WO2018154447A1 - Compositions d'inhibiteurs de dopa-décarboxylase - Google Patents
Compositions d'inhibiteurs de dopa-décarboxylase Download PDFInfo
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- WO2018154447A1 WO2018154447A1 PCT/IB2018/051048 IB2018051048W WO2018154447A1 WO 2018154447 A1 WO2018154447 A1 WO 2018154447A1 IB 2018051048 W IB2018051048 W IB 2018051048W WO 2018154447 A1 WO2018154447 A1 WO 2018154447A1
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- pharmaceutically acceptable
- acceptable salt
- compound
- pharmaceutical composition
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- 239000000203 mixture Substances 0.000 title claims abstract description 198
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 title description 3
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 title description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 163
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 163
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 148
- 229960004502 levodopa Drugs 0.000 claims abstract description 137
- 229940002612 prodrug Drugs 0.000 claims abstract description 115
- 239000000651 prodrug Substances 0.000 claims abstract description 115
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 73
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims abstract description 44
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 25
- 229960003638 dopamine Drugs 0.000 claims abstract description 21
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 15
- 210000005064 dopaminergic neuron Anatomy 0.000 claims abstract description 6
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 123
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- 238000000034 method Methods 0.000 claims description 32
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- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
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- 229950002652 safinamide Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Definitions
- Parkinson's disease is a degenerative condition characterized by reduced concentration of the neurotransmitter dopamine in the brain.
- Levodopa (L-dopa or L-3,4- dihydroxyphenylalanine) is an immediate metabolic precursor of dopamine that, unlike dopamine, is able to cross the blood-brain barrier and is most commonly used for restoring the dopamine concentration in the brain.
- levodopa has remained the most effective therapy for the treatment of Parkinson's disease.
- levodopa has a short half-life in plasma that, even under best common current standard of care, results in pulsatile dopaminergic stimulation. Long-term therapy is therefore complicated by motor fluctuations and dyskinesia that can represent a source of significant disability for some patients.
- L-dopa The metabolic transformation of L-dopa to dopamine is catalyzed by the aromatic L- amino acid decarboxylase enzyme, a ubiquitous enzyme with particularly high concentrations in the intestinal mucosa, liver, brain, and brain capillaries. Due to the possibility of extracerebral metabolism of L-dopa, it is necessary to administer large doses of L-dopa leading to high extracerebral concentrations of dopamine that cause nausea in some patients.
- L-dopa is usually administered concurrently with oral administration of a L-dopa decarboxylase inhibitor, such as carbidopa or benserazide, which reduces by 60-80% the L-dopa dose required for a clinical response, and prevents certain of its side effects by inhibiting the conversion of levodopa to dopamine outside the brain.
- a L-dopa decarboxylase inhibitor such as carbidopa or benserazide
- отно ⁇ inhibitors of enzymes associated with the metabolic degradation of levodopa are well known, for example, decarboxylase inhibitors such as carbidopa and benserazide, monoamine oxidase (MAO)-A or MAO-B inhibitors such as moclobemide, rasagiline, selegiline, and safinamide, and catechol-O-methyl transferase (COMT) inhibitors such as tolcapone and entacapone.
- decarboxylase inhibitors such as carbidopa and benserazide
- MAO monoamine oxidase
- MAO-A or MAO-B inhibitors such as moclobemide, rasagiline, selegiline, and safinamide
- POT catechol-O-methyl transferase
- oral drugs include SINEMET ® and SINEMET ® CR sustained-release tablets that include carbidopa or levodopa; MADOPAR ® tablets containing levodopa and benserazide; and STALEVO ® tablets containing carbidopa, entacapone, and levodopa.
- Carbidopa is a non-competitive inhibitor of L-dopa decarboxylase. When mixed with levodopa, carbidopa inhibits the peripheral conversion of levodopa to dopamine. This results in increased levodopa available for transport to the CNS. Carbidopa also inhibits the metabolism of levodopa in the gastrointestinal (GI) tract, thus, increasing levodopa bioavailability. It is used in Parkinson's disease to reduce the peripheral effect of dopamine. The loss of the hydrazine functional group represents the major metabolic pathway for carbidopa.
- GI gastrointestinal
- Hydrazine N2H4
- salts are used in the production of pharmaceutical products.
- Hydrazine and its salts are used in the pharmaceutical industry as an intermediate to produce drugs with different therapeutic effects including decarboxylase inhibitors, anti-hypertensives, and anti-bacterials. Since hydrazine is toxic and thought to be a possible human carcinogen, its presence is limited in some of these drug substances in the monographs of the European Pharmacopoeia (Ph. Eur.). [007] Accordingly, there is an ongoing and urgent need for liquid formulations and compositions that can achieve continuous dopaminergic stimulation to treat movement disorders such as Parkinson's disease more effectively, containing a safe and tolerable amount of hydrazine.
- compositions which include a prodrug of carbidopa or pharmaceutically acceptable salts thereof, and further including at least one antioxidant.
- Such compositions have shown to be more stable than those containing no antioxidants at all.
- compositions comprising at least two antioxidants have shown to be more stable than corresponding pharmaceutical compositions comprising only a single antioxidant.
- Disclosed formulations have improved resistance to degradation (e.g., have minimal amounts of a degradation species, for example, hydrazine), and are significantly stable.
- a pharmaceutically acceptable formulation comprising:
- R 1 and R 2 are each independently selected from the group consisting of H, C1-C4 alkyl, - P(0)(OH) 2 , and -R 5 -0-P-(0)(OH) 2 ;
- R 5 is a Ci-C 6 alkyl or a C3-C6 cycloalkyl
- R 6 is selected from the group consisting of H, -P(0)(OH) 2 , or a C1-C4 alkyl,
- R 1 , R 2 and R 6 is not H
- a pharmaceutically acceptable carrier wherein the pharmaceutical composition has lower level of hydrazine as compared to a similar pharmaceutical composition comprising one or no antioxidants.
- a pharmaceutical composition may have less than about 10 ⁇ g/ml (10 ppm) hydrazine, less than about 5 ⁇ g/ml (50 ppm) hydrazine, or less than about 1 ⁇ g/ml (1 ppm) hydrazine.
- a disclosed pharmaceutical composition may comprise from about 0.1 % to about 10% by weight of the compound of formula (I), for example, from about 0.5% to about 6% by weight, about 1% to about 4% by weight, about 0.75% by weight, about 1.4% by weight, about 3% by weight, about 3.3% by weight, or about 4% by weight of the compound of formula (I).
- the first antioxidant is ascorbic acid or a pharmaceutically acceptable salt thereof, for example sodium ascorbate, potassium ascorbate, calcium ascorbate, ascorbyl stearate and ascorbyl palmitate, or a combination thereof.
- the pharmaceutically acceptable salt of ascorbic acid is sodium ascorbate.
- the first antioxidant is sodium bisulfite.
- a disclosed pharmaceutical composition may comprise from about 0.1 % to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, for example, from about 0.2% to about 2%, from about 0.4% to about 1.3%, about 0.5%, about 0.6%, about 0.75%, about 0.85%, about 1.0%, or about 1.2% by weight ascorbic acid or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition comprises a second antioxidant.
- the second antioxidant in a disclosed pharmaceutical composition may be, for example, L-cysteine or a pharmaceutically acceptable salt thereof, N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof, glutathione or a pharmaceutically acceptable salt thereof, diacetylcysteine or a pharmaceutically acceptable salt thereof, and sodium bisulfite, or any combination thereof.
- the second antioxidant is selected from the group consisting of cysteine hydrochloride, NAC, and sodium bisulfite, or any combination thereof.
