CN1845728B - Pharmaceutical compositions and method of using levodopa and carbidopa - Google Patents

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

Pharmaceutical composition comprising levodopa and carbidopa

related application

This application claims priority from the following applications: U.S. Application No. 60/499,256, filed August 29, 2003, U.S. Provisional Application No. 60/505,551, filed September 24, 2003, and U.S. Provisional Application No. 60/505,551, filed April 6, 2004 US Provisional Application No. 60/559,864, and US Provisional Application No. 60/586,442, filed July 8, 2004. the

field of invention

The present invention relates to stable compositions of levodopa and carbidopa. the

Background of the invention

Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic pathways in the brain. People with Parkinson's disease often have slowed movements, stiffness, tremors, poor balance, and difficulty walking. For people with Parkinson's disease, simple activities such as making breakfast or making coffee can be very difficult. In particular, handling small items such as pills can be very difficult. One of the most common treatments for Parkinson's disease is the administration of levodopa. Levodopa crosses the blood-brain barrier and is converted into dopamine, replacing or supplementing low levels of dopamine in the brain. Patients with Parkinson's disease typically take 200 mg to 2 g of levodopa per day, with patients with advanced Parkinson's disease taking doses at the lower end of this range. Levodopa monotherapy is often associated with unpleasant side effects such as nausea and vomiting. The combined administration of levodopa and a dopa decarboxylase inhibitor, such as carbidopa, reduces side effects for patients while enhancing drug efficacy. One of the disadvantages of levodopa/carbidopa tablets is that people with Parkinson's disease often experience "wading off" episodes. During these events, the patient becomes rigid or rigid in movement. This stiffness has very detrimental consequences on the quality of life of Parkinson's patients. Patients often administer levodopa/carbidopa tablets sublingually to recover from catalepsy. Administration of the drug sublingually to the patient will generally not relieve the patient from the rigors for 1 hour. Controlled-release tablets of levodopa/carbidopa (trademark, "Sinemet CR") were also given to patients. Xining controlled-release tablets did not bring better clinical effects. As a result, patients taking Sinine extended-release tablets will still experience "winding down" and stiffness. One of the methods that patients have used to avoid or treat these "winding down" conditions is to manufacture liquid formulations of levodopa/carbidopa. A stable liquid formulation of levodopa/carbidopa does not exist. Unstable levodopa/carbidopa liquid suspension is already a home remedy for people with Parkinson's disease. When patients feel their levodopa levels drop, they take a sip of the unstable levodopa/carbidopa liquid suspension. Thus, patients self-administer their levodopa concentrations and manage their Parkinson's disease symptoms. Methods for the manufacture of unstable liquid formulations of levodopa/carbidopa have been provided in the literature. Typically, the patient pulverizes the levodopa/carbidopa pill and adds a liquid such as orange juice or ginger ale. One of the disadvantages of this method is the grinding process. Patients who enter a "tapering off" state have great difficulty grinding the pills. During the waning state, the strength and finger work necessary to grind the pills is missing or insufficient. Additionally, such unapproved mixing can result in incomplete bioavailability or poor stability of levodopa or carbidopa. Carbidopa and levodopa are unstable compounds in liquid for a long time, and there is no stable liquid preparation of carbidopa and levodopa at present. Therefore, there is a need for safer, more stable liquid formulations of carbidopa and levodopa that are easier to use than existing suspensions. the

Summary of the invention

Surprisingly, it has been found that new stable formulations of carbidopa and levodopa are available which can be easily combined with liquids for the treatment of patients with Parkinson's disease. the

In one aspect, the present invention provides carbidopa and levodopa as dry, solid tablets or powders that can be mixed with liquids to form a stable pharmaceutical product. the

In another aspect, the present invention provides a method of treating a Parkinson's disease patient with a liquid formulation of carbidopa and levodopa. the

In a more specific embodiment, the pharmaceutical composition comprises levodopa, carbidopa, an acid and a metal chelating agent. Examples of metal chelating agents include EDTA and deferoxamine mesylate. EDTA can be in its salt or free base form. In one aspect, the concentration of EDTA is at least 0.01 mg/ml. the

In another embodiment, the acid may be selected from carboxylic acids, mineral acids, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, formic acid, formic acid, butyric acid, acetic acid, benzoic acid, butyric acid, malic acid, propionic acid , Epoxysuccinic acid, Muconic acid, Furanacrylic acid, Citramalic acid, Capric acid, Stearic acid, Caprioc acid, Malonic acid, Succinic acid, Diethylacetic acid, Methylbutryic acid ), hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or sulfuric acid. the

In one embodiment, the composition is a stable liquid of levodopa and carbidopa. In one aspect, the stable liquid has less than 10% degradation of carbidopa after 7 days at 25°C. On the other hand, the stable liquid has less than 5% degradation of carbidopa after 7 days at 25°C. In yet another aspect, the stable liquid has less than 10% degradation of carbidopa after 30 days at 25°C. In yet another aspect, the stable liquid has less than 5% degradation of carbidopa after 4 days at 25°C. On the other hand, the stable liquid has less than 5% degradation of carbidopa after 30 days at 4°C. In one aspect, the stable liquid has less than 5% degradation of carbidopa after 250 days at 25°C. On the other hand, the stable liquid has less than 5% degradation of carbidopa after 360 days at 4°C. In yet another aspect, the stable liquid has less than 10% degradation of carbidopa after 9 days at 25°C. the

In another embodiment, a pharmaceutical composition comprises levodopa, carbidopa and acid, wherein the pH of the composition is less than or about 3.0. In one aspect, the composition has less than 10% degradation of carbidopa after 7 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 7 days at 25°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 30 days at 25°C. In yet another aspect, the composition has less than 5% degradation of carbidopa after 4 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 30 days at 4°C. In one aspect, the composition has less than 5% degradation of carbidopa after 250 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 360 days at 4°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 9 days at 25°C. In another aspect, the composition further comprises additional artificial sweeteners or preservatives. the

In yet another embodiment, the aqueous composition comprises levodopa and carbidopa, wherein the concentration of levodopa is 2.5 mg/ml to 9 mg/ml. In yet another embodiment, the concentration of levodopa is about 4 mg/ml. In one aspect, the composition has less than 10% degradation of carbidopa after 7 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 7 days at 25°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 30 days at 25°C. In yet another aspect, the composition has less than 5% degradation of carbidopa after 4 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 30 days at 4°C. In one aspect, the composition has less than 5% degradation of carbidopa after 250 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 360 days at 4°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 9 days at 25°C. In another aspect, the composition further comprises additional artificial sweeteners or preservatives. the

In another embodiment, the composition comprises levodopa, carbidopa, an acid and a metal chelating agent, wherein less than 1.2% of the carbidopa is degraded after 24 hours at 25°C. Examples of metal chelating agents include EDTA and deferoxamine mesylate. the

Yet another embodiment includes a combination of levodopa, carbidopa, acid and a metal chelating agent, wherein less than 2.4% of the carbidopa is degraded after 48 hours at 25°C. the

Yet another composition of the invention includes a stable formulation with low levels of degradants. In one aspect, hydrazine degrades less than currently available levodopa/carbidopa suspensions. In one aspect, the liquid pharmaceutical composition comprises about 0.4 to 1.5 mg/ml of levodopa and carbidopa, wherein the level of hydrazine is less than 0.07 μg/ml after 24 hours at 25°C. In another aspect, the liquid pharmaceutical composition comprises about 0.4 to 1.5 mg/ml of levodopa and carbidopa, wherein the level of hydrazine is less than 0.32 μg/ml after 3 days at 25°C. In yet another aspect, the liquid pharmaceutical composition comprises about 0.4 to 1.5 mg/ml of levodopa and carbidopa, wherein the level of hydrazine is less than 1.6 μg/ml after 7 days at 25°C. In yet another aspect, the liquid pharmaceutical composition comprises about 0.4 to 1.5 mg/ml of levodopa and carbidopa, wherein the level of hydrazine is less than 0.06 μg/ml after 7 days at 4°C. the

In one embodiment, the liquid formulation of levodopa, carbidopa, acid and metal chelator is clear or translucent. the

In yet another embodiment, the pharmaceutical composition comprises levodopa, carbidopa, an acid and a thioether compound. In one aspect, the thioether acts to stabilize carbidopa. Examples of thioethers include methionine, cysteine, glutathione, thioglycerol, sodium thiosulfate, and n-acetylmethionine. In another embodiment, the composition comprises levodopa, carbidopa, an acid, a thioether, and a metal chelating agent. the

One embodiment includes a pharmaceutical composition comprising about 2.5 to 6 mg/ml levodopa, about 0.625 to 1.5 mg/ml carbidopa, about 5 mg/ml to 10 mg/ml citric acid, and greater than about 0.25 mg/ml ml EDTA. The composition may additionally comprise aspartame from about 0.1 mg/ml to about 1 mg/ml, or sodium benzoate from about 0.01 mg/ml to about 1 mg/ml. the

In another embodiment, the pharmaceutical composition comprises about 2.5 to 6 mg/ml levodopa, about 0.25 to 0.6 mg/ml carbidopa, about 5 mg/ml to 10 mg/ml citric acid, and greater than about 0.25 mg/ml EDTA. The composition may additionally comprise water, about 0.1 mg/ml to about 1 mg/ml aspartame, or about 0.01 mg/ml to about 1 mg/ml sodium benzoate. the

