%, less than 1%, less than 2%, less than 5% or less than 10%; With
C. preparation also comprises for example sodium benzoate of antiseptic.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid;
B. at 25 ℃ after following 7 days, the level of the carbidopa of having degraded is less than 0.05%, less than 0.1%, less than 0.2%, less than 0.3%, less than 0.5%, less than 1%, less than 2%, less than 5% or less than 10%; With
C. described carbidopa or levodopa are the form of salt.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid; With
B. wherein, pH is 1 to 10,1 to 8,2 to 8,2 to 6,2 to 4,2.5 to 4.5,2.5 to 4,2.5 to 3.5,3 to 8,3 to 6,3 to 5,3 to 4,1 to 4,1.5 to 3.5,2 to 3 or less than 5, less than 4, less than 3, less than 2.9, less than 2.8, less than 2.7, less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1 or less than 2.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid; With
B. wherein, the concentration of levodopa is greater than 2.5mg/ml, greater than 3mg/ml, greater than 4mg/ml, greater than 5mg/ml, greater than 6mg/ml, greater than 7mg/ml, greater than 8mg/ml or greater than 10g/ml.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid; With
B. wherein, at room temperature (25 ℃) through 12 hours, 24 hours, 36 hours, 48 hours, one the week or one month, the degraded of any active component is less than 10% in the compositions.
In another embodiment, the present composition comprises levodopa, carbidopa and acid:
A. wherein said acid is hydrochloric acid, hydrobromic acid, sulphuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, methanesulfonic acid, ethionic acid, acetic acid, propanoic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmic acid, itaconic acid, glycolic, para-amino benzoic acid, glutamic acid or benzenesulfonic acid; With
B. wherein, through 12 hours, 24 hours, 36 hours, 48 hours, a week or one month, the degraded of any active component was less than 10% in the compositions under 4 ℃.
In one embodiment, preparation comprises 1 to 5mg/ml levodopa, 0.25 to 1.25mg/ml carbidopa, acid and EDTA.In another embodiment, preparation comprises 1 to 5mg/ml levodopa, 0.25 to 1.25mg/ml carbidopa, citric acid and EDTA.In another embodiment, preparation comprises 1 to 5mg/ml levodopa, 0.25 to 1.25mg/ml carbidopa, 3 to 10mg/ml citric acid and EDTA.In a further embodiment, preparation comprises 1 to 5mg/ml levodopa, 0.25 to 1.25mg/ml carbidopa, 3 to 10mg/ml citric acids and at least 0.025 μ g/ml EDTA.
In one embodiment, preparation comprises 2.5 to 5mg/ml levodopa, 0.625 to 1.25mg/ml carbidopa, acid and EDTA.In another embodiment, preparation comprises 2.5 to 5mg/ml levodopa, 0.625 to 1.25mg/ml carbidopa, citric acid and EDTA.In another embodiment, preparation comprises 2.5 to 5mg/ml levodopa, 0.625 to 1.25mg/ml carbidopa, 3 to 10mg/ml citric acid and EDTA.In a further embodiment, preparation comprises 2.5 to 5mg/ml levodopa, 0.625 to 1.25mg/ml carbidopa, 3 to 10mg/ml citric acids and at least 0.025 μ g/ml EDTA.
In one embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, acid and EDTA.In another embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, citric acid and EDTA.In another embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, 3 to 10mg/ml citric acid and EDTA.In a further embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, 3 to 10mg/ml citric acids and at least 0.025 μ g/ml EDTA.
In a further embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, 3 to 10mg/ml citric acids, at least 0.025 μ g/ml EDTA and 0.5 to 7% binding agent.In another embodiment, preparation comprises about 4mg/ml levodopa, about 1mg/ml carbidopa, 3 to 10mg/ml citric acids, at least 0.025 μ g/ml EDTA, 0.5 to 7% binding agent and flavour enhancer.
Can prepare the present composition by different combinations of substances is also mixed together.Material of the present invention is from the commercial channel.Carbidopa can be available from Sigma-Aldrich (2002-2003 Biochemicals and Reagents Catalog, the 368th page).Levodopa can be available from Sigma-Aldrich (2002-2003 Biochemicals and ReagentsCatalog, the 693rd page).The combination of levodopa and carbidopa can be found in the pharmaceutical preparation of listing at present.The method for preparing levodopa and carbidopa is known in the art.Other described material (activating agent and nonactive dose) is from the commercial channel.
The dissolving of the present composition in liquid can be carried out with any known method in this area.In some cases, dissolving is undertaken by mixing, stirring, blending or homogenization.
The dissolving of the present composition can provide significant advantage to the parkinsonian.That the quick dissolving of composition component can help to suffer is stiff, tremble and the patient of stiff situation misery.By the particle size of change compositions with by making some compositions granulation can take place to dissolve faster.In one embodiment, the compositions of levodopa, carbidopa and binding agent has the particle size diameter of about 5 to 20 μ m.The example of applicable binding agent comprises polyvinylpyrrolidone and hydroxypropyl cellulose.In the presence of the liquid in binding agent and some embodiment, compositions has also obtained dissolving faster by granulating.Opposite with dry granulation, wet granulation has caused having the compositions of improved dissolution velocity.
In one embodiment, the present composition has dissolved 3mg/ml levodopa at least in liquid in 5 minutes.In another embodiment, the present composition has dissolved 4mg/ml levodopa at least in liquid in 5 minutes.A kind of suitable liquid is water.
Can pack the present composition with several different methods.The present composition can be packaged in container, structure or the material of independent parcel, multipurpose bottle, multipurpose container or different sizes.
In some embodiments, the present composition is got rid of detergent especially.In other embodiments, the present composition can form the stabilization formulations that only contains levodopa and do not contain the levodopa derivant.In other embodiment, the present composition can form the stabilization formulations that only contains the levodopa derivant and do not contain levodopa.In some embodiments, the present composition comprises two kinds, three kinds or four kinds of different materials and does not need to make up the simple formulations of five kinds or more kinds of materials.In other embodiments, the present composition is without any need for the gelling composition of type.The example of gelling composition is but is not limited to hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or gelatin.
One skilled in the art will appreciate that without departing from the present invention, can make the form described in the application and the various changes of details.To only the present invention be described in more detail now, with reference to appended examples by embodiment.
Embodiment
Embodiment 1: levodopa is in different pH and buffering intensity
Dissolubility in the citrate buffer
Sample preparation
Prepare solution with citric acid and three generations's Trisodium citrate dihydrate.By weighing 19.2g citric acid (FW 192.1), put into the 100mL volumetric flask, with the water dilution of HPLC level, initial preparation 1.0M citric acid solution.Repeat this operation with sodium citrate (FW 294.1), promptly weighing 29.4g sodium citrate is put into the 100mL volumetric flask, is diluted with water to 100mL.A series of 8 20mL scintillation vials of labelling and being prepared as follows then:
Preparation 1.0M pH1.5 (pure citric acid+HCl), 2.5,3.0,3.5,4.0,4.5,5.0,6.0 sample.Carry out the adjustment of these pH with sodium citrate (also being 1.0M), to keep the molar concentration consistent with citrate.2 of preparation molar concentration 0.45 and 0.15M covers solution subsequently from these mother liquid multi-cavity bottles.For 3: 1 buffer were 0.45M, so be 0.15M to 1: 1 buffer.Also the solution that equates with molar concentration is regulated the pH of these solution, with the pH value unanimity after keeping the pH value in each dilution and adding levodopa.Regulate pH with 1N HCl or 1N NaOH as required.