- a disclosed pharmaceutical composition may comprise: (i) from about 0.001% to about 5%, from about 0.01% to about 1%, from about 0.1% to about 0.6%, about 0.3%, or about 0.4% by weight L-cysteine or a pharmaceutically acceptable salt thereof;
- Exemplary embodiments relate to a pharmaceutical composition
- a pharmaceutical composition comprising from about 0.1% to about 10% by weight of the compound of formula (I), from about 0.1% to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and
- a disclosed pharmaceutical composition may comprise from about 0.5% to about 6%, or from about 1% to about 4% by weight of the compound of formula (I), from about 0.2% to about 2%, or from about 0.4% to about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and
- a disclosed pharmaceutical composition may comprise a levodopa and/or prodrug of levodopa or a pharmaceutically acceptable salt thereof, for example, a compound of formula (II) represented by:
- R 3 and R 4 are each independently selected from the group consisting of H, -P(0)(OH) 2 , and -R 5 -0-P(0)(OH) 2 ;
- R 5 is a Ci-C 6 alkyl or a C3-C6 cycloalkyl
- R 6 is H or a Ci-C 4 alkyl
- R 3 , R 4 and/or R 6 is not H.
- the levodopa prodrug may be a levodopa 4' -monophosphate and/or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition may comprise either less than about 1% by weight, or form about 1% to about 20% by weight of a levodopa and/or levodopa prodrug or a pharmaceutically acceptable salt thereof, for example, from about 2% to about 16%, about 4%, about 6%, about 12%, or about 13.2% by weight of a levodopa and/or levodopa prodrug or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition may further comprise arginine, meglumine, or a combination thereof, and optionally further comprising a surfactant.
- the surfactant may be, for example, polysorbate 80.
- a disclosed pharmaceutical composition may comprise from about 0.01% to about 5%, from about 0.1 % to about 0.5%, or about 0.3% by weight surfactant such as polysorbate 80, and/or and from 0% to about 42% by weight arginine, meglumine, or a combination thereof.
- Exemplary embodiments relate to a pharmaceutical composition
- a pharmaceutical composition comprising:
- composition comprises less than about 10 ⁇ g/ml (10 ppm), less than about 5 ⁇ g/ml (5 ppm), or less than about 1 ⁇ g/ml (1 ppm) hydrazine.
- a disclosed pharmaceutical composition may comprise less than about 10 ⁇ g/ml (10 ppm) or less than about 1 ⁇ g/ml (1 ppm) of hydrazine after storage for a period of 1 to 24 hours, 1 to 30 days, 1 to 12 months, or 1 to 3 years, at a temperature in a range of from about -20°C to about 25°C, for example, about -20°C, between about 2°C to about 8°C, or about 25°C.
- the pharmaceutical composition may comprise less than 1 ⁇ g/ml (1 ppm) of hydrazine after 7 days at a temperature of 25°C.
- a disclosed pharmaceutical composition is formulated as a liquid.
- the disclosure at least in part thereof, relates to a method for treating a disease, disorder or condition associated with loss of dopamine or dopaminergic neurons in a subject, the method comprising administering to the subject an effective amount of a disclosed pharmaceutical composition as described herein, thereby treating the subject.
- the disease, disorder or condition may be Parkinson's disease.
- a contemplated pharmaceutical composition used in a disclosed method may be administered substantially continuous.
- the disclosure at least in part thereof, relates to a kit comprising one, two, or more containers, wherein each container includes a disclosed pharmaceutical composition as described herein, wherein the pharmaceutical composition is present in an amount sufficient to treat a disease, disorder or condition associated with loss of dopamine or dopaminergic neurons in an individual in need thereof for at least 1 day, at least 1 week, at least 1 month, at least 2 months, at least 6 months or for at least one year.
- the disease, disorder or condition may be Parkinson's disease.
- Fig. 1 is a bar graph showing the hydrazine concentrations measured in formulations comprising a carbidopa phosphoester (4-carbidopa monophosphate) without antioxidant (Fl), with one antioxidant such as ascorbic acid or sodium bisulfite (F2 and F4, respectively), or with two antioxidants such as ascorbic acid and N-acetylcysteine (NAC) (F3). All formulations were kept at room temperature under N 2 atmosphere.
- Fig. 2 is a bar graph showing the hydrazine concentrations measured in formulations comprising a carbidopa monophosphoester (4-carbidopa monophosphate) and a 4-levodopa monophosphoester without antioxidant (F5) or with two antioxidants such as ascorbic acid and NAC (F6). All formulations were kept at RT without N 2 .
- the disclosure relates, at least in part, to formulations comprising a prodrug of carbidopa and/or a prodrug of levodopa and, optionally, one, two, or more antioxidation agents.
- formulations with a carbidopa prodrug such as, but not limited to, a carbidopa phosphate, and at least one, but preferably two, antioxidants such as ascorbic acid, L-cysteine, or N-acetylcysteine (NAC)
- a carbidopa prodrug such as, but not limited to, a carbidopa phosphate
- at least one, but preferably two, antioxidants such as ascorbic acid, L-cysteine, or N-acetylcysteine (NAC)
- NAC N-acetylcysteine
- the level of hydrazine correlates with the amounts of antioxidant(s) in the formulation, wherein increased amounts of antioxidant(s) may result in decreased release of hydrazine.
- This tendency or dependence of hydrazine release in presence and amount of antioxidant(s) has been established in formulation further comprising a prodrug of levodopa, such as but not limited to, a levodopa phosphate.
- a pharmaceutical composition comprising a prodrug of carbidopa and/or a levodopa and/or prodrug of levodopa and one or more antioxidation agents, and, optionally, a pharmaceutically acceptable carrier.
- compositions and “formulation” are interchangeable and, as used herein, refer to a medicinal preparation which encompass a mixture of different components, including one or more active agents as disclosed herein, combined or formulated together with one or more pharmaceutically acceptable carriers, which can be administered in a specific form, such as, but not limited to, a tablet, linctus, ointment, infusion or injection.
- the formulation may comprise solid and/or non-solid, e.g., liquid, gel, semi-solid (e.g. gel, wax) or gas components.
- compositions and formulations comprising at least one antioxidant.
- similar pharmaceutical composition denotes a composition that is identical to an embodied pharmaceutical composition in terms of all ingredients and amounts thereof it contains, except for being devoid of antioxidant(s).
- liquid pharmaceutical compositions are contemplated herein.
- active agent refers to a compound, which is accountable for a desired biological effect, and in the context of embodiment described herein, the active agent may be at least one of a carbidopa prodrug or a pharmaceutically acceptable salt thereof, and/or levodopa, a prodrug thereof or a pharmaceutically acceptable salt thereof, and any combination thereof, and the biological desired effect is treatment, amelioration, prevention, mitigation and/or curing of a central nervous system (CNS) disease or disorder such as Parkinson's disease.
- CNS central nervous system
- the terms "pharmaceutically acceptable”, “pharmacologically acceptable” and “physiologically acceptable” are interchangeable and mean approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans. These terms include formulations, molecular entities, and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by, e.g., the U.S. Food and Drug Administration (FDA) agency, and the European Medicines Agency (EMA).
- FDA U.S. Food and Drug Administration
- EMA European Medicines Agency
- physiologically suitable carrier refers to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of a possible active agent.
- Physiologically suitable carriers encompass any and all solvents and dispersion media.
- excipient refers to an inert substance added to a pharmaceutical composition (formulation) to further facilitate process and administration of the active ingredients.
- “Pharmaceutically acceptable excipients”, as used herein, encompass preservatives, antioxidants, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents in combination with pharmaceutically active agents is well known in the art.
- the compositions can also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions. Examples, without limitation, of excipients include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
- physiologically acceptable pH is understood to mean a pH of, e.g., a formulation or composition that facilitates administration of the formulation or composition to a patient without significant adverse effects, e.g., a pH of about 4 to about 9.8 (for example, about 4 ⁇ 0.3 to about 9.5 ⁇ 0.3).
- Ambient temperature refers to a temperature of from about 10°C to about 30°C. In exemplary embodiments, ambient temperature can be 25 °C.
- prodrug refers to an inactive substance that is converted to a drug within the body. Hence, a prodrug may itself be biologically inactive and circulate harmlessly until activated by some metabolic process or clinically relevant event in the body, by the action of, for example, enzymes or other chemicals so as to produce an active therapeutic drug.