In one embodiment, the pharmaceutical composition comprises about 500 mg to about 1500 mg levodopa, about 125 mg to about 375 mg carbidopa, about 1065 mg to about 3195 mg citric acid, and about 13 mg to about 41 mg EDTA. The composition may be in the form of a dispersible tablet or as a powder or granules for mixing with a liquid. the

In another embodiment, the pharmaceutical composition comprises about 1000 mg levodopa, about 250 mg carbidopa, about 2130 mg citric acid, and about 27 mg EDTA. The composition may also contain water, aspartame or sodium benzoate. the

One embodiment comprises a pharmaceutical composition of levodopa, carbidopa, acid, metal chelating agent and sugar, wherein the sugar comprises less than 1% of the composition. the

One embodiment includes a method of administering levodopa and carbidopa, wherein a dry or solid formulation of levodopa and carbidopa is added to a liquid; the formulation is mixed for less than 10 minutes, and the formulation is administered to the patient. In one aspect of the invention, the formulation is administered as the first morning dose of the Parkinson's disease patient. the

In another embodiment, the liquid composition is capable of dissolving about 2.5 to 6 mg/ml levodopa and about 0.25 to 0.6 mg/ml carbidopa. In one aspect, the composition has less than 10% degradation of carbidopa after 7 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 7 days at 25°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 30 days at 25°C. In yet another aspect, the composition has less than 5% degradation of carbidopa after 4 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 30 days at 4°C. In one aspect, the composition has less than 5% degradation of carbidopa after 250 days at 25°C. In another aspect, the composition has less than 5% degradation of carbidopa after 360 days at 4°C. In yet another aspect, the composition has less than 10% degradation of carbidopa after 9 days at 25°C. the

Another embodiment of the present invention is a method of preparing a pharmaceutical composition for treating dopamine disorders, which comprises the step of mixing levodopa, carbidopa, acid, metal chelating agent and water. the

In one embodiment, the liquid composition comprises levodopa and carbidopa, wherein the total concentration of metal ions is less than 1 ppm. In another aspect, the free metal ion concentration is less than 1 ppm. In one aspect, the composition further comprises an acid. An example of a relevant acid is hydrochloric acid. In other compositions, the total concentration of metal ions may be less than 0.1 ppm, 0.1 ppm, 0.01 ppm or 1 ppb. the

In one method of the invention, the levodopa and carbidopa formulations contain one or more excipients or active agents, and these excipients or active agents are chromatographed to remove metal ions. Examples of metal ions suitable for removal include iron, lead, zinc or aluminum. the

Other aspects of the invention include administering compositions of the invention to a patient. the

Brief description of the drawings

Figure 1: Demonstration of the solubility of levodopa in citrate buffer as a function of pH and levodopa concentration. the

Detailed description of the invention

The present invention provides stable pharmaceutical compositions comprising carbidopa and levodopa. Previous combinations of levodopa and carbidopa were not stable enough or effective enough for Parkinson's disease patients. The compositions of the present invention may provide advantages over currently marketed levodopa and carbidopa formulations and current home-prepared liquid levodopa/carbidopa formulations. the

"Liquid levodopa/carbidopa" is defined as a preparation of levodopa, carbidopa and liquid, wherein one or more levodopa/carbidopa tablets are mixed with the liquid. the

A "Parkinson's disease patient" is defined as anyone diagnosed with Parkinson's disease by a physician, or anyone diagnosed with a dopamine disorder who would benefit from levodopa treatment. the

Improved methods of stabilizing levodopa and carbidopa compositions have been discovered. One approach to improving stability involves reducing the free metal concentration in the levodopa and carbidopa composition. Another method of improving stability involves lowering the pH of the liquid levodopa and carbidopa composition. Yet another approach to improving stability involves selecting acids that are preferred for the stability of levodopa and carbidopa. the

The present invention provides carbidopa and levodopa formulations which have advantages over the prior art in terms of stability and ease of use. Various degradation products have been found to result from the currently used home-prepared liquid formulations of levodopa/carbidopa. At least one of these degradation products is hydrazine, a potential carcinogen. The current practice of taking 1 g of levodopa daily in liquid form of levodopa/carbidopa in advanced Parkinson's disease patients may result in toxic levels of hydrazine. Although current liquid levodopa/carbidopa formulations provide significant benefits to patients with advanced Parkinson's disease, such home-prepared formulations expose patients to potential carcinogens. This potential carcinogen has been linked to cancer ("Toxological Profile for Hydrazines," U.S. Department of Health and Human Services, September 1997). Additionally, the degradation of carbidopa to hydrazine results in a loss of carbidopa potency, thereby reducing the shelf life of the product. the

There is a need for a formulation that is stable, easy to use for Parkinson's disease patients, while still providing the advantages of liquid formulations of levodopa and carbidopa. Much effort has been made to create stable liquid formulations containing levodopa and carbidopa. After much experimentation, it was found that the metal makes carbidopa unstable. One embodiment of the invention comprises levodopa, carbidopa and a metal chelating agent. Without being bound by any theory, it is believed that metal ions cause the degradation of carbidopa (Example 12). Examples of chelating agents include, but are not limited to, EDTA, deferoxamine mesylate, EGTA, fumaric acid, and malic acid. Included within the definition of EDTA is both the free acid and the salt forms of EDTA. Examples of free acid or salt forms of EDTA include edetate, edetate disodium, edetate dipotassium, edetate calcium disodium, edetate sodium, and edetate trisodium. Any of edetic acid, edetate disodium, edetate dipotassium, edetate calcium disodium, edetate sodium, and edetate trisodium may be excluded from some embodiments of the present invention. In one embodiment, the EDTA concentration is at least 0.01 mg/ml, at least 0.05 mg/ml, at least 0.1 mg/ml, 0.01 to 0.5 mg/ml, 0.05 mg/ml to 0.3 mg/ml, 0.05 mg/ml to 0.2 mg/ml or about 0.1 mg/ml. the

In another embodiment, the compositions of the present invention comprise low levels of metals or no detectable metals. A low level of metal is less than 1 ppm metal ion, less than 0.5 ppm metal ion, less than 0.01 ppm metal ion, or less than 1 ppb metal ion. Specific metal ions that may be excluded or minimized from the compositions of the present invention include, but are not limited to, iron, calcium, magnesium, cobalt, copper, iron, manganese, molybdenum, selenium, zinc, aluminum, arsenic, barium, cadmium, Chromium, lead, mercury, selenium and silver. In a specific embodiment, the levodopa and carbidopa composition comprises less than 1 ppm metal ion. In another embodiment, the combination of levodopa, carbidopa and acid comprises less than 1 ppm metal ion. In yet another embodiment, the levodopa and carbidopa composition comprises less than 0.1 ppm metal ions. In yet another embodiment, the combination of levodopa, carbidopa and acid comprises less than 0.1 ppm metal ion. In some embodiments, the total metal concentration is below a specified level, and in other embodiments, the total concentration of free metal ions is below a specified level. Free metal ions are ions that are not chemically bonded to other molecules (excluding water). the

Metal ions are present in trace amounts in many formulations including commercial formulations of levodopa and carbidopa. In addition, metal ions are present in liquids that can be used in the preparation of liquid formulations of levodopa and carbidopa. The method of the present invention removes metal ions from active ingredients, excipients such as binders, acids, flavoring agents, and diluents such as water. In one embodiment, the compositions of the present invention are prepared by chromatographically removing metal ions. In another embodiment, the compositions of the invention are prepared by subjecting all or a portion of the excipients and active agents to chromatography. In yet another embodiment, the composition of the present invention is obtained by subjecting all or part of the excipients and active agents to chromatography so that the total metal ion concentration of the resulting composition is less than 1 ppm, less than 0.5 ppm, less than 0.1 ppm, less than 0.01 Prepared by ppm or less than 1ppb. In yet another embodiment, the levodopa and carbidopa composition is chromatographed to remove metal ions. Metal ions can be removed from the final composition, or from each individual excipient or active agent of the composition. For example, metal ions can be removed from a formulation of levodopa, carbidopa and hydrochloric acid, or from levodopa, carbidopa and hydrochloric acid alone. the

Additionally, thioether compounds have been found to stabilize the carbidopa molecule, thereby reducing the formation of degradants. Examples of thioethers include, but are not limited to, methionine, cysteine, glutathione, thioglycerol, sodium thiosulfate, and n-acetylmethionine. the

Another embodiment of the invention comprises both a thioether and a chelating agent. The combination of thioether and chelating agent acts to significantly reduce the level of degradation of carbidopa in carbidopa and levodopa compositions. Thus, in one embodiment, the present invention comprises carbidopa, levodopa and one or more substances selected from metal chelating agents or thioethers. Further aspects of the invention are formulations of carbidopa, levodopa and one or more substances selected from metal chelating agents or thioethers, wherein less than 10% of the carbidopa is degraded after 7 days at 25°C . the

In one embodiment, the compositions of the invention are stable. The stable composition has less than 10% carbidopa degradation after 7 days at 25°C, less than 5% carbidopa degradation after 7 days at 25°C, and less than 10% carbidopa degradation after 30 days at 25°C Dopa degraded with less than 5% carbidopa after 4 days at 25°C, less than 5% carbidopa after 30 days at 4°C, and less than 5% carbidopa after 250 days at 25°C Bidopa degraded with less than 5% carbidopa degradation after 360 days at 4°C or with less than 10% carbidopa degradation after 9 days at 25°C. Embodiments of the invention enable formulations having degradant levels of less than parts per million (ppm), less than 0.5 ppm, less than 0.2 ppm, less than 0.1 ppm, less than 0.05 ppm, or less than 0.01 ppm after storage at room temperature for 24 hours. Embodiments of the present invention enable formulations to have less than one part per million (ppm), less than 0.5 ppm, less than 0.2 ppm, less than 0.1 ppm, less than 0.05 ppm of a particular degradant, such as hydrazine, after 48 hours of storage at room temperature. Or a level less than 0.01ppm. Embodiments of the present invention enable formulations having hydrazine levels of less than one part per million (ppm), less than 0.5 ppm, less than 0.2 ppm, less than 0.1 ppm, less than 0.05 ppm, or less than 0.01 ppm after storage of the formulation for one week at 4°C. the