The result
| The sample title | Chemical compound | HPLC concentration | Dilution | Concentration |
| Citrate buffer | Levodopa | mg/ml | Multiple | mg/ml |
| 1.0M pH 1.5 | Levodopa | 0.239 | 75 | 17.93 |
| 1.0M pH 2.5 | Levodopa | 0.619 | 12 | 7.43 |
| 1.0M pH 3.0 | Levodopa | 0.741 | 8 | 5.93 |
| 1.0M pH 3.5 | Levodopa | 0.654 | 8 | 5.23 |
| 1.0M pH 4.0 | Levodopa | 0.93 | 5 | 4.65 |
| 1.0M pH 4.5 | Levodopa | 0.887 | 5 | 4.44 |
| 1.0M pH 5.0 | Levodopa | 0.833 | 5 | 4.17 |
| 1.0M pH 6.0 | Levodopa | 0.773 | 5 | 3.87 |
| 0.45M pH 1.5 | Levodopa | 0.152 | 75 | 11.40 |
| 0.45M pH 2.5 | Levodopa | 0.485 | 12 | 5.82 |
| 0.45M pH 3.0 | Levodopa | 0.606 | 8 | 4.85 |
| 0.45M pH 3.5 | Levodopa | 0.564 | 8 | 4.51 |
| 0.45M pH 4.0 | Levodopa | 0.849 | 5 | 4.25 |
| 0.45M pH 4.5 | Levodopa | 0.85 | 5 | 4.25 |
| 0.45M pH 5.0 | Levodopa | 0.829 | 5 | 4.15 |
| 0.45M pH 6.0 | Levodopa | 0.832 | 5 | 4.16 |
| 0.15M pH 1.5 | Levodopa | 0.096 | 75 | 7.20 |
| 0.15M pH 2.5 | Levodopa | 0.406 | 12 | 4.87 |
| 0.15M pH 3.0 | Levodopa | 0.526 | 8 | 4.21 |
| 0.15M pH 3.5 | Levodopa | 0.488 | 8 | 3.90 |
| 0.15M pH 4.0 | Levodopa | 0.758 | 5 | 3.79 |
| 0.15M pH 4.5 | Levodopa | 0.776 | 5 | 3.88 |
| 0.15M pH 5.0 | Levodopa | 0.776 | 5 | 3.88 |
| 0.15M pH 6.0 | Levodopa | 0.789 | 5 | 3.95 |
Embodiment 2: the stability of levodopa and carbidopa
Sample preparation
1: 3: 0.2 in molar ratio: 1 mixed levodopa/citric acid/carbidopa/sucrose preparation.Concentration with the 5.5mg/ml levodopa is water-soluble with this mixture of powders.Filter this solution by 0.22 micron filter (containing pvdf membrane), preserve down at 4 ℃, 25 ℃ and 40 ℃ then.
Mixed levodopa/ascorbic acid/Lodosyn in 1: 3: 0.25 in molar ratio.Concentration with the 1.0mg/ml levodopa is water-soluble with this mixture of powders.Filter this solution by 0.22 micron filter (containing pvdf membrane), preserve down at 4 ℃, 25 ℃ and 40 ℃ then.
Carry out the HPLC potency test of sample solution at each time point.Change monitoring stability by percent with respect to initial effectiveness.
| The sample title | Chemical compound | At first | The 1st day | The 2nd day | The 3rd day | The 7th day |
| Levodopa/citric acid of 4 ℃ 1/3/0.2/1/carbidopa/sucrose | Levodopa | 100％ | 100％ | 100％ | 100％ | 100％ |
| Carbidopa | 100％ | 100％ | 100％ | 101％ | 100％ | |
| Levodopa/citric acid of 25 ℃ 1/3/0.2/1/carbidopa/sucrose | Levodopa | 100％ | 100％ | 100％ | 100％ | 100％ |
| Carbidopa | 100％ | 98％ | 96％ | 96％ | 91％ | |
| Levodopa/citric acid of 40 ℃ 1/3/0.2/1/carbidopa/sucrose | Levodopa | 100％ | 100％ | 100％ | 100％ | 100％ |
| Carbidopa | 100％ | 91％ | 84％ | 81％ | 75％ | |
| Levodopa/ascorbic acid of 4 ℃ 1/3/0.2/carbidopa | Levodopa | 100％ | 100％ | 100％ | N/A | 102％ |
| Carbidopa | 100％ | 101％ | 101％ | N/A | 101％ | |
| Levodopa/ascorbic acid of 25 ℃ 1/3/0.2/carbidopa | Levodopa | 100％ | 100％ | 100％ | N/A | 102％ |
| Carbidopa | 100％ | 99％ | 97％ | N/A | 87％ | |
| Levodopa/ascorbic acid of 40 ℃ 1/3/0.2/carbidopa | Levodopa | 100％ | 100％ | 101％ | N/A | 104％ |
| Carbidopa | 100％ | 94％ | 88％ | N/A | 88％ |
Embodiment 3: the carbidopa degradation product
The preparation mol ratio is 4: 1: 1 levodopa/carbidopa/citric acid and levodopa/carbidopa/ascorbic acid sample.Sample was preserved 24 hours down at 25 ℃.After 24 hours, use the HPLC analytic sample.Analyze with the Waters Alliance HPLC system that is equipped with 2695 separation assemblies and 2996 PDA detectors.The reversed-phase HPLC method is utilized the Waters Atlantis dC18 post (4.6 * 150mm, 5 μ m) and the bi-component gradient mobile phase of operating down at 30 ℃.Be 30min the flow velocity following running time at 1.0mL/min.With absorbance detection levodopa and the carbidopa impurity and the catabolite at 280nm place, and with they area percent reports with respect to parent peak.Determine that by HPLC/MS a new peak is 3, the 4-dihydroxyphenyl-1-propanone.3,4-dihydroxyphenyl-1-propanone (DHPA) is the carbidopa degradation product.This degradation product also is present in levodopa/carbidopa/orange juice preparation and the levodopa/carbidopa/Ginger Ale preparation.
Embodiment 4: the stability of levodopa and carbidopa
Preparation
Test the carbidopa stability of levodopa, carbidopa and the acid supplement of different pH.4 gram levodopa and 1 gram calories are used various acid and water dissolution with respect to levodopa 3 molar equivalents than DOPA, as shown in the table.Regulate the pH of each solution with 1N HCl or 1N NaOH.Calculate the area % of levodopa area, carbidopa area, % carbidopa residue and DHPA.
Calculate " % carbidopa residue " according to following equation:
Carb
4CIn theory=carb
4C* lev
T/ lev
4C
" % carbidopa residue "=carb
T/ carb
4C* 100 in theory
Wherein, carb
TAnd lev
TRefer to the area value of Carbidopa, lev for described acid, temperature and pH
4CAnd carb
4CIt is 4 ℃ of following levodopa and carbidopa sample area value for pH that is studied and acid.