- Prodrug approaches include chemical modifications of drugs to improve, e.g., stability, permeability and/or bioavailability, in the circulation system and/or in the target cell and tissues, while minimally affecting the pharmacokinetic profile of the drug.
- a prodrug may feature modification of the charge and lipophilicity of a drug in favor of blood brain barrier (BBB) permeability.
- BBB blood brain barrier
- An example of the prodrug approach is L-dopa (levodopa) in Parkinson's therapy. L-Dopa can cross the BBB and convert into the active therapeutic dopamine, which itself cannot cross the BBB.
- Chemical modifications to produce prodrugs include, for example, esterification (i.e. reacting a carboxylic group -COOH in the drug with an alcohol (ROH) to form an ester -COOR and water), amidation (i.e. formation of an amide group -CO-NH2 through the substitution of one or more of the hydrogen atoms by -R-CO-NH2, or replacing in a carboxylic group a carboxylic OH with NH 2 ), and/or salt form formation of the active drug.
- esterification i.e. reacting a carboxylic group -COOH in the drug with an alcohol (ROH) to form an ester -COOR and water
- amidation i.e. formation of an amide group -CO-NH2 through the substitution of one or more of the hydrogen atoms by -R-CO-NH2, or replacing in a carboxylic group a carboxylic OH with NH 2
- salt form formation of the active drug i.e. reacting a carboxy
- modifications include linkage of a prodrug to a biologically active compound (e.g., coupling to phenylethylamine to nicotinic acid), derivatization of drugs to centrally acting amines, enclosing drugs in cyclodextrin caged complexes, and covalent attachment to cationic carriers or membrane -permeable peptides.
- a biologically active compound e.g., coupling to phenylethylamine to nicotinic acid
- derivatization of drugs to centrally acting amines e.g., enclosing drugs in cyclodextrin caged complexes
- covalent attachment to cationic carriers or membrane -permeable peptides e.g., a chemical group used for derivatization of the parent drug molecule, called the progroup, should be nontoxic.
- the present disclosure provides formulations comprising a prodrug of carbidopa, wherein carbidopa is represented by the structural formula:
- Carbidopa is a non-competitive inhibitor of L-dopa decarboxylase, and when mixed with levodopa, it inhibits the peripheral conversion of levodopa to dopamine, resulting in increased levodopa available for transport to the CNS. Carbidopa also inhibits the metabolism of levodopa in the gastrointestinal (GI) tract, thus, increasing levodopa bioavailability as well. Carbidopa is used in Parkinson's disease to reduce the peripheral effect of dopamine.
- GI gastrointestinal
- the carbidopa prodrug may be an ester derivative of carbidopa.
- a carbidopa prodrug may be a carbidopa phosphoester, such as a carbidopa monophosphoester or a carbidopa di-phosphoseter.
- a contemplated formulation comprises a carbidopa prodrug compound of formula (I) represented by the structural formula:
- R 1 and R 2 are each independently selected from the group consisting of H, -P(0)(OH) 2 , and -R 5 -0-P(0)(OH) 2 ;
- R 5 is a Ci-C 6 alkyl or a C3-C6 cycloalkyl
- R 6 is H or a Ci-C 4 -alkyl
- R 1 , R 2 and/or R 6 is not H.
- a contemplated formulation comprises a compound corresponding in structure to a compound of formula (I).
- a contemplated formulation comprises a compound which is a pharmaceutically acceptable salt of a compound corresponding in structure to a compound of formula (I).
- a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be a compound wherein R 1 and R 2 each independently is H or -P(0)(OH) 2 ; and R 6 is H or a Ci-C4-alkyl, provided that at least one of R 1 , R 2 and/or R 6 is not H.
- R 1 may be H and R 2 may be -P(0)(OH) 2 , or R 1 may be - P(0)(OH) 2 and R 2 may H or, alternatively, both R 1 and R 2 are -P(0)(OH) 2 ; and R 6 is H.
- a contemplated formulation comprises a compound of formula
- a contemplated formulation comprises a compound of formula
- a contemplated formulation comprises a compound of formula
- a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R 1 and R 2 each independently is H or -R 5 -0-P(0)(OH)2, and R 6 is H or a Ci-C4-alkyl, provided that at least one of R 1 , R 2 and/or R 6 is not H.
- R 1 may be H and R 2 may be -R 5 -0-P(0)(OH)2, or R 1 may be -R 5 -0-P(0)(OH) 2 and R 2 may H, or, alternatively, both R 1 and R 2 are -R 5 -0-P(0)(OH) 2 ;
- R 5 is a C1-C4 alkyl or a Cs-Ce cycloalkyl; and R 6 is H.
- R 1 and R 2 are -R 5 -0-P(0)(OH)2, and R 5 is an alkyl selected from methyl, ethyl, propyl, butyl, pentyl or hexyl, or a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R 6 is H.
- R 5 is methyl.
- R 5 is ethyl.
- R 5 is propyl such as propyl n-propyl or isopropyl, or R 5 is butyl selected from n- butyl, sec-butyl, isobutyl and/or tert-butyl.
- a contemplated formulation comprises a compound of the formula (Id) corresponding in structure to:
- a contemplated formulation comprises a compound of the formula (Ie) corresponding in structure to:
- a contemplated formulation comprises a compound of the formula (If) corresponding in structure to:
- a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R 1 and R 2 are each independently H or -P(0)(OH) 2 ; and R 6 is a Ci-C4-alkyl.
- R 1 may be H and R 2 may be -P(0)(OH) 2 , or R 1 may be -P(0)(OH) 2 and R 2 may H, or, alternatively, both R 1 and R 2 are -P(0)(OH) 2 ; and R 6 is a Ci-C4-alkyl selected from methyl ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl).
- R 1 and R 2 are -P(0)(OH) 2
- R 6 is an alkyl selected from methyl, ethyl, propyl or butyl.
- R 6 is methyl.
- R 6 is ethyl.
- R 6 is propyl such as n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec -butyl, isobutyl and/or tert- butyl.
- a contemplated formulation comprises a compound of the formula (Ig) corresponding in structure to:
- a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may further be exemplified by a compound wherein R 1 and R 2 are each independently H or -R 5 -0-P(0)(OH) 2 ; R 5 is a C1-C4 alkyl; and R 6 is a Ci-C 4 -alkyl.
- R 1 may be H and R 2 may be -R 5 -0-P(0)(OH) 2 , or R 1 may be -R 5 -0-P(0)(OH) 2 and R 2 may H, or, alternatively, both R 1 and R 2 are -R 5 -0-P(0)(OH) 2 ; and R 5 and R 6 are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec- butyl, isobutyl and/or tert-butyl).
- propyl e.g., n-propyl, isopropyl
- butyl e.g., n-butyl, sec- butyl, isobutyl and/or tert-butyl.
- R 1 and R 2 are -R 5 -0-P(0)(OH) 2
- R 5 is methyl
- R 6 is methyl, ethyl, propyl or butyl.
- R 6 is methyl.
- R 6 is ethyl.
- R 6 is propyl such as n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.
- R 5 and R 6 feature further combinations of R 5 and R 6 , provided that of at least one of R 1 and R 2 is -R 5 -0-P(0)(OH)2.
- R 5 may be ethyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be propyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be butyl and R 6 may be methyl, ethyl, propyl or butyl, or R 5 may be cyclopentyl or cyclohexyl and R 6 may be methyl, ethyl, propyl or butyl.
- a compound corresponding in structure to a compound of formula (I) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein one of R 1 and R 2 is independently -P(0)(OH) 2 or -R 5 -0-P(0)(OH) 2 , provided that R 1 and R 2 are not the same; R 5 is a C1-C4 alkyl; and R 6 is H or a Ci-C4-alkyl.
- R 1 may be -P(0)(OH) 2 and R 2 may be -R 5 -0-P(0)(OH) 2 , or R 1 may be -R 5 -0-P(0)(OH) 2 and R 2 may -P(0)(OH) 2 ;
- R 5 is selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl); and R 6 is H.