In one embodiment, the liquid formulation of the invention has less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after storage for one day at 25°C . In another embodiment, the liquid formulations of the invention have less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% carbidol after storage at 25°C for three days. Bar degradation. In one embodiment, the liquid formulation of the invention has less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.25% degradation of carbidopa after storage for one week at 25°C . In one embodiment, the liquid formulation of the invention has less than 15%, 10%, 5%, 3%, 2%, 1%, 0.5% or 0.25% carbidopa after storage for one month at 25°C. degradation. the

In another embodiment, the levodopa-containing compositions of the present invention are suitably stable for pharmaceutical use. In one embodiment, the liquid forms of levodopa, carbidopa, or formulations thereof of the invention are stable such that less than 1% of either degradation product is formed when stored at room temperature for 24 hours. The term degradant refers herein to the product of a single type of chemical reaction. For example, if a hydrolysis reaction occurs that cleaves one molecule into two products, this would be considered a single degradant for purposes of the present invention. In another embodiment, less than 5% of any one degradant is formed in the composition when stored at 4°C for one week. Alternatively, the composition of the invention comprises less than 10%, less than 5%, less than 3%, less than 2%, less than 1%, less than 0.5% of any one of the degradants when stored at room temperature for 24 hours. Relative humidity (RH) may be specified as ambient RH, 75% RH, or any single integer between 1 and 99% RH. One particular type of degradant is hydrazine. the

In another embodiment, the compositions of the present invention have improved stability over currently employed formulations. In one example, after storage at 25°C for 24 hours, the composition of the present invention has 100 times less carbidol than the currently used formulation prepared by mixing ginger ale with Sinemet tablets (1 mg/ml). Bar degradation. In another example, after 24 hours storage at 25°C, the composition of the present invention has 3 times less degradation of carbidopa than the currently used formulation prepared by mixing orange juice with Sinney cereal (1 mg/ml). In another example, the composition of the present invention exhibited 15 times less carbidopa degradation than a currently used formulation prepared by mixing orange juice with Sinny oats (1 mg/ml) after storage at 25°C for 3 days. In yet another embodiment, the composition of the present invention has 60 times less carbidopa degradation than a currently used formulation prepared by mixing orange juice with Sinney cereal (1 mg/ml) after storage at 25° C. for 7 days. the

In some embodiments of the invention, the compositions have lower levels of carbidopa degradation than currently employed formulations. It has been found that currently used liquid levodopa/carbidopa contains carbidopa degradants in home made formulations (see Examples 3 and 6). For example, patients are often encouraged to mix levodopa/carbidopa tablets with orange juice, which contains ascorbic acid to dissolve the levodopa/carbidopa tablets. Ascorbic acid can cause reactions that produce carbidopa degradation products. These degradants can cause negative biological effects and reduce drug efficacy because the degraded drug is no longer functional. Experiments with other acids have demonstrated that other carbidopa degradants are likely to exist. Two specific degradants that can form in liquid levodopa/carbidopa formulations are hydrazine and 3,4-dihydroxypropiophenone (DHPA). Without being bound by any particular theory, it is believed that carbidopa degrades into equal proportions of DHPA and hydrazine. Therefore, the presence of DHPA can indicate the presence of hydrazine. The compositions of the present invention reduce the levels of these degradants. For example, the compositions of the present invention can prevent the formation of these degradants, or keep the formation of these degradants at 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%. the

In another embodiment, the levodopa-containing compositions of the present invention are suitably stable for pharmaceutical use. Preferably, the solid dosage forms of levodopa, carbidopa, or solid form formulations thereof of the present invention are stable such that less than 0.2% of either degradation product is formed when stored at 30°C for 2 years . The term degradant refers herein to the product of a single type of chemical reaction. For example, if a hydrolysis reaction occurs that splits one molecule into two products, this is considered a single degradant for purposes of the present invention. More preferably, less than 0.2% of any one degradation product is formed when stored at 40°C for 2 years. Alternatively, less than 0.2%, or 0.15%, or 0.1% of any of the degradants formed when stored at 30°C for 3 months, or any Each degradation product is less than 0.2%, or 0.15%, or 0.1%. More alternatively, when stored at 60°C for 4 weeks, less than 0.2%, or 0.15%, or 0.1% of either degradation product is formed. Relative humidity (RH) may be specified as ambient RH, 75% RH, or any single integer between 1 and 99% RH. the

One embodiment of the invention includes a combination of carbidopa, levodopa and one or more acids. Examples of acids include, but are not limited to, carboxylic acids, mineral acid salts, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, formic acid, formic acid, butyric acid, acetic acid, benzoic acid, butyric acid, malic acid, propionic acid, Epoxysuccinic acid, muconic acid, furanacrylic acid, citramalic acid, capric acid, stearic acid, caproic acid, malonic acid, succinic acid, diethylacetic acid, methylbutyric acid, hydrochloric acid, hydrobromic acid, phosphoric acid , nitric acid and sulfuric acid. Can be according to about 0.5 mole levodopa to about 20 moles acid, about 0.5 mole levodopa to about 2 moles acid, about 1 mole levodopa to about 5 moles acid, about 1 mole levodopa to about 7 moles acid, The acid is added in a molar ratio of about 1 mole of levodopa to about 10 moles of acid, about 1 mole of levodopa to about 3 moles of acid, or about 1 mole of levodopa to about 4 moles of acid. One skilled in the art can increase the concentration of acid to increase the level of carbidopa or levodopa that can be dissolved in the liquid. Included within the scope of this invention is the use of increased ionic strength to increase the solubility of carbidopa or levodopa. For example, adding HCl to a combination of levodopa, carbidopa, and citric acid may further solubilize levodopa, or may allow higher levels of levodopa to be solubilized. the

In some embodiments, any specific acid may be excluded from the present invention. Examples of acids which may be specifically excluded include, but are not limited to, carboxylic acid, citric acid, tartaric acid, ascorbic acid, dehydroascorbic acid, acetic acid, formic acid, formic acid, butyric acid, acetic acid, benzoic acid, butyric acid, malic acid, propionic acid, Epoxysuccinic acid, muconic acid, furanoic acid, citramalic acid, capric acid, stearic acid, caproic acid, diethylacetic acid, methylbutyric acid, hydrochloric acid, malonic acid, succinic acid, phosphoric acid, and sulfuric acid. the

Adjustments of ionic strength can be made to affect solubility. Example 7 shows that salt has little negative effect on carbidopa stability. Therefore, in some embodiments, ionic strength is adjusted to maintain optimal stability. For example, the salt concentration in certain compositions 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

The pH of a liquid levodopa/carbidopa formulation can affect the stability of the formulation. As demonstrated in Example 8, lowering the pH can increase the stability of the formulation. The composition of the present invention 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, A pH of less than 2.1, or less than 2. the

The pharmaceutical composition of the present invention may comprise levodopa, carbidopa, one, two, three, four or more other adjuvants or additives. Excipients or additives can be inert, or they can be active, affecting the other components of the composition. Adjuvants or additives may include, but are not limited to, acids, bases, salts, surfactants, emulsifiers, detergents, binders, wetting agents, salts, polymers, solvents, antimicrobials, preservatives, fillers, Sugar, alcohol, coloring, flavoring and buffering agents. Excipients can serve to stabilize the formulation or to reduce or eliminate degradation of the active agent. Included in the present invention as embodiments are compositions containing any known adjuvant, including those disclosed in Gower Publishing, 1995, Handbook of Pharmaceutical Additives, edited by Michael and Irene Ash. the

In some embodiments, any one or more specific substances may be excluded. Examples of substances that may be excluded include, but are not limited to, acids, bases, salts, surfactants, emulsifiers, detergents, binders, wetting agents, salts, polymers, solvents, antimicrobials, preservatives, Bulking agents, sugars, alcohols, or additives disclosed in the Handbook of Pharmaceutical Additives. the

Other excipients may include particulate binders. Particular particulate binders include, but are not limited to, hydroxypropylcellulose and hydroxypropylmethylcellulose, and polyvinylpyrrolidone. In one embodiment, water-soluble particulate binders are used in the formulations of the invention. In another embodiment, 3 to 10%, 4 to 6%, or 4 to 5% by weight binder is employed. the

In some embodiments, other substances are added to the composition to prevent the formation of degradants. Any substance which satisfies the conditions of limiting, reducing or inhibiting the formation of degradants in the compositions of the invention is conceivable. Specific examples include, but are not limited to, ammonium bisulfite, ammonium sulfite, ammonium thiosulfate, arsenic sulfide, arsenic trisulfide, calcium dithionite, chromous chloride, ferrous chloride, ferrous oxalate, Beta-mercaptoethanol, dithiothreitol, vitamin E, vitamin C, beta-carotene, lycopene and flavonoids. the