| Acid | pH | ℃ | The levodopa area | The carbidopa area | % carbidopa residue | The area % of DHPA |
| Acetic acid | 2 | 4 | 2864780 | 556275 | 100.0 | 0 |
| 25 | 2920134 | 562629 | 99.2 | 1.14 | ||
| 40 | 2927442 | 555971 | 97.8 | 2.29 | ||
| 2.4 | 4 | 1255379 | 297891 | 100.0 | 0 | |
| 25 | 3007344 | 589068 | 82.5 | 0.93 | ||
| 40 | 2952343 | 565106 | 80.7 | 3.13 | ||
| 3 | 4 | 2861179 | 596623 | 100.0 | 0 | |
| 25 | 2883225 | 592870 | 98.6 | 1.51 | ||
| 40 | 2573780 | 493081 | 91.9 | 3.92 | ||
| Citric acid | 2 | 4 | 3142973 | 603604 | 100.0 | 0 |
| 25 | 3133573 | 591206 | 98.2 | 1.83 | ||
| 40 | 2960941 | 566867 | 99.7 | 0.75 | ||
| 2.4 | 4 | 3108393 | 597902 | 100.0 | 0 | |
| 25 | 3122562 | 599299 | 99.8 | 0.71 | ||
| 40 | 3181927 | 600710 | 98.1 | 1.73 | ||
| 3 | 4 | 2986595 | 571393 | 100.0 | 0.92 | |
| 25 | 3108402 | 589580 | 99.1 | 1.21 | ||
| 40 | 3111696 | 577629 | 97.0 | 2.85 | ||
| HCl | 2 | 4 | 2956816 | 572525 | 100.0 | 0 |
| 25 | 2943735 | 567786 | 99.6 | 0.84 | ||
| 40 | 3003245 | 568938 | 97.8 | 2.28 | ||
| 2.4 | 4 | 3014797 | 581503 | 100.0 | 0.80 | |
| 25 | 2837880 | 545321 | 99.6 | 1.15 | ||
| 40 | 2947773 | 549080 | 96.6 | 3.30 | ||
| 3 | 4 | 2907279 | 558606 | 100.0 | 0.99 | |
| 25 | 2837293 | 540713 | 99.2 | 1.56 | ||
| 40 | 2818351 | 512352 | 94.6 | 4.96 | ||
| L-(-)-malic acid | 2 | 4 | 3139874 | 604922 | 100.0 | 0.62 |
| 25 | 3091146 | 592188 | 99.4 | 0.90 | ||
| 40 | 3121877 | 587787 | 97.7 | 2.22 | ||
| 2.4 | 4 | 3114444 | 602433 | 100.0 | 0.57 | |
| 25 | 3007871 | 578488 | 99.4 | 0.90 | ||
| 40 | 3049661 | 577045 | 97.8 | 2.21 | ||
| 3 | 4 | 3061962 | 595963 | 100.0 | 0.53 | |
| 25 | 2879955 | 557074 | 99.4 | 0.85 | ||
| 40 | 3121864 | 582676 | 95.9 | 2.22 | ||
| L-(+)-tartaric acid | 2 | 4 | 3137768 | 598319 | 100.0 | 0.53 |
| 25 | 3323491 | 622853 | 98.3 | 1.71 | ||
| 40 | 3037389 | 499461 | 86.2 | 10.22 | ||
| 2.4 | 4 | 3164710 | 598138 | 100.0 | 0.64 | |
| 25 | 3191366 | 589671 | 97.8 | 1.94 | ||
| 40 | 3165751 | 512299 | 85.6 | 11.36 | ||
| 3 | 4 | 3042627 | 573035 | 100.0 | 0.96 | |
| 25 | 2932384 | 537924 | 97.4 | 2.37 | ||
| 40 | 3080403 | 508334 | 87.6 | 9.15 |
| Malonic acid | 2 | 4 | 3198987 | 618183 | 100.0 | 0.44 |
| 25 | 2956945 | 564456 | 98.8 | 0.76 | ||
| 40 | 3091218 | 581615 | 97.4 | 2.16 | ||
| 2.4 | 4 | 2928983 | 561988 | 100.0 | 0.64 | |
| 25 | 3194883 | 609472 | 99.4 | 1.13 | ||
| 40 | 3123140 | 588045 | 98.1 | 2.36 | ||
| 3 | 4 | 3060381 | 585961 | 100.0 | 0.84 | |
| 25 | 3027405 | 573498 | 98.9 | 1.62 | ||
| 40 | 3040114 | 560576 | 96.3 | 3.63 | ||
| H 3PO 4 | 2 | 4 | 3043106 | 580763 | 100.0 | 0.50 |
| 25 | 3121711 | 592491 | 99.5 | 0.76 | ||
| 40 | 2920381 | 546560 | 98.1 | 1.83 | ||
| 2.4 | 4 | 3076836 | 585580 | 100.0 | 0.63 | |
| 25 | 21741837 | 519759 | 99.6 | 0.70 | ||
| 40 | 3042791 | 566757 | 97.9 | 2.06 | ||
| 3 | 4 | 3016323 | 574096 | 100.0 | 0.58 | |
| 25 | 2827873 | 533847 | 99.2 | 0.84 | ||
| 40 | 2828586 | 516553 | 95.9 | 3.27 | ||
| Succinic acid | 2 | 4 | 2967669 | 586937 | 100.0 | 0.77 |
| 25 | 3062470 | 602825 | 99.5 | 1.20 | ||
| 40 | 3107285 | 594742 | 96.8 | 3.19 | ||
| 2.4 | 4 | 2991187 | 592581 | 100.0 | 0.72 | |
| 25 | 2969082 | 584084 | 99.3 | 1.22 | ||
| 40 | 2921618 | 559184 | 96.6 | 3.28 | ||
| 3 | 4 | 2905509 | 621872 | 100.0 | 0.91 | |
| 25 | 3003987 | 603028 | 93.8 | 1.54 | ||
| 40 | 3059716 | 579495 | 88.5 | 4.10 | ||
| Sulphuric acid | 2 | 4 | 2434399 | 491414 | 100.0 | 0.89 |
| 25 | 2163586 | 432313 | 99.0 | 1.14 | ||
| 40 | 2303265 | 444509 | 95.6 | 3.83 | ||
| 2.4 | 4 | 2175680 | 435950 | 100.0 | 1.02 | |
| 25 | 2210814 | 440745 | 99.5 | 1.32 | ||
| 40 | 2324408 | 448587 | 96.3 | 4.14 | ||
| 3 | 4 | 2232850 | 442564 | 100.0 | 1.46 | |
| 25 | 2187525 | 430200 | 99.2 | 2.05 | ||
| 40 | 2303472 | 425755 | 93.3 | 6.98 |
These data show that it is important selecting specific acid in levodopa and carbidopa liquid preparation.The combination of the acid that these are different can create more stable liquid preparation, and this is possible.
Embodiment 5: the ratio of carbidopa and levodopa
Preparation levodopa/citric acid/sucrose sample of 1/3/1, levodopa concentration are 4mg/ml and add carbidopa with the w/w ratio with respect to levodopa 0.5,0.125 and 0.05.Dilute sample is used for the HPLC analysis after preserving 24 hours under 4 ℃, 25 ℃ and 40 ℃.
| With respect to the area %DHPA of carbidopa area, as the function of the ratio of temperature and levodopa/carbidopa | |||
| 0.50w/w carbidopa/levodopa | 0.125w/w carbidopa/levodopa | 0.05w/w carbidopa/levodopa | |
| 4℃ | 0.60 | 0.57 | 0.00 |
| 25℃ | 0.97 | 0.73 | 0.00 |
| 40℃ | 2.45 | 1.76 | 1.51 |
Data show carbidopa to the scale effect of levodopa the stability of carbidopa.
Embodiment 6: the levodopa in the Ginger Ale and the stability of carbidopa
Stability with Ginger Ale test levodopa and Lodosyn.Preparation and the combination of 100ml Ginger Ale with 4mg/ml levodopa and 1mg/ml carbidopa.Preparation was preserved 24 hours down at 4 ℃, 25 ℃ and 40 ℃.After 24 hours, dilute sample, and analyze with HPLC.Keep the HPLC sample room at 5 ℃.Analyze with the Waters Alliance HPLC system that is equipped with 2695 separation assemblies and 2996PDA detector.The reversed-phase HPLC method is utilized the Waters Atlantis dC18 post (4.6 * 150mm, 5 μ m) and the bi-component gradient mobile phase of operating down at 30 ℃.Be 30min the flow velocity following running time at 1.0mL/min.With absorbance detection levodopa and the carbidopa impurity and the catabolite at 280nm place, and with they area percent reports with respect to parent peak.
Ginger Ale has two main peaks at RT=11.2min and 19.3min place, and the λ maximum is respectively 285 and 229.7nm.Following table shown after 24 hours form 3, the amount of 4-dihydroxyphenyl-1-propanone degradation product.Carbidopa is degraded into 3, the 4-dihydroxyphenyl-1-propanone.Therefore, measuring this degradation product is measuring of carbidopa stability.
| Temperature | 4℃ | 25℃ | 40℃ |
| DHPA | 6.3 | 24.4 | 57.6 |
Carbidopa under 25 ℃ and 40 ℃ through the degraded of significant level was arranged in 24 hours.At RT9.77min (is constant at 5 ℃ and 25 ℃) and RT=14.27min place other degradation product is still less arranged.