- R 1 and R 2 are different and each independently is - P(0)(OH) 2 or -R 5 -0-P(0)(OH) 2
- R 5 and R 6 are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl).
- R 1 and R 2 are not the same and each independently is -P(0)(OH) 2 or -R 5 -0-P(0)(OH) 2 , R 5 is methyl and R 6 is methyl, ethyl, propyl or butyl.
- R 6 is methyl.
- R 6 is ethyl.
- R 6 is propyl such as n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.
- a contemplated formulation comprises a compound of the formula (Hi) corresponding in structure to:
- R 5 and R 6 feature further combinations of R 5 and R 6 , wherein none of R 1 and R 2 is H, and R 1 and R 2 are different phosphoester groups as defined herein.
- R 5 may be ethyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be propyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be butyl and R 6 may be methyl, ethyl, propyl or butyl.
- the disclosure provides a formulation with levodopa (L-dopa), a prodrug of levodopa (L-dopa), 3,4-dihydroxyphenylalanine, wherein L-dopa is represented by the structural formula:
- L-Dopa is an amino acid that is made and used as part of the normal biology of humans, some animals and plants. Some animals and humans make it via biosynthesis from the amino acid L- tyrosine.
- Levodopa is the precursor to the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline), which are collectively known as catecholamines. Furthermore, levodopa itself mediates neurotrophic factor release by the brain and CNS.
- L-Dopa can be manufactured and in its pure form is sold as a psychoactive drug used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.
- the levodopa prodrug may be an ester derivative of L-dopa.
- a levodopa prodrug may be a L-dopa phosphoester, such as a L-dopa monophosphoester or L-dopa di- phosphoseter.
- a contemplated formulation comprises a levodopa prodrug compound of formula (II), represented by the structural formula:
- R 3 and R 4 are each independently selected from the group consisting of H, -P(0)(OH) 2 , and -R 5 -0-P(0)(OH) 2 ;
- R 5 is a Ci-C 6 alkyl or a C3-C6 cycloalkyl
- R 6 is H or a Ci-C 4 -alkyl
- R 3 , R 4 and/or R 6 is not H.
- a levodopa prodrug corresponds in structure to a compound of formula (II). In some embodiments, a levodopa prodrug is a pharmaceutically acceptable salt of a compound corresponding in structure to a compound of formula (II).
- a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be a compound wherein R 3 and R 4 each independently is H or -P(0)(OH) 2 ; and R 6 is H or a Ci-C 4 -alkyl, provided that at least one of R 3 , R 4 and/or R 6 is not H.
- R 3 may be H and R 4 may be -P(0)(OH) 2 , or R 3 may be - P(0)(OH) 2 and R 4 may H, or, alternatively, both R 3 and R 4 are -P(0)(OH) 2 ; and R 6 is H.
- a contemplated formulation comprises a compound of formula
- a contemplated formulation comprises a compound of formula
- a contemplated formulation comprises a compound of formula (lie), corresponding in structure to:
- a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R 3 and R 4 are each independently H or -R 5 -0-P(0)(OH) 2 , for example, R 3 may be H and R 4 may be -R 5 -0- P(0)(OH) 2 , or R 3 may be -R 5 -0-P(0)(OH) 2 and R 4 may H, or, alternatively, both R 3 and R 4 are - R 5 -0-P(0)(OH) 2 ; R 5 is a C1-C4 alkyl or a C 5 -C 6 cycloalkyl; and R 6 is H.
- R 3 and R 4 are -R 5 -0-P(0)(OH) 2
- R 5 is an alkyl selected from methyl, ethyl, propyl or butyl, pentyl or hexyl, or a cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
- R 6 is H.
- R 5 is methyl.
- R 5 is ethyl.
- R 5 is propyl such as propyl n-propyl or isopropyl, or R 5 is butyl selected from n- butyl, sec-butyl, isobutyl and/or tert-butyl.
- a contemplated formulation comprises a compound of the formula (lid), corresponding in structure to:
- a contemplated formulation comprises a compound of the formula (He), corresponding in structure to: HO
- a contemplated formulation comprises a compound of the formula (Ilf) corresponding in structure to:
- a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein R 3 and R 4 are each independently H or -P(0)(OH) 2 ; and R 6 is a Ci-C4-alkyl.
- R 3 may be H and R 4 may be -P(0)(OH) 2 , or R 3 may be -P(0)(OH) 2 and R 4 may H, or, alternatively, both R 3 and R 4 are -P(0)(OH) 2 ; and R 6 is a Ci-C4-alkyl selected from methyl ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl).
- R 3 and R 4 are -P(0)(OH) 2
- R 6 is an alkyl selected from methyl, ethyl, propyl or butyl.
- R 6 is methyl.
- R 6 is ethyl.
- R 6 is propyl such as n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec -butyl, isobutyl and/or tert- butyl.
- a contemplated formulation comprises a compound of the formula (Ilg), corresponding in structure to:
- a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may further be exemplified by a compound wherein R 3 and R 4 are each independently H or -R 5 -0-P(0)(OH) 2 ; R 5 is a C1-C4 alkyl; and R 6 is a Ci-C 4 -alkyl.
- R 3 may be H and R 4 may be -R 5 -0-P(0)(OH) 2 , or R 3 may be -R 5 -0-P(0)(OH) 2 and R 4 may H or, alternatively, both R 3 and R 4 are -R 5 -0-P(0)(OH) 2 ; and R 5 and R 6 are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec- butyl, isobutyl or tert-butyl).
- propyl e.g., n-propyl, isopropyl
- butyl e.g., n-butyl, sec- butyl, isobutyl or tert-butyl.
- R 3 and R 4 are -R 5 -0-P(0)(OH) 2 , R 5 is methyl and R 6 is methyl, ethyl, propyl or butyl.
- R 6 is methyl.
- R 6 is ethyl.
- R 6 is propyl such as propyl n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert- butyl.
- R 5 may be ethyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be propyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be butyl and R 6 may be methyl, ethyl, propyl or butyl, or R 5 may be cyclopentyl or cyclohexyl and R 6 may be methyl, ethyl, propyl or butyl.
- a compound corresponding in structure to a compound of formula (II) or to a pharmaceutically acceptable salt thereof may be exemplified by a compound wherein one of R 3 and R 4 is each independently -P(0)(OH)2 or -R 5 -0-P(0)(OH)2, provided that R 3 and R 4 are not the same; R 5 is a C1-C4 alkyl; and R 6 is H or a Ci-C4-alkyl.
- R 3 may be -P(0)(OH)2 and R 4 may be -R 5 -0-P(0)(OH) 2 , or R 3 may be -R 5 -0-P(0)(OH) 2 and R 4 may -P(0)(OH) 2 ;
- R 5 is selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec-butyl, isobutyl, tert-butyl); and R 6 is H.
- R 1 and R 2 are different and each independently is - P(0)(OH)2 or -R 5 -0-P(0)(OH)2, and R 5 and R 6 are each independently selected from ethyl, propyl (e.g., n-propyl, isopropyl), and butyl (e.g., n-butyl, sec -butyl, isobutyl and/or tert-butyl).
- R 3 and R 4 are not the same and each independently is -P(0)(OH) 2 or -R 5 -0-P(0)(OH) 2 , R 5 is methyl and R 6 is methyl, ethyl, propyl or butyl. In an exemplary embodiment, R 6 is methyl. In a further exemplary embodiment, R 6 is ethyl.
- R 6 is propyl such as n-propyl or isopropyl, or R 6 is butyl selected from n-butyl, sec-butyl, isobutyl and/or tert-butyl.
- a contemplated formulation comprises a compound of the formula (IHi) corresponding in structure to:
- R 5 and R 6 feature further combinations of R 5 and R 6 , wherein none of R 3 and R 4 is H, and R 3 and R 4 are different phosphoester groups as defined herein.