In one aspect the present invention provides carbidopa and levodopa compositions for use in the treatment of Parkinson's disease patients. For some people with Parkinson's disease, liquid formulations of carbidopa and levodopa are more beneficial than other formulations. As Parkinson's disease progresses, patients often require continually higher doses of levodopa to maintain exercise capacity. These high levels of dosing requirements often make patients more susceptible to catalepsy. Therefore, people with advanced Parkinson's disease often require high levels of levodopa to avoid stiffness. Some embodiments of the present invention will be particularly useful for patients with advanced Parkinson's disease to avoid catalepsy, or to rapidly release the patient from catalepsy by rapidly providing high concentrations of levodopa to the patient. the

The preparations of levodopa and carbidopa involved in the present invention can be made into powders, tablets or granules, and mixed with liquids to prepare stable liquid preparations. These formulations can be used, for example, for administration to patients with Parkinson's disease. The pharmaceutical compositions of the invention can take the form of several different embodiments. In one embodiment, levodopa and carbidopa are provided in dry sachet form, which can be mixed with liquid. In another embodiment, levodopa and carbidopa are formulated as pills or tablets, which can be mixed with a liquid. In another embodiment, levodopa and carbidopa can be formulated in any dosage form that can be mixed into a liquid. Examples of suitable dosage forms include, but are not limited to, powders, granules, tablets, capsules, dispersions, solutions and gels. the

Currently marketed levodopa and carbidopa drug products are in solid dosage form. People with Parkinson's disease can go into a catalepsy and have to wait a long time for a drug product to do its job. This waiting and freezing phase severely limits the freedom and safety of Parkinson's patients. Compositions of the present invention can provide a faster onset of action, thereby reducing the time to stiffness. In some embodiments, 80% or more of a composition of the invention can pass through the stomach within 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 minutes, or within 1 to 30, 1 Intestinal absorption begins within 20, 3 to 20, 3 to 15, 5 to 10, 10 to 30, 10 to 20, or 20 to 30 minutes, thereby accelerating absorption into the body. In another embodiment, 90% or more of the composition of the invention can pass through the stomach within 1, 2, 3, 4, 5, 10, 15, 20, 25 or 30 minutes, or within 1 to 30, Intestinal absorption begins within 1 to 20, 3 to 20, 3 to 15, 5 to 10, 10 to 30, 10 to 20, or 20 to 30 minutes, thereby accelerating absorption into the body. the

In addition, the compositions of the present invention may also include agents that enhance gastric motility. A side effect of Parkinson's disease or Parkinson's disease drug treatment is decreased gastric motility. Formulations of levodopa, carbidopa, and gastric motility regulators provide rapid onset medications for patients with Parkinson's disease. Examples of suitable drugs include, but are not limited to, dopamine antagonists such as cisapride and domperidone. One class of gastric motility regulators acts to relax the pyloric sphincter and allow gastric contents to pass into the intestine. Drug formulations that enhance gastric motility allow levodopa and carbidopa to be administered with food. Many people with Parkinson's disease avoid food close to the time of their levodopa dosing regimen. Food is known to decrease the absorption of levodopa. Formulations of levodopa and carbidopa with gastric motility agents allow patients to eat while taking their necessary drug doses. Thus, one embodiment entails administering a formulation of the invention comprising levodopa, carbidopa, and a gastric motility agent 1, 2, 3, 4, 5, 10, 20, 25, or 30 minutes before a meal to reduce the likelihood of food Effects on the bioavailability of levodopa. the

Embodiments of the invention with and without gastric motility agents provide faster and more predictable absorption of levodopa in the digestive system. Thus, one aspect of the invention entails administering embodiments of the invention with food, or at a time close to the feeding phase. Thus, in some embodiments of the invention, the absorption of levodopa may not be affected by food. Another embodiment includes compositions administered with or during mealtimes. the

In some embodiments, the bioavailability of the compositions of the present invention may be higher than that of currently marketed products. Higher bioavailability can lead to faster action. For example, the composition of the present invention can increase the concentration of levodopa in plasma to greater than 1 nmol/ml, greater than 2 nmol/ml, greater than 3 nmol/ml, greater than 4 nmol/ml, greater than 5 nmol/ml , greater than 6 nmol/ml, or greater than 10 nmol/ml. The levodopa of the composition is greater than 1 nmole/ml, greater than 2 nmoles/ml, greater than 3 nmoles/ml, greater than 4 nmoles/ml, greater than 5 nmoles/ml, greater than 6 nmoles/ml, or greater than 10 nmol/ml prevents, reduces or stops stiffness. Thus, in some embodiments of the invention, the composition reduces or prevents the stiffness condition. In another embodiment, the composition of the present invention can reach a plasma levodopa level of 3 nanomoles/ml within 10 minutes of ingesting the composition, and can reach a plasma levodopa level of 3 nanomoles/ml within 15 minutes of ingesting the composition. A level of nanomoles/ml that can reach a level of plasma levodopa of 3 nmoles/ml within 20 minutes of ingesting the composition and can reach a level of plasma levodopa of 4 nmoles/ml within 10 minutes of ingesting the composition The level of plasma levodopa of 4 nanomoles/ml can be reached within 15 minutes of ingesting the composition, or the level of plasma levodopa of 4 nanomoles/ml can be reached within 20 minutes of ingesting the composition. Patients vary in their reliance on levodopa. Thus, by administering sufficient plasma concentrations of levodopa, the compositions of the invention can prevent, reduce or arrest the catalepsy condition. Doctors, pharmacists or patients can adjust the dosage of the preparation of the present invention according to the specific conditions of patients with Parkinson's disease. the

People with Parkinson's disease often have difficulty swallowing pills. Liquid formulations of levodopa and carbidopa can act to reduce or eliminate the difficulty of administration. Current liquid levodopa/carbidopa home formulations do not dissolve well in liquids as described in the art. Therefore, patients do not know whether carbidopa and levodopa are completely dissolved. Additionally, currently described liquid levodopa/carbidopa formulations are typically administered at 1 mg/ml levodopa, requiring Parkinson's disease patients to drink 1 liter or more of liquid levodopa/carbidopa per day . Large volumes of liquid can be difficult for people with Parkinson's disease to swallow. The compositions of the present invention meet these needs. The compositions of the present invention may contain higher levels of levodopa or carbidopa than the home-prepared liquid levodopa/carbidopa formulations described in the art. the

In some embodiments, the liquid formulation may comprise levodopa at a concentration of up to about 0.5 mg/ml, up to about 1 mg/ml, up to about 2 mg/ml, up to about 3 mg/ml, up to about 4 mg/ml, up to about 5 mg/ml ml, up to about 10 mg/ml, up to about 20 mg/ml, up to about 30 mg/ml, or about 0.5 mg/ml to 30 mg/ml, about 0.5 mg/ml to 1 mg/ml, about 1 mg/ml to 5 mg/ml, about 1 mg/ml to 4 mg/ml, about 1.5 mg/ml to 2 mg/ml, about 1.5 mg/ml to 4 mg/ml, about 2 mg/ml to 5 mg/ml, about 2 mg/ml to 7 mg/ml, about 3 mg/ml 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 ml, about 4.5 mg/ml to 6 mg/ml, about 4.5 mg/ml to 7 mg/ml, about 4.5 mg/ml to 8 mg/ml, about 7 mg/ml to 20 mg/ml, about 10 mg/ml to 30 mg/ml, About 15 mg/ml to 20 mg/ml, or about 20 mg/ml to 30 mg/ml. In some embodiments, the liquid formulations of the present invention may comprise carbidopa at a concentration of up to 0.5 mg/ml, up to about 1 mg/ml, up to about 2 mg/ml, up to about 3 mg/ml, up to about 4 g/ml, up to about 5 mg/ml, up to about 10 mg/ml, up to about 20 mg/ml, up to about 30 mg/ml, or about 0.5 mg/ml to 30 mg/ml, about 0.5 mg/ml to 1 mg/ml, about 1 mg/ml to 5 mg/ml ml, about 1 mg/ml to 4 mg/ml, about 1.5 mg/ml to 2 mg/ml, about 1.5 mg/ml to 4 mg/ml, about 2 mg/ml to 5 mg/ml, about 2 mg/ml to 7 mg/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

The amount of dissolved levodopa or carbidopa can be adjusted according to the needs of the patient. A skilled practitioner can determine the required dosage. In addition, the ratio of carbidopa to levodopa can affect stability. The composition of the present invention can change the ratio of carbidopa to levodopa to reduce or eliminate degradation products in the preparation and enhance stability (see Example 5). The ratio of carbidopa to levodopa can act to stabilize carbidopa. Previous products contained carbidopa:levodopa in ratios of 1:4 and 1:10. Compositions of the invention may be used in other proportions which serve to provide greater stability to the formulation. In some embodiments, the ratio of carbidopa to levodopa will be 1 molar equivalent of carbidopa to 3 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 4 molar equivalents of levodopa 1 molar equivalent of carbidopa to 5 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 6 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 7 molar equivalents of levodopa Dopa, 1 molar equivalent of carbidopa to 8 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 9 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 10 molar equivalents of Levodopa, 2 molar equivalents of carbidopa to 5 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 15 molar equivalents of levodopa, 1 molar equivalent of carbidopa to 20 molar equivalents levodopa, 1 molar equivalent of carbidopa to 25 molar equivalents of levodopa, or 2 molar equivalents of carbidopa to 9 molar equivalents of levodopa. the