Embodiment 7: the influence of ionic strength
Mol ratio in the preparation NaCl solution is levodopa/carbidopa/citric acid/sucrose preparation of 1/0.25/3/1, and the concentration of levodopa is 4mg/ml, and the concentration of [NaCl] is 0.00,0.05,0.125,0.250 and 0.5M.Dilute sample after 24 hours is analyzed (as mentioned above) with HPLC.The HPLC sample room maintains 5 ℃.Shown 3, the 4-dihydroxyphenyl-1-propanone as the function of temperature and ionic strength, is represented the stability of carbidopa with respect to the area % of carbidopa area.
| 0M NaCl | 0.05M | 0.125M | 0.25M | 0.5M | |
| 4℃ | 0.53 | 0.64 | 0.54 | 0.61 | 0.50 |
| 25℃ | 0.72 | 0.81 | 0.89 | 0.84 | 0.88 |
| 40℃ | 2.08 | 2.17 | 2.17 | 2.44 | 2.64 |
As if salt has negative effect to carbidopa stability, and this may be because the heavy metal contaminants in the salt.
Embodiment 8:pH is to the influence of stability
Preparation carbidopa and citric acid sample.Sample was preserved 24 hours down at 4 ℃, 25 ℃ and 40 ℃.After 24 hours, dilute sample, and analyze with HPLC.Analyze with the Waters Alliance HPLC system that is equipped with 2695 separation assemblies and 2996 PDA detectors.The reversed-phase HPLC method is utilized the Waters Atlantis dC18 post (4.6 * 150mm, 5 μ m) and the bi-component gradient mobile phase of operating down at 30 ℃.Be 30min the flow velocity following running time at 1.0mL/min.With the absorbance detection carbidopa impurity and the catabolite at 280nm place, and with their area with respect to the report of the area percent of parent peak.
Keep the HPLC sample room at 5 ℃.Shown 3, the 4-dihydroxyphenyl-1-propanone as the function of temperature and pH, is represented the stability of carbidopa with respect to the area % of carbidopa area.
| 4℃ | 25℃ | 40℃ | |
| pH 2.0 | 0.85 | 2.40 | 8.78 |
| pH 2.5 | 0.99 | 3.60 | 11.83 |
| pH 3.0 | 1.25 | 3.92 | 10.60 |
| pH 4.0 | 1.74 | 22.51 | 45.33 |
| pH 5.5 | 7.92 | Free of data | 44.65 |
This result shows that the pH that reduces preparation has strengthened the stability of carbidopa.
Levodopa/carbidopa/citric acid/sucrose the sample of preparation 1/0.25/3/1 in water, the concentration of levodopa is 4.0mg/ml, if necessary, with HCl or NaOH pH regulator to 1.8,2.0,2.2,2.4,2.6,2.8,3.0 and 3.2 with solution.The three equal parts of every kind of solution are transferred in the bottle, preserve down at 4 ℃, 25 ℃ and 40 ℃.Dilute sample after 24 hours is analyzed with HPLC.Shown 3, the 4-dihydroxyphenyl-1-propanone as the function of temperature and pH, is represented the stability of carbidopa with respect to the area % of carbidopa area.
| pH | 4℃ | 25℃ | 40℃ |
| 1.8 | --- | 0.53 | 1.77 |
| 2.0 | Can not detect | 0.53 | 2.02 |
| 2.2 | Can not detect | 0.57 | 1.99 |
| 2.4 | Can not detect | 0.68 | 2.34 |
| 2.6 | Can not detect | 0.82(0.82) | 2.46 |
| 2.8 | Can not detect | ---(1.21) | 2.83 |
| 3.0 | Can not detect | ---(2.02) | 4.62 |
| 3.2 | Can not detect | ---(2.43) | 6.38 |
Embodiment 9: sugar is to the influence of stability
4mg/ml levodopa+1mg/ml carbidopa+3 equivalent citric acid (with respect to levodopa) samples the influence that 24 hour in DHPA form of sugar to preserving down at 4,25 and 40 ℃.The value of being reported is with respect to carbidopa " DHPA area % ".
| 4℃ | 25℃ | 40℃ | |
| Sugar-free | 0 | 0.39 | 1.53 |
| 0.5 | 0 | 0.38 | 1.69 |
| 1.0 | 0 | 0.51 | 1.94 |
| 1.0 | 0 | 0.56 | 2.27 |
| 1.0 | 0 | 0.52 | 2.39 |
Under 4 ℃, there is not detectable degraded.Through after 24 hours, not sacchariferous sample is as broad as long with the sample that contains 0.5% sucrose under RT.But under 40 ℃, not sacchariferous preparation is favourable.Along with the increase of sucrose concentration, the amount of degraded increases.With other aldehydes or ketones also corresponding effects can appear.
Embodiment 10: antiseptic is to the influence of stability
Levodopa/carbidopa/citric acid/sucrose the sample of preparation 1/0.25/3/1 in water, the concentration of levodopa is 5.0mg/ml, and preservative sodium benzoate and potassium sorbate are added in the solution.Each adds antiseptic with maximum acceptable concentration 0.1%.Place solution about 24 hours stability, analyze with HPLC.Analyze with the Waters Alliance HPLC system that is equipped with 2695 separation assemblies and 2996 PDA detectors.The reversed-phase HPLC method is utilized the Waters Atlantis dC18 post (4.6 * 150mm, 5 μ m) and the bi-component gradient mobile phase of operating down at 30 ℃.Be 30min the flow velocity following running time at 1.0mL/min.With absorbance detection levodopa and the carbidopa impurity and the catabolite at 280nm place, and with their area with respect to the report of the area percent of parent peak.
In 25 ℃ potassium sorbate sample, observe the new peak of RT=17.54min.The peak has 321.9 λ maximum.The area % value at peak is 0.04%.When uniting use sodium benzoate and potassium sorbate, also there is the peak of identical size.This peak does not occur in the sample that does not contain any potassium sorbate.Under 40 ℃ through 24 hours after, peak space consuming 0.19%.
The preparation matched group, whether relevant to determine new peak with potassium sorbate itself, or from the interaction between potassium sorbate and levodopa or the carbidopa.First matched group is the potassium sorbate aqueous solution of preserving under 4 ℃, 25 ℃ and 40 ℃ 24 hours.Approximately there is a broad peak at the RT=17.5min place in 4 ℃ of samples, but almost disappears in 25 ℃ of samples, and part occurs again in 40 ℃ sample.Second matched group comprises the sucrose (with respect to citric acid) of 14.5mg/ml citric acid and 1/3 molar equivalent.Under any temperature of being studied, the RT=17.5min peak does not appear in this sample.
Between levodopa or carbidopa and sodium benzoate, there is not observable interaction to take place.When potassium sorbate and levodopa and carbidopa coupling, have at least a new degradation product to form at the RT=17.5min place.
Estimate each antiseptic to 3, the influence of the area % of 4-dihydroxyphenyl-1-propanone degradation product.In 4 ℃ of samples, do not exist detectable 3, the 4-dihydroxyphenyl-1-propanone.At 25 ℃, sodium benzoate is to 3, and influence is not to there being a little negative effect (0.71% have with 0.88% do not have) for the area % of 4-dihydroxyphenyl-1-propanone, and in comprising the sample of potassium sorbate, the size of degradation product but doubles.Keep tendency at 40 ℃, not containing antiseptic is 2.69 area %, and sodium benzoate is 2.89%, and potassium sorbate has caused 10.7% carbidopa to be transformed into 3, the 4-dihydroxyphenyl-1-propanone.