- R 5 may be ethyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be propyl and R 6 may be methyl, ethyl, propyl or butyl; or R 5 may be butyl and R 6 may be methyl, ethyl, propyl or butyl.
- the term "pharmaceutically acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are commensurate with a reasonable benefit/risk ratio.
- Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, fumaric, benzoic acid, cinnamic acid, a sulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; and (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion such as lithium, sodium or potassium, an al
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, laurate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.
- salts of amines, carboxylic acids, and other types of compounds are well known in the art.
- S.M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1 -19 (1977).
- the salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting a free base or free acid function with a suitable reagent.
- a free base function can be reacted with a suitable acid.
- L-dopa prodrugs and carbidopa prodrugs described above are contemplated.
- Such crystalline forms include L-dopa 4' -monophosphate anhydrate (i), L-dopa 4'-monophosphate anhydrate (ii), L-dopa 3 '-monophosphate, L-dopa 3',4'-diphosphate trihydrate, carbidopa 4'-monophosphate trihydrate, carbidopa 4'-monophosphate dihydrate, carbidopa 4'-monophosphate dehydrate, carbidopa 3 '-monophosphate (i), carbidopa 3'- monophosphate (ii), and carbidopa 3', 4'-diphosphate sodium salt.
- the levodopa prodrug compound included in the pharmaceutical composition is levodopa 4' -monophosphate, levodopa 3 '-monophosphate, or a pharmaceutically acceptable salt thereof.
- a disclosed formulation may comprise a carbidopa prodrug, for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to about 10% by weight.
- a carbidopa prodrug for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to about 10% by weight.
- a carbidopa prodrug for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to about 10% by weight.
- a carbidopa prodrug for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to about 10% by weight.
- a carbidopa prodrug for example a compound of formula (I), or a pharmaceutically acceptable salt thereof in an amount which is in a range of from about 0.01% to
- a contemplated formulation may comprise about 0.01%, about 0.1%, about 0.25%, about 0.50%, about 0.75%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 2%, about 2.5%, about 3.0%, about 3.3% about 3.5%, about 4%, about 4.5%, about 5.0%, about 5.5%, about 6%, about 6.5%, about 7%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0% carbidopa prodrug for example a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.
- a disclosed formulation may comprise levodopa or a levodopa prodrug thereof, for example a compound of formula (II) or a pharmaceutically acceptable salt thereof, in varying amounts, for example, in an amount which is in a range of from about 1% to about 20% by weight.
- levodopa or a levodopa prodrug thereof and/or a pharmaceutically salt thereof For example, from about 2% to about 8%, from about 2% to about 16%, from about 4% to about 7%, from about 8% to about 20%, from about 8% to about 16%, from about 10% to about 14%, or from about 11% to about 14%, from about 11% to about 15% or from about 12% to about 14% by weight, and any amounts therebetween, of levodopa or a levodopa prodrug thereof and/or a pharmaceutically salt thereof.
- a contemplated formulation may comprise about 5%, about 6%, about 12% or about 13.2% by weight levodopa and/or a prodrug thereof or a pharmaceutically acceptable salt thereof.
- any of the active agents as defined herein may undergo oxidation and/or degradation resulting in release of various degradants.
- hydrazine may result from oxidative degradation of a carbidopa prodrug such as a carbidopa phosphoester.
- Hydrazine is a carcinogen, thus, it is important to reduce the release of hydrazine into the pharmaceutical compositions.
- antioxidant refers to a substance which slows down the damage that can be caused to other substances by the effects of oxygen. In other words, an antioxidant inhibits the oxidation of other molecules. Antioxidants include two different groups of substances: industrial chemicals which are added to products to prevent oxidation, and natural chemicals found in foods and body tissue.
- antioxidants include ascorbic acid (vitamin C) or a salt thereof (e.g., sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate); cysteine or a cysteine derivative such as L-cysteine, N- acetyl cysteine (NAC), glutathione, thiol precursor such as L-2-oxo-4-thiazolidine carboxylic acid (OTC), diacetylcysteine, S-methyl-N-acetylcysteine amide, acetyl derivatives of S-methyl-N- acetylcysteine methylhydrazide, S-methylcysteine morpholineamide, and S-methyl-N- acetylcysteine morpholineamide, or a salt thereof; lipoic acid; uric acid; carotenes; a-tocopherol (vitamin E); and ubi
- antioxidants contemplated herein are phenolic antioxidants such as di-tert- butyl methyl phenols, tert-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tertiarybutylhydroxyquinone (TBHQ)), propyl gallate (PG), flavonoid compounds, cinnamic acid derivatives, coumarins, and others.
- phenolic antioxidants such as di-tert- butyl methyl phenols, tert-butyl-methoxyphenols, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), polyphenols, tocopherols, ubiquinones (e.g., caffeic acid, tertiarybutylhydroxyquinone (TBHQ)), propyl gall
- Ascorbic acid is a monosaccharide oxidation -reduction (redox) catalyst found in both animals and plants. Ascorbic acid acts as an oxygen scavenger to reduce molecular oxygen.
- redox oxidation -reduction
- Thiol containing compounds such as cysteine, NAC, glutathione and thiol precursors such as OTC have several potential antioxidant effects. These agents can directly scavenge radicals via hydrogen donation from their SH group, resulting in formation of a thiyl (S) radical.
- Formulations including at least two antioxidants can result in substantially lower levels of hydrazine, as compared to formulations with fewer antioxidants. For example, when two antioxidants are included in the formulation they may be ascorbic acid and L-cysteine, or ascorbic acid and NAC, or sodium ascorbate and L-cysteine, or sodium ascorbate and NAC.
- Such formulations can, e.g., reduce formation of undesired degradation products and/or provide substantially stable formulations.
- Oxidation of carbidopa prodrugs may further occur in the body, for example, by tyrosinase, and may produce 3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid and 6,7-dihydroxy- 3-methylcinnoline.
- the catechol (di-hydroxy phenyl) moiety can oxidize to an o-quinone.
- Tyrosinase a copper-containing enzyme, is involved in the conversion of an o- diphenol (or a di-hydroxy phenyl moiety) to the corresponding o-quinone.
- Disclosed formulations may include active agents such as a carbidopa prodrug, levodopa and/or levodopa prodrug and/or pharmaceutically acceptable salts thereof and any combination thereof, and further include one or more agents that inhibit the formation of oxidation products as well as other degradants after the prodrugs are administered into the body.
- active agents such as a carbidopa prodrug, levodopa and/or levodopa prodrug and/or pharmaceutically acceptable salts thereof and any combination thereof, and further include one or more agents that inhibit the formation of oxidation products as well as other degradants after the prodrugs are administered into the body.
- agents may be e.g., antioxidants, tyrosinase inhibitors and/or Cu ++ chelators.
- Tyrosinase inhibitors contemplated herein include, but not limited to, captopril, methimazole, quercetin, arbutin, aloesin, N-acetylglucoseamine, retinoic acid, a-tocopheryl, ferulate, Mg ascorbyl phosphate (MAP), substrate analogues (e.g., sodium benzoate, L- phenylalanine) and/or Cu ++ chelators.
- captopril methimazole
- quercetin arbutin
- aloesin N-acetylglucoseamine
- retinoic acid retinoic acid
- a-tocopheryl ferulate
- substrate analogues e.g., sodium benzoate, L- phenylalanine
- Cu ++ chelators e.g., Cu ++ chelators.
- Cu ++ chelators include, Na 2 -EDTA, Na 2 -EDTA-Ca, DMSA (succimer), D-penicillamine (DPA), trientine-HCl, dimercaprol, clioquinol, sodium thiosulfate, TETA, TEPA, curcumin, neocuproine, tannin, and/or cuprizone.
- a contemplated pharmaceutical composition comprises a carbidopa prodrug compound of the formula (I) as defined herein, for example, one or more compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/ or (Ih), as defined herein, at least one antioxidant.
- a contemplated pharmaceutical composition comprises a levodopa prodrug compound of the formula (II) as defined herein, for example, one or more compounds of formulae (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg) and/ or (Ilh), as defined herein, at least one antioxidant.