In one embodiment, the compositions of the present invention further comprise a thickening or gelling agent. Thickening or gelling agents can make swallowing easier for people with Parkinson's disease. Examples of thickening or gelling agents include, but are not limited to, dextrin, ethyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, cellulose, polyethylene glycol, pectin, xanthan gum or zinc stearate. the

The composition of the invention allows for easy swallowing of the formulation. The compositions can be mixed with aqueous or water-based liquids. Examples of liquids include, but are not limited to, water, juice, tea, milk, carbonated beverages, saline, and dextrose solutions. Liquids commonly available at home provide ease of mixing and use. Additionally, the compositions of the present invention may require minimal administration volumes. In one embodiment, the liquid is sugar-free or contains less than 1% sugar. Examples of sugars include fructose and sucrose. In some embodiments, the patient may drink 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 100 mg levodopa in a volume of 25ml to 100ml, about 50ml to 100ml, about 75ml to 200ml, or about 100ml to 400ml. the

The compositions of the present invention provide additional stability over liquid levodopa/carbidopa. Examples 3 and 6 demonstrate stability issues associated with previous liquid levodopa/carbidopa formulations. Stable liquid formulations contain no phase separation, drug or excipient separation, with minimal drug degradation. The compositions of the present invention are stable at 4°C for 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. Additionally, certain compositions of the present invention are stable at room temperature (22° C.) for 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. the

One embodiment of the invention includes compositions additionally comprising a preservative, antibacterial, antimicrobial or bacteriostatic agent. Preservatives, antimicrobials, antimicrobials or bacteriostats can function to protect the composition both before mixing in the liquid and after mixing in the liquid. Examples of preservatives, antiseptics, antimicrobials, or bacteriostats include, but are not limited to, benzyl alcohol, metabisulfite, benzoic acid, butylparaben, chlorocresol, dimethylsulfoxide, p-hydroxy Ethyl benzoate, hydroacetic acid, miridone, methylparaben, and propylparaben. One embodiment of the invention includes the preservative sodium benzoate. In one embodiment, the compositions of the present invention do not contain any antibacterial or antimicrobial agents. the

In some embodiments, other substances may be added to improve the taste of the composition. Artificial sweeteners can be used to improve the taste of the composition. As shown in Example 9, sugars can reduce the stability of liquid formulations of carbidopa and levodopa. Thus, in one embodiment, the compositions of the invention utilize less than 1% sugar. Some artificial sweeteners can be used to improve the taste of the formulations of the invention without causing sugar stability problems. Examples of artificial sweeteners include aspartame, saccharin, sucralose, neotame, and acesulfame potassium. One embodiment includes aspartame-containing compositions. the

Included within the scope of this invention are combinations of different physical forms of levodopa and carbidopa. Examples of different physical forms of carbidopa and levodopa include, but are not limited to, pharmaceutically acceptable salts, solvates, co-crystals, polymorphs, hydrates, solvates of salts, co-crystals of salts, Shaped substances and free forms of drugs. Depending on the physical form of carbidopa or levodopa, different sets of excipients may be required in the formulation. The compositions of the present invention may include salts of levodopa or carbidopa to increase the stability of the formulation. As shown in Example 11, salts such as HCl salts can act to lower the pH of the formulation, thereby increasing the stability of the formulation. Examples of inorganic acid addition salts of levodopa or carbidopa include hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate. Examples of organic acid addition salts of levodopa or carbidopa include maleate, fumarate, benzoate, ascorbate, succinate, oxalate, dimethylenesalicylic acid Salt, mesylate, edisulfonate, acetate, propionate, tartrate, salicylate, citrate, gluconate, lactate, malate, mandelate, cinnamon salt, citrate, aspartate, stearate, palmitate, itaconate, glycolate, p-aminobenzoate, glutamate and besylate. the

The compositions of the present invention may also contain a third, fourth, fifth or more active ingredient. Additional active ingredients may act to enhance or ameliorate a treatment or condition associated with Parkinson's disease. Examples of additional active ingredients include selegiline, COMT inhibitors such as entacapone or tolcapone, dopamine agonists such as bromocriptine, ropinirole, pergolide, rotigotine or pramipexole , dopamine decarboxylase inhibitors such as benserazide, and gastric motility regulators such as cisapride or domperidone. the

Carbidopa acts as a peripheral dopamine decarboxylase inhibitor. Thus, carbidopa prevents or limits decarboxylation of levodopa in the peripheral systems of the body, thereby allowing most of levodopa to cross the blood-brain barrier. Included within the scope of this invention are formulations in which carbidopa is replaced by benserazide, another dopamine decarboxylase inhibitor. the

In another embodiment of the invention, the composition may comprise levodopa and/or carbidopa derivatives. The compositions may comprise prodrugs such as levodopa and/or carbidopa ester derivatives. Examples of levodopa derivatives include, but are not limited to, levodopa esters, including levodopa methyl ester and levodopa ethyl ester, and the like. Examples of carbidopa derivatives include, but are not limited to, carbidopa methyl ester and carbidopa ethyl ester. the

Another aspect of the present invention provides levodopa compositions without any carbidopa. For some patients with Parkinson's disease, plasma carbidopa levels may be sufficient, or the patient may be taking other medications that contain carbidopa. Thus, carbidopa may be eliminated from any composition of the invention. Patients can take pills of carbidopa or benserazide and a liquid form of levodopa. Other embodiments include carbidopa-free compositions of levodopa. the

One embodiment of the invention comprises levodopa, carbidopa and thioethers. Specific examples of such thioethers include, but are not limited to, methionine or cysteine. the

Another embodiment comprises levodopa, carbidopa and a metal chelating agent. Specific examples of metal chelating agents may include, but are not limited to, EDTA and deferoxamine mesylate. the

Another embodiment comprises levodopa, carbidopa, thioethers and chelating agents. the

In one embodiment, the composition of the invention comprises levodopa, carbidopa and acid. In another embodiment, the composition comprises levodopa, carbidopa and an acid, wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid , Benzoic Acid, Succinic Acid, Oxalic Acid, Bismethylenesalicylic Acid, Methanesulfonic Acid, Ethylenedisulfonic Acid, Acetic Acid, Propionic Acid, Tartaric Acid, Salicylic Acid, Citric Acid, Gluconic Acid, Lactic Acid, Malic Acid, Mandelic Acid , cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid. the

Another embodiment of the invention comprises levodopa, carbidopa, acid and thioether. Another embodiment includes a combination of levodopa, carbidopa, acid and chelating agent. Yet another embodiment comprises levodopa, carbidopa, acids, thioethers and chelating agents. the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. Wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid; and

b. After 7 days at 25°C, the level of degraded carbidopa 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%. the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, formic acid Sulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid;

b. After 7 days at 25°C, the level of degraded carbidopa 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%; and

c. The formulation also contains a preservative such as sodium benzoate. the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, formic acid Sulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid;

b. After 7 days at 25°C, the level of degraded carbidopa 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%; and

c. The carbidopa or levodopa is in the form of a salt. the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. Wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid; and

b. where 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. the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. Wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid; and

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 . the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. Wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid; and

b. wherein the composition degrades less than 10% of any active ingredient over 12 hours, 24 hours, 36 hours, 48 hours, one week or one month at room temperature (25°C). the

In another embodiment, the composition of the present invention comprises levodopa, carbidopa and acid:

a. Wherein said acid is hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, dimethylene salicylic acid, Methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, Palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, or benzenesulfonic acid; and

b. wherein the degradation of any active ingredient in the composition is less than 10% over 12 hours, 24 hours, 36 hours, 48 hours, one week or one month at 4°C. the

In one embodiment, the formulation comprises 1 to 5 mg/ml levodopa, 0.25 to 1.25 mg/ml carbidopa, acid and EDTA. In another embodiment, the formulation comprises 1 to 5 mg/ml levodopa, 0.25 to 1.25 mg/ml carbidopa, citric acid and EDTA. In yet another embodiment, the formulation comprises 1 to 5 mg/ml levodopa, 0.25 to 1.25 mg/ml carbidopa, 3 to 10 mg/ml citric acid and EDTA. In yet another embodiment, the formulation comprises 1 to 5 mg/ml levodopa, 0.25 to 1.25 mg/ml carbidopa, 3 to 10 mg/ml citric acid and at least 0.025 μg/ml EDTA. the

In one embodiment, the formulation comprises 2.5 to 5 mg/ml levodopa, 0.625 to 1.25 mg/ml carbidopa, acid and EDTA. In another embodiment, the formulation comprises 2.5 to 5 mg/ml levodopa, 0.625 to 1.25 mg/ml carbidopa, citric acid and EDTA. In yet another embodiment, the formulation comprises 2.5 to 5 mg/ml levodopa, 0.625 to 1.25 mg/ml carbidopa, 3 to 10 mg/ml citric acid and EDTA. In yet another embodiment, the formulation comprises 2.5 to 5 mg/ml levodopa, 0.625 to 1.25 mg/ml carbidopa, 3 to 10 mg/ml citric acid and at least 0.025 μg/ml EDTA. the

In one embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, acid and EDTA. In another embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, citric acid and EDTA. In yet another embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, 3 to 10 mg/ml citric acid, and EDTA. In yet another embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, 3 to 10 mg/ml citric acid, and at least 0.025 μg/ml EDTA. the

In yet another embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, 3 to 10 mg/ml citric acid, at least 0.025 μg/ml EDTA and 0.5 to 7% binder. In another embodiment, the formulation comprises about 4 mg/ml levodopa, about 1 mg/ml carbidopa, 3 to 10 mg/ml citric acid, at least 0.025 μg/ml EDTA, 0.5 to 7% binder and flavor enhancer. the