Therefore, with respect to not containing antiseptic or comprising the solution of sodium benzoate, potassium sorbate has increased by 3, the formation ratio of 4-dihydroxyphenyl-1-propanone.
Embodiment 11: the influence of citric acid concentration
Analyzed citric acid content and levodopa HCl salt pair carbidopa is degraded into 3, the influence of the ratio of 4-dihydroxyphenyl-1-propanone.The sample of preparation 4mg/ml levodopa HCl salt or levodopa free form, 1mg/ml carbidopa and 4mg/ml sucrose.As listed in detail in the following table, add 0 to 3 normal citric acid (with respect to levodopa).By watching 3, the influence of citric acid concentration to 24 hours stability of carbidopa analyzed in the formation of 4-dihydroxyphenyl-1-propanone.Following table has been listed DHPA area %.
| Citric acid concentration is to containing the influence of levodopa HCl sample | |||
| The equivalent of citric acid | 4℃ | 25℃ | 40 |
| 0 | 0 | 1.08 | 5.95 |
| 0.5 | 0 | 0.74 | 3.95 |
| 1 | 0 | 0.6 | 3.87 |
| 2 | 0 | 0.8 | 3.59 |
| Citric acid concentration is to containing the influence of levodopa sample | |||
| The equivalent of citric acid | 4℃ | 25℃ | 40 |
| 0 | 1.32 | 12.8 | 24.1 |
| 0.5 | 0.41 | 1.01 | 3.89 |
| 1 | 0.24 | 0.75 | 2.82 |
| 2 | 0.23 | 0.84 | 2.45 |
| 3 | 0.3 | 0.75 | 2.26 |
Free form with levodopa repeats above process, and preparation does not contain sucrose.
| Citric acid concentration is to the influence of 24 hours stability of the levodopa/carbidopa of 1/0.25 weight ratio: formed DHPA area % | |||
| The equivalent of citric acid | 4℃ | 25℃ | 40 |
| 1 | 0.32 | 0.64 | 2.0 |
| 1.3 | 0.2 | 0.57 | 1 |
| 1.6 | 0.2 | 0.53 | 2.0 |
| 2 | 0.28 | 0.52 | 1.0 |
This digital proof increases citric acid concentration and causes carbidopa stability to increase.In addition, the HCl salt of levodopa has increased carbidopa stability.
Develop an analytical method and tested hydrazine solution.Test does not contain a series of solution of hydrazine.Have linear correlation between the amount of following column data and figure demonstration UV absorption and hydrazine, this amount is represented between 0.27ppm and 13.5ppm with ppm.
| The hydrazine of representing with ppm | UV absorbs |
| 13.5 | 0.32 |
| 2.7 | 0.063 |
| 1.35 | 0.033 |
| 0.27 | 0.007 |
When analyzing the 0.10ml sample, this hydrazine analytical plan has the detectability of the hydrazine of 0.27ppm level.The size that increases sample is to 0.50ml, to reduce lower quantitative limit to being lower than 0.10ppm.More the detectability of large sample volume is 0.05ppm.Following data show the linear dependence between UV absorption and the tested sample liquor capacity.
| Dependency between UV absorption and the tested liquor capacity | ||||
| The hydrazine standard solution | 0.27 ppm | 0.27 ppm | 0.05 ppm | 0.05 ppm |
| The sample solution volume | 0.1ml | 0.2ml | 0.5 ml | 1.0ml |
| | 0.006 | 0.011 | 0.006 | 0.011 |
| | 0.006 | 0.011 | 0.006 | 0.011 |
| | 0.005 | 0.011 | 0.006 | 0.011 |
Think that carbidopa is the source that hydrazine forms in the levodopa/carbidopa formulation soln.Thinking that DHPA is the main degradation product of carbidopa in the acid solution, is the co-product that hydrazine forms.Can detect DHPA by the HPLC analysis.Following data show, between the amount of DHPA% and the hydrazine represented with ppm good dependency are arranged.
| TPI is main preparation | Attach ratios | |
| ％DHPA | Hydrazine (ppm) | The ppm of %DHPA/ hydrazine |
| 0.5 | 0.433 | 1.154 |
| 0.8 | 0.788 | 1.016 |
| 0.95 | 0.906 | 1.049 |
| 1.7 | 1.457 | 1.167 |
With HPLC test and hydrazine testing experiment several levodopa/carbidopa formulation solns.
| Under 25 ℃ through 24 hours levodopa/carbidopa formulation soln | ％DHPA | The hydrazine of representing with ppm |
| Sinemet/ascorbic acid solution | 0.40 | 0.33 |
| The levodopa/carbidopa solution of 4: 1 ratios | 0.51 | 0.41 |
| Levodopa/carbidopa solution+the cystine of 4: 1 ratios | 0.28 | |
| Levodopa/carbidopa solution+the methionine of 4: 1 ratios | 0.31 | |
| Levodopa/carbidopa solution+methionine+the deferoxamine of 4: 1 ratios | 0.15 | |
| Levodopa/carbidopa solution+cystine+the EDTA of 4: 1 ratios | 0.00 | 0.00 |
| Levodopa/carbidopa solution+cystine+the deferoxamine of 4: 1 ratios | 0.00 | 0.00 |
| Levodopa/carbidopa solution+methionine+the EDTA of 4: 1 ratios | 0.00 | 0.00 |
Digital proof, thioether and intercalating agent can be used for reducing the hydrazine that levodopa and Lodosyn exist.
Embodiment 13
Compare the practice that does not have trade mark that TPI-926 preparation and parkinsonian prepare liquid levodopa and carbidopa beverage at present.TPI-926 comprises:
The 4mg/ml levodopa
The 1mg/ml carbidopa
7.8mg/ml citric acid
0.1mg/ml Na EDTA
0.5mg/ml aspartame
The cumulative volume of TPI-926 is a 100ml water., and it is mixed preparation 1mg/ml levodopa and the liquid preparation of 0.25mg/ml carbidopa in orange juice and Ginger Ale by grinding 1 tablet of levodopa/carbidopa tablet (100: 25) with 100ml orange juice or Ginger Ale., and it is mixed preparation levodopa, carbidopa and ascorbic acid preparation by grinding 1 tablet of levodopa/carbidopa tablet (100: 25) with 100ml water and 2mg/ml ascorbic acid.
Sample was placed 24 hours, 3 days and 7 days down at 4 and 25 ℃.With hydrazine in the HPLC analytic sample and DHPA content.DHPA is the catabolite of carbidopa.Therefore, DHPA is 1: 1 ratio with respect to the carbidopa of degrading.The DHPA of 1% level is relevant with the carbidopa degraded of 1% level in the expection sample.
By with the amount of the hydrazine of maximum length in time sample or DHPA divided by natural law, calculate the concentration of every day.
4 ℃ hydrazine (mcg/ sample)
| The 1st day | The 3rd day | The 7th day | Every day | |
| ‘926 | ＜1.5 | ＜1.5 | 1.5 | 0.2 |
| The aqueous solution of ascorbic acid | ＜6.0 | ＜6.0 | 6.2 | 0.9 |
| Orange juice | 7.3 | 10.1 | n.m. | |
| Ginger Ale | 21.2 | 121.5 | n.m. | 40.5 |
25 ℃ hydrazine (mcg/ sample)
| The 1st day | The 3rd day | The 7th day | Every day | |
| ‘926 | ＜1.5 | 2.6 | 5.6 | 0.8 |
| The aqueous solution of ascorbic acid | 7.3 | 32.5 | 160.3 | 23 |
| Orange juice | 24.1 | 37.1 | n.m. | |
| Ginger Ale | 253 | 765 | n.m. | 255 |
25 ℃ DHPA (mcg/ sample)
| The 1st day | The 3rd day | The 7th day | Every day | |
| ‘926 | ＜25.0 | ＜25.0 | 25.6 | 3.7 |
| The aqueous solution of ascorbic acid | 81 | 346 | 1704 | 238 |
| Orange juice | ||||
| Ginger Ale | 3210 | 9038 | 3013 |
This digital proof is under 4 and 25 ℃, and TPI-926 prevents or reduced the formation of hydrazine.