- a contemplated pharmaceutical composition comprises a carbidopa prodrug compound of the formula (I), herein also referred to as a "first active agent”, and a levodopa and/or levodopa prodrug compound of the formula (II) herein also referred to as a "second active agent", at least one antioxidant.
- a contemplated formulation may comprise any combination of a carbidopa prodrug of formula (I) which may be, for example, one or more compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), or a pharmaceutically acceptable salt thereof, as defined herein (a first active agent), and a levodopa prodrug of formula (II) which may be, for example, one or more compounds of formulae (Ila), (lib), (lie), (lid), (He), (Ilf), (Ilg) and/or (Ilh), or a pharmaceutically acceptable salt thereof, as defined herein (a second active agent).
- a carbidopa prodrug of formula (I) which may be, for example, one or more compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), or a pharmaceutically acceptable salt thereof, as defined herein
- Disclosed formulations can include one, two, or more antioxidants.
- a disclosed formulation can include one, two, or more of an agent selected from the group consisting of ascorbic acid or a salt thereof, for example, sodium ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl stearate, particularly sodium ascorbate, and cysteine or a cysteine derivative, for example, L-cysteine, NAC, glutathione, diacetylcystine, S-methyl-N- acetylcysteine amide, acetyl derivatives of S-methyl-N-acetylcysteine methylhydrazide, S- methylcysteine morpholineamide, and S-methyl-N-acetylcysteine morpholineamide, or a salt thereof.
- an agent selected from the group consisting of ascorbic acid or a salt thereof for example, sodium ascorbate, calcium as
- a disclosed formulation may include ascorbic acid, or a salt thereof.
- Contemplated formulation that comprise ascorbic acid or a salt thereof may include from about 0.1% to about 10% by weight, or more ascorbic acid (or salt thereof). For example, from about 0.1% to about 2.0%, from about 0.1% to about 1.0%, from about 0.1% to about 5%, about 0.2% by weight to about 1.0%, from about 0.2% to about 1.5%, from about 0.2% to about 2.0%, from about 0.2% to about 2.5%, from about 0.2% to about 5%, from about 0.3% to about 1.2%, from about 0.4% to about 1.0%, from about 0.4% to about 1.3%, from about 0.4% to about 2.0%, from about 0.4% to about 3.0%, from about 0.8% to about 1.3%, from about 1% to about 2.5%, from about 1.0% to about 3.0%, from about 1.0% to about 5.0%, from about 1% to about 10.0%, from about 2.0% to about 5.0%, from about 3.0% to about 5.0%, from about 3.0% to about 7.0%, from about 5.0% to about 7.0%
- a disclosed formulation may include, for example, about 0.01%, about 0.1%, about 0.25%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.75%, about 0.8%, about 0.85%, about 0.9%, about 0.95%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.3%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about 6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about 9.0%, about 9.5%, or about 10.0% by weight sodium ascorbate or ascorbic acid.
- disclosed formulations may include a bisulfite, e.g., sodium bisulfite or other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite.
- a bisulfite e.g., sodium bisulfite or other sulfite salts, e.g., sodium hydrogen sulfite or sodium metabisulfite.
- a disclosed formulation may comprise L-cysteine or a pharmaceutically acceptable salt thereof, N-acetylcysteine (NAC) or a pharmaceutically acceptable salt thereof, glutathione or a pharmaceutically acceptable salt thereof, diacetylcysteine or a pharmaceutically acceptable salt thereof, or sodium bisulfite.
- NAC N-acetylcysteine
- glutathione or a pharmaceutically acceptable salt thereof
- diacetylcysteine or a pharmaceutically acceptable salt thereof or sodium bisulfite.
- Contemplated pharmaceutical compositions may comprise from about 0.001% to about 5% by weight, or more, L-cysteine.
- a disclosed pharmaceutical composition includes from about 0.01% to about 1%, from about 0.1% to about 0.6% or from about 0.3% to about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition includes about 0.3%, about 0.4% or about 0.5% by weight L-cysteine or a pharmaceutically acceptable salt thereof.
- Contemplated pharmaceutical compositions may include NAC at varying concentrations in a range of, for example, from about 0.001% to about 5%, or more.
- a disclosed pharmaceutical composition includes from about 0.01% to about 1% by weight NAC.
- a disclosed pharmaceutical composition includes about 0.1%, about 0.2%, about 0.3%, about 0.4% or about 0.5% by weight NAC or a pharmaceutically acceptable salt thereof.
- Contemplated pharmaceutical compositions may include sodium bisulfite at varying concentrations ranging, for example, from about 0.01% to about 2%, or more.
- a disclosed pharmaceutical composition includes from about 0.075% to about 0.75% by weight sodium bisulfite or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition includes about 0.1 % by weight sodium bisulfite.
- Contemplated pharmaceutical compositions may include glutathione at varying concentrations ranging, for example, from about 0.001% to about 5.0% by weight, or more.
- a disclosed pharmaceutical composition includes from about 0.1% to about 1.0% by weight glutathione or a pharmaceutically acceptable salt thereof.
- Contemplated pharmaceutical compositions may include diacetylcysteine or a pharmaceutically acceptable salt thereof at varying concentrations ranging, for example, from about 0.001% to about 5.0% by weight, or more.
- a disclosed pharmaceutical composition includes, from about 0.01% to about 1.0% by weight diacetylcysteine or a pharmaceutically acceptable salt thereof.
- Contemplated formulation may comprise, for example, NAC, L-cysteine, diacetylcystine, and/or glutathione, and/or a pharmaceutically acceptable salt thereof.
- a disclosed pharmaceutical composition may include: from about 0.001% to about 5.0%, from about 0.01% to about 1.0%, from about 0.1% to about 0.6%, about 0.3% or about 0.4% by weight L-cysteine or a pharmaceutically acceptable salt thereof such as L- cysteine hydrochloride; from about 0.001% to about 5.0%, from about 0.01% to about 1.0%, about 0.1%, about 0.2%, about 0.3%, or about 0.4% by weight NAC; from about 0.01% to about 2.0%, from about 0.075% to about 0.75%, or about 0.1% by weight sodium bisulfite; from about 0.001% to about 5.0%, or from about 0.1 % to about 1.0% by weight glutathione; and/or from about 0.001 % to about 5.0%, or from about 0.01% to about 1% by weight diacetylcysteine or a pharmaceutically acceptable salt thereof.
- L-cysteine or a pharmaceutically acceptable salt thereof such as L- cysteine hydrochloride
- NAC from about 0.0
- a formulation includes from about 0.001% to about 5%, from about 0.01% to about 5%, from about 0.1% to about 5%, from about 0.001% to about 1%, from about 0.01% to about 1%, or from about 0.1% to about 1% by weight of a compound selected from the group consisting of NAC, L-cysteine, diacetylcystine, and/or glutathione, or a pharmaceutically acceptable salt thereof.
- a disclosed formulation can include from about 0.01% to about 5%, e.g., from about 0.05% to about 1%, from 0.1% to about 0.6%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, or about 0.5% by weight of NAC and/or L-cysteine.
- a contemplated formulation may comprise a fist antioxidant which is ascorbic acid or a salt thereof, and a second antioxidant which is L-cysteine and/or a cysteine derivative, or a pharmaceutically acceptable salt thereof such as cysteine hydrochloride, NAC, or sodium bisulfite.
- a disclosed formulation may include ascorbic acid, or salt thereof, and a cysteine derivative.
- Exemplary embodiments contemplate a pharmaceutical composition comprising ascorbic acid and L-cysteine, sodium ascorbate and NAC, ascorbic acid and NAC, sodium ascorbate and L-cysteine, ascorbic acid and diacetylcystine, sodium ascorbate and diacetylcystine, ascorbic acid and glutathione, or sodium ascorbate and glutathione.
- a disclosed formulation can include ascorbic acid (or a salt thereof) and a cysteine derivative such as L-cysteine, NAC and/or diacetylcystine.