Compositions of the invention may be prepared by combining and mixing the different materials. The materials of the present invention were obtained from commercial sources. Carbidopa can be purchased from Sigma-Aldrich (2002-2003 Biochemicals and Reagents Catalog, p. 368). Levodopa can be purchased from Sigma-Aldrich (2002-2003 Biochemicals and Reagents Catalog, p. 693). Combinations of levodopa and carbidopa can be found in currently marketed pharmaceutical formulations. Methods of preparing levodopa and carbidopa are known in the art. Other stated materials (active and inactive) were obtained from commercial sources. the

Dissolution of the compositions of the present invention in liquids can be carried out by any method known in the art. In some cases, dissolution occurs by mixing, stirring, blending or homogenizing. the

Dissolution of the compositions of the present invention can provide significant advantages to patients with Parkinson's disease. The rapid dissolution of the components of the composition can help patients suffering from rigors, tremors and stiff conditions. Faster dissolution can occur by varying the particle size of the compositions and by granulating certain compositions. In one embodiment, the combination of levodopa, carbidopa and binder has a particle size diameter of about 5 to 20 μm. Examples of applicable binders include polyvinylpyrrolidone and hydroxypropylcellulose. The composition also achieves faster dissolution by granulation in the presence of a binder and, in some embodiments, a liquid. In contrast to dry granulation, wet granulation results in compositions with improved dissolution rates. the

In one embodiment, the composition of the invention dissolves at least 3 mg/ml levodopa in the liquid within 5 minutes. In another embodiment, the composition of the invention dissolves at least 4 mg/ml levodopa in the liquid within 5 minutes. One suitable liquid is water. the

Compositions of the invention can be packaged in a variety of ways. Compositions of the invention may be packaged in individual packets, multi-use vials, multi-use containers or containers of different sizes, constructions or materials. the

In some embodiments, the compositions of the present invention specifically exclude detergents. In other embodiments, the compositions of the present invention may form stable formulations containing only levodopa and no levodopa derivatives. In yet other embodiments, the compositions of the present invention may form stable formulations containing only levodopa derivatives and no levodopa. In some embodiments, compositions of the invention comprise two, three or four different substances without requiring a simple formulation combining five or more substances. In other embodiments, the compositions of the present invention do not require any type of gelling component. Examples of gelling ingredients are, but are not limited to, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol or gelatin. the

It will be understood by those skilled in the art that various changes in form and details described herein may be made without departing from the scope of the invention. The invention will now be described in more detail, by way of example only, with reference to the appended examples. the

Example

Embodiment 1: Levodopa at different pH and buffer strength

Solubility in citrate buffer

Sample Preparation

A solution was prepared with citric acid and trisodium citrate dihydrate. A 1.0 M citric acid solution was initially prepared by weighing 19.2 g of citric acid (FW 192.1) into a 100 mL volumetric flask and diluting with HPLC grade water. Repeat this operation with sodium citrate (FW 294.1), that is, weigh 29.4g of sodium citrate, put it into a 100mL volumetric flask, and dilute with water to 100mL. A series of 8 20mL scintillation vials were then labeled and prepared as follows:

Prepare 1.0M samples of pH 1.5 (pure citric acid + HCl), 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 6.0. These pH adjustments were made with sodium citrate (also 1.0M) to maintain a consistent molarity with citrate. Two subsequent sets of solutions at 0.45 and 0.15 M molarity were prepared from these stock bottles. 0.45M for 3:1 buffer and 0.15M for 1:1 buffer. The pH of these solutions was also adjusted with equal molarity solutions to maintain the same pH during each dilution and after the addition of levodopa. Adjust pH with 1N HCl or 1N NaOH as needed. the

result

sample name 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

Mix the levodopa/citric acid/carbidopa/sucrose preparation at a molar ratio of 1:3:0.2:1. The powder mixture was dissolved in water at a concentration of 5.5 mg/ml levodopa. The solution was filtered through a 0.22 micron filter (with PVDF membrane) and stored at 4°C, 25°C and 40°C. the

Mix the levodopa/ascorbic acid/carbidopa preparation at a molar ratio of 1:3:0.25. The powder mixture was dissolved in water at a concentration of 1.0 mg/ml levodopa. The solution was filtered through a 0.22 micron filter (with PVDF membrane) and stored at 4°C, 25°C and 40°C. the

HPLC potency tests of the sample solutions were performed at various time points. Stability was monitored as a percent change from initial potency. the

sample name compound initially Day 1 Day 2 3rd day Day 7 4°C 1/3/0.2/1 Levodopa/citric acid/carbidopa/sucrose Levodopa 100% 100% 100% 100% 100% the Carbidopa 100% 100% 100% 101% 100% Levodopa/citric acid/carbidopa/sucrose at 25°C 1/3/0.2/1 Levodopa 100% 100% 100% 100% 100% the Carbidopa 100% 98% 96% 96% 91% Levodopa/citric acid/carbidopa/sucrose at 40°C 1/3/0.2/1 Levodopa 100% 100% 100% 100% 100% the Carbidopa 100% 91% 84% 81% 75% the the the the the the the 4°C 1/3/0.2 Levodopa/Ascorbic Acid/Carbidopa Levodopa 100% 100% 100% N/A 102% the Carbidopa 100% 101% 101% N/A 101% 25°C 1/3/0.2 Levodopa/Ascorbic Acid/Carbidopa Levodopa 100% 100% 100% N/A 102% the Carbidopa 100% 99% 97% N/A 87% 40°C 1/3/0.2 Levodopa/ Ascorbic Acid/ Carbidopa Levodopa 100% 100% 101% N/A 104% the Carbidopa 100% 94% 88% N/A 88%

Embodiment 3: carbidopa degradant

Levodopa/carbidopa/citric acid and levodopa/carbidopa/ascorbic acid samples were prepared at a molar ratio of 4:1:1. Samples were stored at 25°C for 24 hours. After 24 hours, samples were analyzed by HPLC. Analysis was performed on a Waters Alliance HPLC system equipped with a 2695 separation module and a 2996 PDA detector. The reverse phase HPLC method utilized a Waters Atlantis dC18 column (4.6 x 150 mm, 5 μm) operated at 30°C and a two-component gradient mobile phase. The run time was 30 min at a flow rate of 1.0 mL/min. Levodopa and carbidopa impurities and degradation products were detected by absorbance at 280 nm and reported as their area percent relative to the parent peak. A new peak was identified by HPLC/MS as 3,4-dihydroxypropiophenone. 3,4-Dihydroxypropiophenone (DHPA) is a carbidopa degradation product. This degradant was also present in levodopa/carbidopa/orange juice formulations and levodopa/carbidopa/ginger ale formulations. the

Embodiment 4: the stability of levodopa and carbidopa

preparation

The carbidopa stability of levodopa, carbidopa and acid formulations at different pHs was tested. 4 grams of levodopa and 1 gram of carbidopa were dissolved with 3 molar equivalents to levodopa of each acid and water, as shown in the table below. The pH of each solution was adjusted with 1N HCl or 1N NaOH. Calculate the area of levodopa, area of carbidopa, % carbidopa remaining and % area of DHPA. the

Calculate "% carbidopa remaining" according to the following equation:

Carb _4C theoretically = carb _4C *lev _T /lev _4C

"% carbidopa remaining" = carb _T / carb _4C theoretically * 100

Wherein, carb _T and lev _T refer to the area values of carbidopa and levodopa for the acid, temperature and pH, and lev _4C and carb _4C are the area values of levodopa and carbidopa samples at 4°C for all Study the pH and acid area values.

This data suggests that the choice of specific acids in liquid formulations of levodopa and carbidopa is important. It is possible that combinations of these different acids could create more stable liquid formulations. the

Embodiment 5: the ratio of carbidopa and levodopa

A 1/3/1 levodopa/citric acid/sucrose sample was prepared with a levodopa concentration of 4 mg/ml and carbidopa was added at w/w ratios of 0.5, 0.125 and 0.05 relative to levodopa. Samples were diluted for HPLC analysis after storage at 4°C, 25°C and 40°C for 24 hours. the

The data suggest that the ratio of carbidopa to levodopa affects the stability of carbidopa. the

Example 6: Stability of Levodopa and Carbidopa in Ginger Ale

Stability testing of levodopa and carbidopa formulations with ginger ale. A formulation of 4 mg/ml levodopa and 1 mg/ml carbidopa was combined with 100 ml ginger ale. Formulations were stored at 4°C, 25°C and 40°C for 24 hours. After 24 hours, samples were diluted and analyzed by HPLC. Keep the HPLC sample chamber at 5 °C. Analysis was performed on a Waters Alliance HPLC system equipped with a 2695 separation module and a 2996 PDA detector. The reverse phase HPLC method utilized a Waters Atlantis dC18 column (4.6 x 150 mm, 5 μm) operated at 30°C and a two-component gradient mobile phase. The run time was 30 min at a flow rate of 1.0 mL/min. Levodopa and carbidopa impurities and degradation products were detected by absorbance at 280 nm and reported as their area percent relative to the parent peak. the