Calculate the percent of carbidopa loss.Total mcg of DHPA is changed into the mcg of carbidopa.
TPI-926
100ml TPI-926 produces 3.7mcg DHPA every day.Because DHPA and carbidopa molar equivalent equate that this is consistent with 5mcg carbidopa degraded every day.A slice sinemet comprises 25, the 000mcg carbidopa.Therefore, for every 250mg, TPI-926 has the degradation rate of carbidopa every day 0.02%.
The aqueous solution of levodopa/carbidopa and ascorbic acid
100ml ascorbic acid sample produces 238mcg DHPA every day.Because DHPA and carbidopa molar equivalent equate that this is consistent with 323mcg carbidopa degraded every day.A slice sinemet comprises 25, the 000mcg carbidopa.Therefore, for every 250mg dosage, ascorbic acid has the degradation rate of carbidopa every day 1.2%.
The orange juice solution of levodopa/carbidopa
100ml orange juice sample produces 3013mcg DHPA every day.Because DHPA and carbidopa molar equivalent equate that this is consistent with 4083mcg carbidopa degraded every day.A slice sinemet comprises 25, the 000mcg carbidopa.Therefore, for every 250mg, this orange juice sample has the degradation rate of carbidopa every day 16.3%.
The test levodopa is a dissolubility in the ascorbic acid solution of 3.5mg/ml in ascorbic acid concentrations.By the 70.0mg ascorbic acid being added in the 20ml water ascorbic acid sample of preparation 3.5mg/ml.Then, under RT, stirred 24 hours, 80.0mg levodopa powder is dissolved in the ascorbic acid sample of 3.5mg/ml.The levodopa concentration of plan is 4mg/ml.Sample filters by 0.22 μ m PVDF filter, removes undissolved levodopa.10 times of dilute with waters are analyzed filtrate with HPLC.The HPLC data show that the concentration of levodopa is 2.0mg/ml in the filtrate.Therefore, the maxima solubility of levodopa in the 3.5mg/ml ascorbic acid solution is 2mg/ml.
Embodiment 15
Levodopa and Lodosyn have been prepared with low-level metal ion content.
Preparation is:
Levodopa 4mg/ml
Carbidopa 1mg/ml
Hydrochloric acid 0.02N
Dehydration EDTA-Na 0.11mg/ml
Glucide 0.5mg/ml
Sodium benzoate 0.10mg/ml
Deionized water adds to 1ml
Utilization is equipped with cation and is removed the purification that the deionization process of filter cylinder (available from the HoseNipple Cartridge D8905 of Barnstead International) carries out water.All components all are dissolved in after the pure water, with the Chelex-100 step of dialysing.With the pH regulator of solution to 2.0-2.3.Measure the carbidopa Degradation Level of said preparation.In 0 moment, 0.125% carbidopa has been degraded.After (25 ℃) following two weeks, 0.196% carbidopa has been degraded in room temperature.After at room temperature one month, 0.233% carbidopa has been degraded.After 40 ℃ of following two weeks, 0.618% carbidopa has been degraded.After 40 ℃ of next months, 1.276% carbidopa has been degraded.
Tested the dissolved speed of preparation.The levodopa of buying has the mean diameter of 76 μ m, and wherein 50% granule is less than 67 μ m, and 90% granule is less than 146 μ m, and 100% granule is less than 364 μ m.The solid preparation that uses is:
Levodopa 100mg
Carbidopa 27mg
Citric acid monohydrate compound 213mg
Dehydration EDTA-NA 2.75mg
Aspartame 12.5mg
Sodium benzoate 2.5mg
Levodopa has above-mentioned granulometric range, is not dissolved in the deionized water fully with interior levodopa at 24 hours.The method of mix preparation component is jolting.
Use identical preparation, only described levodopa is replaced by the levodopa of mean diameter 5.5 μ m, and wherein, 50% granule is less than 5.11 μ m, and 90% granule is less than 10.4 μ m, and 100% granule is less than 19.4 μ m (II particle diameter batch).Another preparation of test mean diameter 17.3 μ m, wherein, 50% granule is less than 13.95 μ m, and 90% granule is less than 37 μ m, and 100% granule is less than 78 μ m (I6 particle diameter batch).By manual water grinding I9 batch is granulated.Said preparation is dissolving fully in 1 hour.As follows, add polyvinylpyrrolidone and ethanol and also improved dissolving.
| Expt.ID | The TPI-926 grinding and cutting | Binding agent | The adding method | Liquid | The adding of citric acid | The 90%TPI-926 dissolving | Dissolving fully | |
| 1 | I1 | - | - | Water | Granule | ＜1 minute | ＞1hr *( *Significantly＜1hr) | |
| 4 | | PVP | 5% solid | Ethanol | Granule | ＜1 minute | ～10 | |
| 3 | | PvP | 5% solid | Ethanol | Blended w/ granule | ＜1 minute | ～5 minutes | |
| A | | PVP | 5% solid | Ethanol | Blended w/ granule | ＜1 minute | ～5 minutes | |
| | I6 | PVP | 5% solid | Ethanol | Blended w/ granule | ＜4 minutes | ＞1hr *( *Significantly～10 minute) | |
| | I1 | PVP | 10% solid | Ethanol | Blended w/ granule | ＜1 minute | ～5 minutes |
Particle diameter between 7 to 13 μ m demonstrates fast dissolving.For example polyvinylpyrrolidone or hydroxypropyl cellulose have increased dissolution velocity to add binding agent.
Claims (122)
1. comprise the pharmaceutical composition of levodopa, carbidopa and acid, the metal concentration of wherein said compositions is less than 1ppm.
2. the pharmaceutical composition that comprises levodopa, carbidopa, acid and metal-chelate mixture.
3. the compositions of claim 2, wherein said metal-chelate mixture is selected from down group:
EDTA; With
Deferoxamine mesylate.
4. the compositions of claim 3, wherein said EDTA is the form of the salt of free alkali.
5. the compositions of claim 3, the concentration of wherein said EDTA are 0.01mg/ml at least.
6. the compositions of claim 1, wherein said acid is selected from carboxylic acid, mineral acid, citric acid, tartaric acid, ascorbic acid, hydroascorbic acid, acetic acid, formic acid, formic acid, butanoic acid, acetic acid, benzoic acid, butanoic acid, malic acid, propanoic acid, Epoxysuccinic acid, muconic acid, furylacrylic acid, citramalic acid, capric acid, stearic acid, caproic acid, malonic acid, succinic acid, diethacetic acid, methylbutanoic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulphuric acid.
7. the compositions of claim 1, wherein said acid is not ascorbic acid.
8. the compositions of claim 1, wherein said compositions does not contain sugar.
9. the compositions of claim 1, wherein said compositions is a liquid.
10. the compositions of claim 9, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 10%.
11. the compositions of claim 9, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 5%.
12. the compositions of claim 9, wherein at 25 ℃ after following 30 days, the described carbidopa degraded less than 10%.
13. the compositions of claim 9, wherein at 25 ℃ after following 4 days, the described carbidopa degraded less than 5%.
14. the compositions of claim 9, wherein at 4 ℃ after following 30 days, the described carbidopa degraded less than 5%.
15. the compositions of claim 9, wherein at 25 ℃ after following 250 days, the described carbidopa degraded less than 5%.
16. the compositions of claim 9, wherein at 4 ℃ after following 360 days, the described carbidopa degraded less than 5%.
17. the compositions of claim 9, wherein at 25 ℃ after following 9 days, the described carbidopa degraded less than 10%.
18. the compositions of claim 1 also comprises artificial sweetener.
19. the compositions of claim 1, wherein said artificial sweetener is an aspartame.