- a disclosed formulation includes from about 0.1% to about 10% ascorbic acid (or salt thereof), and from about 0.001% to about 5%, or from about 0.001% to about 1% by weight L-cysteine and/or NAC and/or diacetylcystine and/or glutathione.
- a contemplated formulation may comprise:
- the formulation has less than about 5 ⁇ g/ml (5 ppm) of hydrazine, as determined by a gas chromatography-mass spectrometry (GC-MS) method, and/or less than 5% or less than 1% by weight of a degradant, as calculated relative to the initial amount of carbidopa prodrug.
- GC-MS gas chromatography-mass spectrometry
- formulations that include a carbidopa prodrug thereof, for example, a compound of formula (I) herein, or one or more of the compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), as defined herein, or a pharmaceutically acceptable salt thereof, having less than 0.1 ⁇ g/ml (0.1 ppm) or less than 0.5 ⁇ g/ml (0.5 ppm) by weight hydrazine, as determined by GC-MS, and/or less than 5% or less than 1% by weight of a degradant, as calculated relative to the initial amount of carbidopa prodrug.
- a carbidopa prodrug for example, a compound of formula (I) herein, or one or more of the compounds of formulae (la), (lb), (Ic), (Id), (Ie), (If), (Ig) and/or (Ih), as defined herein, or a pharmaceutically
- degradation is the product of the process of degradation, namely, the breakdown of an organic compound.
- the degradation process may be, for example, a chemical, physical or a biological, for example, enzymatic, process.
- degradationants encompass the breakdown products of ingredients of a contemplated formulation, before and/or after administration or use thereof.
- a degradant may be a desired component such as the main active agent or a secondary active agent.
- a degradant may be a drug obtained or released after degradation or breakdown of a corresponding prodrug compound.
- a degradant may also feature an undesired consequence e.g., of a chemical breakdown process of a compound, for example, an active agent or a prodrug form thereof.
- Undesired degradants for example in a formulation, may be the consequence of lack of stability of one or more ingredients of the formulation, for example due to certain conditions provided to the formulation (e.g., pH, temperature, solvent, atmosphere, cross-reactivity and the like).
- Formulations may comprise various degradants.
- a degradant is hydrazine (H2N-NH2).
- Hydrazine is the product of an oxidative degradation of compounds comprising the -HN-NH2 moiety such as carbidopa and/or a prodrug thereof, for example, a compound of formula (I).
- an upper limit of the amount of hydrazine is set.
- the maximum level of hydrazine is less than about 10 ⁇ g/ml (10 ppm) or less than about 1 ⁇ g/ml (1 ppm) 1-48 hours, 1- 30 days, 1-12 months, or 1-3 years, at a temperature in a range of about -20°C to about 25°C.
- Contemplated pharmaceutical compositions may have less than about 10 ⁇ g/ml (10 ppm), less than about 9 ⁇ g/ml (9 ppm), less than about 8 ⁇ g/ml (8 ppm), less than about 7 ⁇ g/ml (7 ppm), less than about 6 ⁇ g/ml (6 ppm), less than about 5 ⁇ g/ml (5 ppm), less than about 4 ⁇ g/ml (4 ppm), less than about 3 ⁇ g/ml (3 ppm), less than about 2 ⁇ g/ml (2 ppm), or less than about 1 ⁇ g/ml (1 ppm) of hydrazine, after storage for periods of 1-24 hours, 1-30 days, 1-12 months, or 1- 3 years, at a temperature in a range of from about -20°C to about 25 °C, from about -20°C to about 0°C, from about 0°C to about 25°C, from about 2°C to about 8°C, from about 0°
- the pharmaceutical composition includes less than 1 ⁇ g/ml (1 ppm) of hydrazine after 7 days storage at a temperature of 25 °C.
- a disclosed pharmaceutical composition may have less than about 1 ⁇ g/ml (1 ppm), less than about 0.5 ⁇ g/ml (0.5 ppm), or less than about 0.1 ⁇ g/ml (0.1 ppm) of hydrazine, as determined by a GC-MS method.
- a disclosed pharmaceutical composition has from about 0.1 ⁇ g/ml (0.1 ppm) to about 1.0 ⁇ g/ml (1.0 ppm), from about 1.0 ⁇ g/ml (1.0 ppm) to about 5.0 ⁇ g/ml (5.0 ppm), from about 3.0 ⁇ g/ml (3.0 ppm) to about 5.0 ⁇ g/ml (5.0 ppm), from about 5.0 ⁇ g/ml (5.0 ppm) to about 7.0 ⁇ g/ml (7.0 ppm), from about 1.0 ⁇ g/ml (1.0 ppm) to about 10.0 ⁇ g/ml (10.0 ppm), from about 7.0 ⁇ g/ml (7.0 ppm) to about 10 ⁇ g/ml (10.0 ppm), or from about 5.0 ⁇ g/ml to about 10.0 ⁇ g/ml (from about 5.0 ppm to about 10.0 ppm) of hydrazine.
- a contemplated pharmaceutical composition comprises a degradant which is a compound of the formula (III) represented by the structural formula:
- R 1 and R 2 are each independently selected from the group consisting of H, -P(0)(OH) 2 , and -R 5 -0-P(0)(OH) 2 ;
- R 3 is H or a Ci-C 4 -alkyl
- R 5 is a Ci-C 6 -alkyl
- R 6 is H or a Ci-C4-alkyl or a C3-C6 cycloalkyl.
- At least one of R 1 , R 2 , R 3 , and R 6 in the degradant is not hydrogen.
- R 1 and/or R 2 is -P(0)(OH) 2 or -R 5 -0-P(0)(OH) 2 .
- R 1 , R 2 and R 6 in the degradant are hydrogens, and R 3 is hydrogen or alkyl.
- the degradant is the compound 3,4-dihydroxyphenyl-2-methyl propionic acid.
- Contemplated formulations may have less than about 5.0% by weight of a degradant, for example a degradant of formula (III) herein, as calculated, for example, relative to the amount of a carbidopa prodrug of formula (I).
- a degradant for example a degradant of formula (III) herein, as calculated, for example, relative to the amount of a carbidopa prodrug of formula (I).
- the amount of a degradant may be less than 4.0%, less than 3.0%, less than 2.0%, less than 1.0%, less than 0.5%, less than 0.3%, less than 0.2%, less than 0.1% or less than 0.05% by weigh relative to the amount of a carbidopa prodrug.
- Contemplated pharmaceutical compositions may include one or more of excipients selected from basic compounds such as arginine, a glucose amine such as meglumine, a pharmaceutically acceptable salt thereof or any combination thereof in varying amounts, to facilitate stabilization and solubilization of the active agents.
- Arginine and meglumine may form salts with levodopa thereby increasing their stability in the formulation.
- a disclosed pharmaceutical composition includes arginine.
- a disclosed pharmaceutical composition includes meglumine.
- a disclosed pharmaceutical composition includes arginine and meglumine.
- the pharmaceutical composition may include arginine, meglumine, or a combination thereof in a range of from about 0% to about 42% by weight. For example, from about 0% to about 3%, from about 0.1% to about 40%, from about 1% to about 10%, from about 2% to about 7%, from about 12% to about 18%, from about 10% to about 20%, from about 10% to about 25%, from about 2% to about 40%, from about 12% to about 36%, or from about 15.2% to about 32%, from about 30% to about 38%, from about 32% to about 40%, or from about 25% to about 40% by weight, arginine, meglumine, or a combination thereof.
- a contemplated formulation may comprise about 3.2%, about 3.4%, about 3.6%, about 3.7%, or about 4.6%, about 12.8%, about 14.8%, about 15.2%, about 15.5%, about 18.5%, about 32% or about 36% by weight arginine and/or meglumine and/or a salt thereof.
- a disclosed formulation may not include arginine and/or meglumine at all, or include 32% arginine, 32% meglumine, 36% arginine, or 36% meglumine.
- Contemplated pharmaceutical compositions may include a surfactant, for example, polysorbate 20, 40, 60 and/or 80.