Ginger ale has two main peaks at RT=11.2min and 19.3min, and the maximum value of λ is 285 and 229.7nm respectively. The table below shows the amount of 3,4-dihydroxypropiophenone degradation products formed after 24 hours. Carbidopa degrades to 3,4-dihydroxypropiophenone. Therefore, measuring this degradant is a measure of the stability of carbidopa. the

temperature 4°C 25℃ 40℃ DHPA 6.3 24.4 57.6

Carbidopa degraded to a significant level over 24 hours at 25°C and 40°C. There were other less degradants at RT 9.77 min (constant at 5°C and 25°C) and RT = 14.27 min. the

Embodiment 7: the influence of ionic strength

Prepare the levodopa/carbidopa/citric acid/sucrose preparation whose molar ratio in the NaCl solution is 1/0.25/3/1, the concentration of levodopa is 4mg/ml, and the concentration of [NaCl] is 0.00, 0.05 , 0.125, 0.250 and 0.5M. After 24 hours the samples were diluted and analyzed by HPLC (as described above). The HPLC sample chamber was maintained at 5°C. The area % of 3,4-dihydroxypropiophenone relative to the area of carbidopa is shown as a function of temperature and ionic strength, representing the stability of carbidopa. the

the 0M NaCl 0.05M 0.125M 0.25M 0.5M 4°C 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

Salt appears to have a negative effect on carbidopa stability, possibly due to heavy metal contamination in the salt. the

Embodiment 8: the impact of pH on stability

Preparation of carbidopa and citric acid samples. Samples were stored at 4°C, 25°C and 40°C for 24 hours. After 24 hours, samples were diluted and analyzed by HPLC. Analysis was performed on a Waters Alliance HPLC system equipped with a 2695 separation module and a 2996 PDA detector. The reverse phase HPLC method utilizes a Waters Atlantis dC18 column (4.6 x 150 mm, 5 μm) operated at 30 °C with a two-component gradient mobile phase. The run time was 30 min at a flow rate of 1.0 mL/min. Carbidopa impurities and degradation products were detected by absorbance at 280 nm and reported as their area relative to the area of the parent peak. the

Keep the HPLC sample chamber at 5 °C. The area % of 3,4-dihydroxypropiophenone relative to the area of carbidopa is shown as a function of temperature and pH, representing the stability of carbidopa. the

the 4°C 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 no data 44.65

This result indicates that lowering the pH of the formulation enhances the stability of carbidopa. the

Prepare a 1/0.25/3/1 sample of levodopa/carbidopa/citric acid/sucrose in water at a concentration of 4.0 mg/ml of levodopa and adjust the pH of the solution with HCl or NaOH if necessary to 1.8, 2.0, 2.2, 2.4, 2.6, 2.8, 3.0 and 3.2. Three aliquots of each solution were transferred to vials and stored at 4°C, 25°C and 40°C. After 24 hours the samples were diluted and analyzed by HPLC. The area % of 3,4-dihydroxypropiophenone relative to the area of carbidopa is shown as a function of temperature and pH, representing the stability of carbidopa. the

pH 4°C 25℃ 40℃ 1.8 --- 0.53 1.77 2.0 not detectable 0.53 2.02 2.2 not detectable 0.57 1.99 2.4 not detectable 0.68 2.34 2.6 not detectable 0.82(0.82) 2.46 2.8 not detectable ---(1.21) 2.83 3.0 not detectable ---(2.02) 4.62 3.2 not detectable ---(2.43) 6.38

Example 9 : Effect of sugar on stability

Effect of sugar on DHPA formation over 24 hours in samples of 4 mg/ml levodopa + 1 mg/ml carbidopa + 3 equivalents of citric acid (relative to levodopa) stored at 4, 25 and 40°C. Values reported are "DHPA area %" relative to carbidopa. the

the 4°C 25℃ 40℃ sugar free 0 0.39 1.53 0.5 equivalent of sucrose 0 0.38 1.69 1.0 equivalent of sucrose 0 0.51 1.94 1.0 equiv fructose 0 0.56 2.27 1.0 equivalent glucose 0 0.52 2.39

There was no detectable degradation at 4°C. After 24 hours at RT, the samples without sugar were indistinguishable from those containing 0.5% sucrose. But at 40°C, sugar-free formulations are advantageous. The amount of degradation increased with increasing sucrose concentration. Corresponding effects can also occur with other aldehydes or ketones. the

Embodiment 10: the influence of preservative on stability

Prepare 1/0.25/3/1 levodopa/carbidopa/citric acid/sucrose samples in water, the concentration of levodopa is 5.0 mg/ml, add preservatives sodium benzoate and potassium sorbate to the solution . Each preservative was added at a maximum allowable concentration of 0.1%. Regarding 24 hour stability the solutions were left and analyzed by HPLC. Analysis was performed on a Waters Alliance HPLC system equipped with a 2695 separation module and a 2996 PDA detector. The reverse phase HPLC method utilized a Waters Atlantis dC18 column (4.6 x 150 mm, 5 μm) operated at 30°C and a two-component gradient mobile phase. The run time was 30 min at a flow rate of 1.0 mL/min. Levodopa and carbidopa impurities and degradation products were detected by absorbance at 280 nm and reported as their area relative to the area percent of the parent peak. the

In the potassium sorbate sample at 25°C, a new peak at RT = 17.54 min was observed. The peak has a lambda maximum of 321.9. The area % value of the peak is 0.04%. Peaks of the same size were also present when sodium benzoate and potassium sorbate were used in combination. This peak does not appear in samples that do not contain any potassium sorbate. After 24 hours at 40°C, the peak occupies 0.19% of the area. the

Controls were prepared to determine if the new peak was related to potassium sorbate itself, or from an interaction between potassium sorbate and levodopa or carbidopa. The first control group was an aqueous potassium sorbate solution stored at 4°C, 25°C and 40°C for 24 hours. There is a broad peak at about RT=17.5min in the 4°C sample, but it almost disappears in the 25°C sample, and partly appears in the 40°C sample. A second control group contained 14.5 mg/ml citric acid and 1/3 molar equivalent of sucrose (relative to citric acid). The RT = 17.5 min peak did not appear in this sample at any of the temperatures studied. the

No observable interactions occurred between levodopa or carbidopa and sodium benzoate. When potassium sorbate was used in combination with levodopa and carbidopa, at least one new degradant was formed at RT=17.5min. the

The effect of each preservative on the area % of 3,4-dihydroxypropiophenone degradation products was evaluated. In the 4°C samples, there was no detectable 3,4-dihydroxypropiophenone present. At 25°C, sodium benzoate had no effect to a slight negative effect on the area % of 3,4-dihydroxypropiophenone (0.71% with and 0.88% without), while in samples containing potassium sorbate, the size of the degradants was double. Preservative free was 2.69 area%, sodium benzoate was 2.89%, and potassium sorbate resulted in 10.7% conversion of carbidopa to 3,4-dihydroxypropiophenone at 40°C. the

Potassium sorbate thus increases the rate of formation of 3,4-dihydroxypropiophenone relative to solutions without preservatives or containing sodium benzoate. the

Example 11: Effect of Citric Acid Concentration

The effect of citric acid content and levodopa HCl salt on the rate of degradation of carbidopa to 3,4-dihydroxypropiophenone was analyzed. Samples of 4 mg/ml levodopa HCl salt or levodopa free form, 1 mg/ml carbidopa and 4 mg/ml sucrose were prepared. As detailed in the table below, 0 to 3 equivalents of citric acid (relative to levodopa) were added. The effect of citric acid concentration on the 24-hour stability of carbidopa was analyzed by looking at the formation of 3,4-dihydroxypropiophenone. The table below lists the DHPA area %. the

The above process was repeated with the free form of levodopa, which was formulated without sucrose. the

This data demonstrates that increasing citric acid concentrations lead to increased carbidopa stability. Additionally, the HCl salt of levodopa increases carbidopa stability. the

Example 12

An analytical method was developed to test hydrazine solutions. A series of solutions without hydrazine were tested. The following data and graphs show that there is a linear correlation between UV absorption and the amount of hydrazine expressed in ppm between 0.27 ppm and 13.5 ppm. the

Hydrazine in ppm UV absorption 13.5 0.32 2.7 0.063 1.35 0.033 0.27 0.007

This hydrazine analysis protocol has a detection limit of hydrazine at the level of 0.27 ppm when analyzing 0.10 ml of sample. Increase the sample size to 0.50ml to lower the lower limit of quantitation below 0.10ppm. The limit of detection for larger sample volumes is 0.05 ppm. The following data demonstrate a linear correlation between UV absorbance and the volume of the sample solution tested. the

Carbidopa is believed to be the source of hydrazine formation in solutions of levodopa/carbidopa formulations. It is believed that DHPA is the main degradation product of carbidopa in acidic solution and is the co-product of hydrazine formation. DHPA was detectable by HPLC analysis. The following data show a good correlation between % DHPA and the amount of hydrazine expressed in ppm. the

Several levodopa/carbidopa formulation solutions have been tested with HPLC test and hydrazine test. the

Levodopa/carbidopa preparation solution after 24 hours at 25°C %DHPA Hydrazine in ppm Sinnema/Ascorbic Acid Solution 0.40 0.33 4:1 ratio of levodopa/carbidopa solution 0.51 0.41 4:1 ratio of levodopa/carbidopa solution + cystine 0.28 the 4:1 ratio of levodopa/carbidopa solution + methionine 0.31 the 4:1 ratio of levodopa/carbidopa solution + methionine + deferoxamine 0.15 the 4:1 ratio of levodopa/carbidopa solution + cystine + EDTA 0.00 0.00 4:1 ratio of levodopa/carbidopa solution + cystine + deferoxamine 0.00 0.00 4:1 ratio of levodopa/carbidopa solution + methionine + EDTA 0.00 0.00