20. the compositions of claim 1 also comprises antiseptic.
21. the compositions of claim 1, wherein said antiseptic is a sodium benzoate.
22. comprise the pharmaceutical composition of levodopa, carbidopa and acid, the pH of wherein said compositions less than or approximately be 3.0.
23. the compositions of claim 22, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 10%.
24. the compositions of claim 22, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 5%.
25. the compositions of claim 22, wherein at 25 ℃ after following 30 days, the described carbidopa degraded less than 10%.
26. the compositions of claim 22, wherein at 25 ℃ after following 4 days, the described carbidopa degraded less than 5%.
27. the compositions of claim 22, wherein at 4 ℃ after following 30 days, the described carbidopa degraded less than 5%.
28. the compositions of claim 22, wherein at 25 ℃ after following 250 days, the described carbidopa degraded less than 5%.
29. the compositions of claim 22, wherein at 4 ℃ after following 360 days, the described carbidopa degraded less than 5%.
30. the compositions of claim 22, wherein at 25 ℃ after following 9 days, the described carbidopa degraded less than 10%.
31. the compositions of claim 22 also comprises artificial sweetener.
32. the compositions of claim 22, wherein said artificial sweetener is an aspartame.
33. the compositions of claim 22 also comprises antiseptic.
34. the compositions of claim 22, wherein said antiseptic is a sodium benzoate.
35. the waterborne compositions of levodopa and carbidopa, the concentration of wherein said levodopa is 2.5mg/ml to 5mg/ml.
36. the compositions of claim 35, the concentration of wherein said levodopa are about 4mg/ml.
37. the compositions of claim 35, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 10%.
38. the compositions of claim 35, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 5%.
39. the compositions of claim 35, wherein at 25 ℃ after following 30 days, the described carbidopa degraded less than 10%.
40. the compositions of claim 35, wherein at 25 ℃ after following 4 days, the described carbidopa degraded less than 5%.
41. the compositions of claim 35, wherein at 4 ℃ after following 30 days, the described carbidopa degraded less than 5%.
42. the compositions of claim 35, wherein at 25 ℃ after following 250 days, the described carbidopa degraded less than 5%.
43. the compositions of claim 35, wherein at 4 ℃ after following 360 days, the described carbidopa degraded less than 5%.
44. the compositions of claim 35, wherein at 25 ℃ after following 9 days, the described carbidopa degraded less than 10%.
45. the compositions of claim 35 also comprises artificial sweetener.
46. the compositions of claim 35, wherein said artificial sweetener is an aspartame.
47. the compositions of claim 35 also comprises antiseptic.
48. the compositions of claim 35, wherein said antiseptic is a sodium benzoate.
49. the compositions of levodopa, carbidopa, acid and metal-chelate mixture, wherein at 25 ℃ after following 24 hours, the described carbidopa degraded less than 1.2%.
50. the compositions of claim 49, wherein said metal-chelate mixture is selected from down group:
EDTA; With
Deferoxamine mesylate.
51. the compositions of claim 50, wherein said metal-chelate mixture is EDTA.
52. the compositions of levodopa, carbidopa, acid and metal-chelate mixture, wherein at 25 ℃ after following 48 hours, the described carbidopa degraded less than 2.4%.
53. the compositions of claim 52, wherein said metal-chelate mixture is selected from down group:
EDTA; With
Deferoxamine mesylate.
54. the compositions of claim 53, wherein said metal-chelate mixture is EDTA.
55. comprise the composition of liquid medicine of about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein at 25 ℃ after following 24 hours, the level of hydrazine is lower than 0.07 μ g/ml.
56. comprise the composition of liquid medicine of about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein at 25 ℃ after following 3 days, the level of hydrazine is lower than 0.32 μ g/ml.
57. comprise the composition of liquid medicine of about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein at 25 ℃ after following 7 days, the level of hydrazine is lower than 1.6 μ g/ml.
58. comprise the composition of liquid medicine of about 0.4 to 1.5mg/ml levodopa and carbidopa, wherein at 4 ℃ after following 7 days, the level of hydrazine is lower than 0.06 μ g/ml.
59. the liquid preparation of levodopa, carbidopa, acid and metal-chelate mixture, wherein said solution are clarifying or translucent.
60. comprise the pharmaceutical composition of levodopa, carbidopa, acid and sulfide compound.
61. the compositions of claim 60, wherein said thioether is used for stablizing carbidopa.
62. the compositions of claim 60, wherein said thioether is selected from following material:
Methionine;
Cysteine;
Glutathion;
Thioglycerol;
Sodium thiosulfate; With
Just-acetyl methionine.
63. the compositions of claim 60 also comprises the metal-chelate mixture.
64. the compositions of claim 63, wherein said metal-chelate mixture is EDTA.
65. a pharmaceutical composition, it comprises:
About 2.5 to 6mg/ml levodopa;
About 0.625 to 1.5mg/ml carbidopa;
About 5mg/ml to 10mg/ml citric acid; With
Greater than about 0.25mg/ml EDTA.
66. the compositions of claim 65 also comprises about 0.1mg/ml to about 1mg/ml aspartame.
67. the compositions of claim 65 also comprises about 0.01mg/ml to about 1mg/ml sodium benzoate.
68. a pharmaceutical composition, it comprises:
About 2.5 to 6mg/ml levodopa;
About 0.25 to 0.6mg/ml carbidopa;
About 5mg/ml to 10mg/ml citric acid; With
Greater than about 0.25mg/ml EDTA.
69. the compositions of claim 68, it also comprises water.
70. the compositions of claim 68, it also comprises about 0.1mg/ml to about 1mg/ml aspartame.
71. the compositions of claim 68, it also comprises about 0.01mg/ml to about 1mg/ml sodium benzoate.
72. a pharmaceutical composition, it comprises:
About 500mg is to about 1500mg levodopa;
About 125mg is to about 375mg carbidopa;
About 1065mg is to about 3195mg citric acid; With
About 13mg is to about 41mg EDTA.
73. the compositions of claim 72, wherein said compositions is the form of dispersible tablet.
74. the compositions of claim 72, wherein said compositions are the form that is used for the powder or the granule of liquid mixing.
75. a pharmaceutical composition, it comprises:
About 1000mg levodopa;
About 250mg carbidopa;
About 2130mg citric acid; With
About 27mg EDTA.
76. the compositions of claim 75, it also comprises water.
77. the compositions of claim 75, wherein said compositions is the form of dispersible tablet.
78. the compositions of claim 75, wherein said compositions are the form that is used for the powder or the granule of liquid mixing.
79. the compositions of claim 75, it also comprises about 125mg aspartame.
80. the compositions of claim 75, it also comprises about 25mg sodium benzoate.
81. the pharmaceutical composition of levodopa, carbidopa, acid, metal-chelate mixture and sugar, wherein said sugar account for compositions less than 1%.
82. give the method for levodopa and carbidopa, it comprises the steps:
A. drying or the solid preparation with levodopa and carbidopa adds in the liquid;
B. mix preparation is below 10 minutes; With
C. the patient is used about 100mg levodopa.
83. the method for claim 82, the administration of wherein said levodopa are dosage in first in morning.
84. can dissolve the liquid preparation of about 2.5 to 6mg/ml levodopa and about 0.25 to 0.6mg/ml carbidopa.
85. the compositions of claim 84, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 10%.
86. the compositions of claim 84, wherein at 25 ℃ after following 7 days, the described carbidopa degraded less than 5%.
87. the compositions of claim 84, wherein at 25 ℃ after following 30 days, the described carbidopa degraded less than 10%.
88. the compositions of claim 84, wherein at 25 ℃ after following 4 days, the described carbidopa degraded less than 5%.
89. the compositions of claim 84, wherein at 4 ℃ after following 30 days, the described carbidopa degraded less than 5%.