The data demonstrate that thioethers and chelating agents can be used to reduce the presence of hydrazine in levodopa and carbidopa formulations. the

Example 13

Comparison of the TPI-926 formulation with the current unbranded practice of preparing liquid levodopa and carbidopa beverages in patients with Parkinson's disease. TPI-926 contains:

4mg/ml levodopa

1mg/ml carbidopa

7.8mg/ml citric acid

0.1mg/ml Na EDTA

0.5mg/ml aspartame

The total volume of TPI-926 is 100ml of water. Prepare 1 mg/ml levodopa and 0.25 mg/ml carbidopa in orange juice and Liquid preparation in ginger ale. A formulation of levodopa, carbidopa and ascorbic acid was prepared by grinding 1 levodopa/carbidopa tablet (100:25) and mixing it with 100 ml water and 2 mg/ml ascorbic acid. the

The samples were kept at 4 and 25°C for 24 hours, 3 days and 7 days. The hydrazine and DHPA contents in the samples were analyzed by HPLC. DHPA is a degradation product of carbidopa. Therefore, the ratio of DHPA to degraded carbidopa is 1:1. A 1% level of DHPA in the samples is expected to be associated with a 1% level of carbidopa degradation. the

Concentrations per day were calculated by dividing the amount of hydrazine or DHPA for the longest duration sample by the number of days. the

Hydrazine at 4°C (mcg/sample)

the Day 1 3rd day Day 7 every day '926 ＜1.5 ＜1.5 1.5 0.2 Aqueous solution of ascorbic acid ＜6.0 ＜6.0 6.2 0.9 Orange juice 7.3 10.1 n.m. the ginger ale 21.2 121.5 n.m. 40.5

Hydrazine (mcg/sample) at 25 °C

the Day 1 3rd day Day 7 every day '926 ＜1.5 2.6 5.6 0.8 Aqueous solution of ascorbic acid 7.3 32.5 160.3 twenty three Orange juice 24.1 37.1 n.m. the ginger ale 253 765 n.m. 255

DHPA at 25°C (mcg/sample)

the Day 1 3rd day Day 7 every day '926 ＜25.0 ＜25.0 25.6 3.7 Aqueous solution of ascorbic acid 81 346 1704 238 Orange juice the the the the ginger ale 3210 9038 the 3013

This data demonstrates that TPI-926 prevents or reduces hydrazine formation at both 4 and 25°C. the

Calculate the percent loss of carbidopa. Convert total mcg of DHPA to mcg of carbidopa. the

TPI-926

100ml TPI-926 produces 3.7mcg DHPA per day. Since DHPA and carbidopa are in equal molar equivalents, this is consistent with degradation of carbidopa at 5 mcg per day. One tablet of Sinesia contains 25,000mcg of carbidopa. Therefore, TPI-926 has a degradation rate of 0.02% carbidopa per day for every 250 mg. the

Aqueous solution of levodopa/carbidopa and ascorbic acid

A 100ml sample of ascorbic acid produces 238mcg DHPA per day. Due to equal molar equivalents of DHPA and carbidopa, this is consistent with 323 mcg carbidopa degradation per day. One tablet of Sinesia contains 25,000mcg of carbidopa. Thus, ascorbic acid has a daily degradation rate of 1.2% carbidopa per 250 mg dose. the

Levodopa/Carbidopa in Orange Juice Solution

A 100ml sample of orange juice produced 3013mcg DHPA per day. Due to equal molar equivalents of DHPA and carbidopa, this is consistent with 4083 mcg carbidopa degradation per day. One tablet of Sinesia contains 25,000mcg of carbidopa. Thus, the orange juice sample had a degradation rate of 16.3% carbidopa per day per 250 mg. the

Example 14

The solubility of levodopa was tested in an ascorbic acid solution having an ascorbic acid concentration of 3.5 mg/ml. A 3.5 mg/ml ascorbic acid sample was prepared by adding 70.0 mg ascorbic acid to 20 ml water. Then, with stirring at RT for 24 hours, 80.0 mg of levodopa powder was dissolved in a 3.5 mg/ml sample of ascorbic acid. The planned levodopa concentration is 4 mg/ml. Samples were filtered through a 0.22 μm PVDF filter to remove undissolved levodopa. It was diluted 10 times with water and the filtrate was analyzed by HPLC. HPLC data indicated that the concentration of levodopa in the filtrate was 2.0 mg/ml. Therefore, the maximum solubility of levodopa in a 3.5 mg/ml ascorbic acid solution is 2 mg/ml. the

Example 15

Formulations of levodopa and carbidopa with low levels of metal ion content were prepared. the

The preparation is:

Levodopa 4mg/ml

Carbidopa 1mg/ml

Hydrochloric acid 0.02N

Dehydrated EDTA-Na 0.11mg/ml

Saccharin 0.5mg/ml

Sodium Benzoate 0.10mg/ml

Add deionized water to 1ml

进行透析步骤。将溶液的pH调节至2.0-2.3。测量该制剂的卡比多巴降解水平。在0时刻，0.125％卡比多巴已经降解了。在室温(25℃)下两周后，0.196％卡比多巴已经降解了。在室温下一个月后，0.233％卡比多巴已经降解了。在40℃下两周后，0.618％卡比多巴已经降解了。在40℃下一个月后，1.276％卡比多巴已经降解了。  Water purification was performed using a deionization method equipped with a cation removal cartridge (HoseNipple Cartridge D8905 from Barnstead International). After all components are dissolved in purified water, use

Carry out the dialysis step. The pH of the solution was adjusted to 2.0-2.3. The level of carbidopa degradation of this formulation was measured. At time 0, 0.125% carbidopa has degraded. After two weeks at room temperature (25°C), 0.196% carbidopa had degraded. After one month at room temperature, the 0.233% carbidopa had degraded. After two weeks at 40°C, 0.618% carbidopa had degraded. After one month at 40°C, 1.276% carbidopa had degraded.

Example 16

The speed of formulation dissolution was tested. The purchased levodopa has an average particle size of 76 μm, with 50% of the particles smaller than 67 μm, 90% of the particles smaller than 146 μm, and 100% of the particles smaller than 364 μm. The solid formulations used are:

Levodopa 100mg

Carbidopa 27mg

Citric acid monohydrate 213mg

Dehydrated EDTA-NA 2.75mg

Aspartame 12.5mg

Sodium Benzoate 2.5mg

Levodopa had the above particle range, and Levodopa was not completely dissolved in deionized water within 24 hours. A method of mixing the formulation components is by shaking. the

The same formulation was used except that the levodopa was replaced by levodopa with a mean particle size of 5.5 μm, with 50% of the particles smaller than 5.11 μm, 90% of the particles smaller than 10.4 μm, and 100% of the particles smaller than 19.4 μm (Il particle size batch). Another formulation was tested with an average particle size of 17.3 μm, wherein 50% of the particles were smaller than 13.95 μm, 90% of the particles were smaller than 37 μm, and 100% of the particles were smaller than 78 μm (16 particle size batch). Batch 19 was granulated by hand milling with water. The formulation dissolved completely within 1 hour. Addition of polyvinylpyrrolidone and ethanol also improved dissolution as shown below. the

Expt.ID TPI-926 grinding and cutting Adhesive join method liquid Addition of citric acid 90% TPI-926 dissolved completely dissolved 1 I1 - - water particles ＜1 minute ＞1hr ^＊ ( ^＊ significantly＜1hr) 4 I1 PVP 5% solids ethanol particles ＜1 minute ~10 minutes 3 I1 PVP 5% solids ethanol Mixed w/ Granules ＜1 minute ~5 minutes A I1 PVP 5% solids ethanol Mixed w/ Granules ＜1 minute ~5 minutes B I6 PVP 5% solids ethanol Mixed w/ Granules ＜4 minutes ＞1hr ^＊ ( ^＊ significantly ~10 minutes) C I1 PVP 10% solids ethanol Mixed w/ Granules ＜1 minute ~5 minutes

Particle sizes between 7 and 13 μm showed fast dissolution. The addition of binders such as polyvinylpyrrolidone or hydroxypropylcellulose increases the rate of dissolution. the

Claims (12)

1. the pharmaceutical composition that comprises levodopa, carbidopa and acid, the pH of wherein said compositions less than or be approximately 3.0, described acid is selected from citric acid and hydrochloric acid.

2. the pharmaceutical composition of claim 1, it also comprises the metal-chelate mixture.

3. the pharmaceutical composition of claim 2, wherein said metal-chelate mixture is selected from lower group:

EDTA; And

Deferoxamine mesylate.

4. the pharmaceutical composition of claim 3, wherein said metal-chelate mixture is EDTA.

5. the pharmaceutical composition of claim 4, wherein said EDTA is the form of the salt of free alkali.

6. the pharmaceutical composition of claim 4, the concentration of wherein said EDTA are 0.01mg/ml at least.

7. the pharmaceutical composition of claim 1～6 any one, also comprise artificial sweetener.

8. the pharmaceutical composition of claim 7, wherein said artificial sweetener is aspartame.

9. the pharmaceutical composition of claim 1～6 any one, also comprise antiseptic.

10. the pharmaceutical composition of claim 9, wherein said antiseptic is sodium benzoate.

11. the pharmaceutical composition of claim 2, wherein said compositions are clarification or translucent.

12. the pharmaceutical composition of claim 2, it also comprises sugar, and what wherein said sugar accounted for described compositions is less than 1%.