90. the compositions of claim 84, wherein at 25 ℃ after following 250 days, the described carbidopa degraded less than 5%.
91. the compositions of claim 84, wherein at 4 ℃ after following 360 days, the described carbidopa degraded less than 5%.
92. the compositions of claim 84, wherein at 25 ℃ after following 9 days, the described carbidopa degraded less than 10%.
93. the method for the pharmaceutical composition of preparation treatment dopamine obstacle, this method comprises levodopa, carbidopa, acid, metal-chelate mixture; And the blended step of water.
94. the method for claim 93, the concentration of wherein said levodopa is 2.5mg/ml to 6mg/ml.
95. the method for claim 93, wherein said metal-chelate mixture is EDTA.
96. the method for claim 95, the concentration of wherein said EDTA is greater than 0.25mg/ml.
97. the method for claim 93, wherein said water is tap water.
98. treatment patient's method, it comprises the compositions of using claim 1.
99. treatment patient's method, it comprises the compositions of using claim 22.
100. treatment patient's method, it comprises the compositions of using claim 35.
101. treatment patient's method, it comprises the compositions of using claim 68.
102. the application of the compositions of levodopa, carbidopa, acid and metal-chelate mixture in the medicine of the means of preparation conduct treatment dopamine obstacle.
103. about 500mg is to the extremely application of compositions in the medicine of the means of preparation conduct treatment dopamine obstacle of about 375mg carbidopa, acid and metal-chelate mixture of about 1500mg levodopa, about 125mg.
104. about 500mg is to the extremely application of compositions in the medicine of the means of preparation conduct treatment dopamine obstacle of about 375mg carbidopa, citric acid and EDTA of about 1500mg levodopa, about 125mg.
105. comprise the fluid composition of levodopa and carbidopa, wherein concentration of metal ions is less than 1ppm.
106. the compositions of claim 105, wherein said compositions also comprises acid.
107. the compositions of claim 105, wherein said metal ion is a free metal ion.
108. the compositions of claim 106, wherein said acid are not citric acids.
109. the compositions of claim 105, wherein said concentration of metal ions is less than 0.1ppm.
110. prepare the method for levodopa and Lodosyn, wherein one or more excipient or the activating agent with compositions carries out chromatography to remove metal ion.
111. the method for claim 109, wherein said metal ion are ferrum, lead, zinc or aluminum.
112. the method for claim 110, wherein said method also comprises dialysis liquid.
113. the compositions of levodopa, carbidopa and binding agent, wherein the particle diameter of compositions has about 5 to 20 μ m diameters.
114. the compositions of claim 113, wherein said binding agent is selected from polyvinylpyrrolidone and hydroxypropyl cellulose.
115. the compositions of claim 113, wherein the compositions of one or more components of compositions prepares by granulation.
116. the compositions of claim 115, wherein said granulation is a wet granulation.
117. the method for compositions of preparation levodopa, carbidopa, acid and binding agent, it comprises independent component mixing and the step of granulating with liquid.
118. the method for claim 117, wherein said binding agent account for 3 to 10% of compositions by weight.
119. the compositions of levodopa, carbidopa, acid and binding agent, it has dissolved the levodopa of 3mg/ml at least in liquid in 5 minutes.
120. the compositions of claim 119, wherein said liquid is water.
121. the compositions of levodopa, carbidopa, acid and binding agent, it has dissolved the levodopa of 4mg/ml at least in liquid in 5 minutes.
122. the compositions of claim 121, wherein said liquid is water.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US49925603P | 2003-08-29 | 2003-08-29 | |
| US60/499,256 | 2003-08-29 | ||
| US50555103P | 2003-09-24 | 2003-09-24 | |
| US60/505,551 | 2003-09-24 | ||
| US55986404P | 2004-04-06 | 2004-04-06 | |
| US60/559,864 | 2004-04-06 | ||
| US58644204P | 2004-07-08 | 2004-07-08 | |
| US60/586,442 | 2004-07-08 | ||
| PCT/US2004/027607 WO2005023185A2 (en) | 2003-08-29 | 2004-08-26 | Pharmaceutical compositions and method of using levodopa and carbidopa |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1845728A true CN1845728A (en) | 2006-10-11 |
| CN1845728B CN1845728B (en) | 2013-06-19 |
Family
ID=37064581
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| Application Number | Title | Priority Date | Filing Date |
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| CN200480024879.8A Expired - Fee Related CN1845728B (en) | 2003-08-29 | 2004-08-26 | Pharmaceutical compositions and method of using levodopa and carbidopa |
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| Country | Link |
|---|---|
| CN (1) | CN1845728B (en) |
| ES (1) | ES2360759T3 (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106413754A (en) * | 2014-03-13 | 2017-02-15 | 纽罗德姆有限公司 | Dopa decarboxylase inhibitor compositions |
| CN107072973A (en) * | 2014-09-04 | 2017-08-18 | 劳波索尔制药有限公司 | Pharmaceutical composition and its application process containing levodopa, dopamine decarboxylase enzyme inhibitor and COMT inhibitor |
| CN110753538A (en) * | 2017-06-05 | 2020-02-04 | 迪兹林制药公司 | Levodopa infusion solutions |
| CN111362980A (en) * | 2014-10-21 | 2020-07-03 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN113396897A (en) * | 2021-07-26 | 2021-09-17 | 苏州华测生物技术有限公司 | Method for stabilizing carbidopa/levodopa in biological matrix |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4771073A (en) * | 1985-12-30 | 1988-09-13 | Merck & Co., Inc. | Rectally absorbable form of L-dopa |
| DE4101873C2 (en) * | 1991-01-23 | 1993-12-09 | Isis Pharma Gmbh | Orally administrable drug form for the treatment of central dopamine deficiency states |
-
2004
- 2004-08-26 CN CN200480024879.8A patent/CN1845728B/en not_active Expired - Fee Related
- 2004-08-26 ES ES04782161T patent/ES2360759T3/en active Active
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106413754A (en) * | 2014-03-13 | 2017-02-15 | 纽罗德姆有限公司 | Dopa decarboxylase inhibitor compositions |
| CN106413754B (en) * | 2014-03-13 | 2019-11-29 | 纽罗德姆有限公司 | Dopa decarboxylase inhibitor composition |
| CN107072973A (en) * | 2014-09-04 | 2017-08-18 | 劳波索尔制药有限公司 | Pharmaceutical composition and its application process containing levodopa, dopamine decarboxylase enzyme inhibitor and COMT inhibitor |
| US11413262B2 (en) | 2014-09-04 | 2022-08-16 | Intrance International Ab | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof |
| US10786472B2 (en) | 2014-09-04 | 2020-09-29 | Lobsor Pharmaceuticals Aktiebolag | Pharmaceutical compositions comprising levodopa, a dopamine decarboxylase inhibitor and a COMT inhibitor and method of administration thereof |
| CN111494395A (en) * | 2014-10-21 | 2020-08-07 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN111454290A (en) * | 2014-10-21 | 2020-07-28 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN111362980A (en) * | 2014-10-21 | 2020-07-03 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN111362980B (en) * | 2014-10-21 | 2022-10-18 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN111454290B (en) * | 2014-10-21 | 2022-12-23 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN111494395B (en) * | 2014-10-21 | 2024-06-21 | 艾伯维公司 | Carbidopa and levodopa prodrugs and their use for treating parkinson's disease |
| CN110753538A (en) * | 2017-06-05 | 2020-02-04 | 迪兹林制药公司 | Levodopa infusion solutions |
| US11633353B2 (en) | 2017-06-05 | 2023-04-25 | Dizlin Pharmaceuticals Ab | Levodopa infusion solution |
| CN113396897A (en) * | 2021-07-26 | 2021-09-17 | 苏州华测生物技术有限公司 | Method for stabilizing carbidopa/levodopa in biological matrix |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1845728B (en) | 2013-06-19 |
| ES2360759T3 (en) | 2011-06-08 |
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