- a surfactant for example, polysorbate 20, 40, 60 and/or 80.
- polysorbate 80 Tween® 80
- Disclosed formulations can have a pH that is pharmaceutically acceptable for subcutaneous administration, e.g., a pH of about 7 to about 10, for example, about 9.1 to about 9.8, for example, 9.2 to 9.6, at 25 °C.
- the carbidopa prodrugs and/or levodopa prodrugs disclosed herein can be combined and formulated in the same pharmaceutical composition, namely, as a single unit dosage from, or can be present in separate pharmaceutical compositions, namely a plurality of dosage unit forms, for example, two or more dosage unit form, each comprising one or more of a first active agent (e.g., a compound corresponding in structure to a compound of formula (I)), and/or a second active agent (e.g., a compound corresponding in structure to a compound of formula (II)).
- a first active agent e.g., a compound corresponding in structure to a compound of formula (I)
- a second active agent e.g., a compound corresponding in structure to a compound of formula (II
- a formulation disclosed herein can comprise a first unit dosage form with a carbidopa prodrug and a second unit dosage form with a L-dopa prodrug.
- a formulation can comprise a carbidopa prodrug and L-dopa prodrug in the same pharmaceutical composition.
- a formulation of any of the above embodiments may be in a form selected from the group consisting of liquid, gel, cream, solid, film, emulsion, suspension, solution, and aerosol (e.g., a liquid formulation).
- Exemplary embodiments disclosed herein pertain to formulations comprising various combinations of a first active agent, a second active agent, a first antioxidant, a second antioxidant, and various excipients and other components as defined herein. These formulations have improved resistance to oxidative degradation (e.g., have minimal amounts of a degradation species, for example, hydrazine), and are significantly stable.
- oxidative degradation e.g., have minimal amounts of a degradation species, for example, hydrazine
- a disclosed formulation comprises levodopa or a prodrug thereof such as a compound of formula (II), from about 0.1 % to about 6% by weight of a carbidopa prodrug such as a compound of formula (I), and at least at least one antioxidant.
- a disclosed formulation comprises form about 8% to about 16% (e.g., from about 11% to about 15%, or from about 12% to about 14%) by weight levodopa or a prodrug thereof such as a compound of formula (II), or a pharmaceutically acceptable salt thereof; from about 1% to about 4% by weight of a carbidopa prodrug such as compound of formula (I), or a pharmaceutically acceptable salt thereof; and at least one antioxidant.
- any of the formulations above may comprise one or more antioxidants selected from: ascorbic acid or a salt thereof in amounts ranging from about 0.1% to about 10% by weight; NAC in amounts ranging from about 0.01% to about 3% by weight; L-cysteine in amounts ranging from about 0.01% to about 1 % by weight; glutathione in amounts ranging from about 0.001% to about 1% by weight; and/or diacetylcystine or a salt thereof in amounts ranging from about 0.001% to about 1 % by weight.
- antioxidants selected from: ascorbic acid or a salt thereof in amounts ranging from about 0.1% to about 10% by weight; NAC in amounts ranging from about 0.01% to about 3% by weight; L-cysteine in amounts ranging from about 0.01% to about 1 % by weight; glutathione in amounts ranging from about 0.001% to about 1% by weight; and/or diacetylcystine or a salt thereof in amounts ranging from about 0.001% to about 1
- a disclosed formulation comprises:
- a carbidopa prodrug such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount within a range, for example, of from about 0.1% to about
- 10% by weight e.g., from about 0.1% to about 6%, from about 0.1 % to about 4%, from about 0.6% to about 1.4 %, from about 1.2% to about 4%, about 0.75%, about 1.4%, about 3%, or about 3.3% by weight;
- ascorbic acid or a salt thereof in an amount within a range, for example, of from about 0.1% to 10% (e.g., from about 0.3% to about 2%, from about 0.4% to about 0.6%, from about 0.4% to about 1%, from about 1.0% to about 1.3%, about 0.5%, about 1.2%, or about 1.3%) by weight; and
- antioxidants such as: (i) L-cysteine or a pharmaceutically acceptable salt thereof in an amount within a range, for example, of from about 0.001% to about 5%, or from about 0.01% to about 1% (e.g., from about 0.1% to about 0.6%, from about 0.1% to about 1%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, or about 0.8%); (ii) NAC in an amount within a range, for example, of from about 0.001% to about 5%, or from about 0.01% to about 3% (e.g., from about 0.1% to about 0.6%, from about 0.1% to about 1%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, or about 0.8%); and, optionally, (iii) glutathione and/or diacetylcystine or a salt thereof.
- L-cysteine or a pharmaceutically acceptable salt thereof in an amount within a range, for example, of from about 0.00
- a disclosed pharmaceutical composition comprises form about 0.1% to about 10% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, from about 0.1% to about 10% by weight ascorbic acid or a pharmaceutically acceptable salt thereof, and either from about 0.001 % to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof, from about 0.001% to about 5% by weight NAC, or from about 0.01% to about 2% by weight sodium bisulfite.
- the pharmaceutical composition comprises from about 0.5% to about 6.0% or from about 1.0% to about 4.0% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; from about 0.2% to about 2.0% or from about 0.4% to about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.01% to about 1.0% or from about 0.1% to about 0.6% by weight of L-cysteine or a pharmaceutically acceptable salt thereof; and either from about 0.01% to about 3.0% or from about 0.1% to about 2% by weight NAC or from about 0.075% to about 0.75% by weight sodium bisulfite.
- a disclosed pharmaceutical composition comprises about 12% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II) or a pharmaceutically acceptable salt thereof, about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.2% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or cysteine hydrochloride.
- a disclosed pharmaceutical composition comprises about 13.2% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)) or a pharmaceutically acceptable salt thereof, about 3.3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.3% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or cysteine hydrochloride.
- a disclosed pharmaceutical composition comprises about 12% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.2% by weight sodium ascorbate, and about 0.3% by weight NAC.
- a levodopa prodrug e.g., compound of formula (II)
- a pharmaceutically acceptable salt thereof about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 1.2% by weight sodium ascorbate, and about 0.3% by weight NAC.
- a disclosed pharmaceutical composition comprises from about 2% to about 16% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 1.2% to about 3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, from about 1.0% to about 1.3% by weight sodium ascorbate, and about 0.3% by weight L-cysteine or NAC.
- a levodopa prodrug e.g., compound of formula (II)
- a pharmaceutically acceptable salt thereof e.g., compound of formula (II)
- a disclosed pharmaceutical composition comprises about 6.0% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 1.4% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.
- a levodopa and/or a levodopa prodrug e.g., compound of formula (II)
- a pharmaceutically acceptable salt thereof about 1.4% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.
- a disclosed pharmaceutical composition comprises about 6.0% by weight of levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt thereof, about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.
- a levodopa and/or a levodopa prodrug e.g., compound of formula (II)
- a pharmaceutically acceptable salt thereof about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.4% by weight L-cysteine, and about 0.3% by weight polysorbate 80.
- a disclosed pharmaceutical composition comprises about 6.0% by weight levodopa and/or a levodopa prodrug (e.g., compound of formula (II)), or a pharmaceutically acceptable salt or an ester thereof, about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.5% by weight NAC, and about 0.3% by weight polysorbate 80.
- a levodopa prodrug e.g., compound of formula (II)
- a pharmaceutically acceptable salt or an ester thereof about 0.75% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, about 0.5% by weight ascorbic acid, about 0.5% by weight NAC, and about 0.3% by weight polysorbate 80.
- the formulation may have less than about 1.0 g ml (1.0 ppm), less than about 0.75 ⁇ g/ml (0.75 ppm), less than about 0.5 ⁇ g/ml (0.5 ppm), less than about 0.25 ⁇ g/ml (0.25 ppm), less than about 0.1 ⁇ g/ml (0.1 ppm), or less than about 0.05 ⁇ g/ml (0.05 ppm) of hydrazine, e.g., as determined by a gas chromatography-mass spectrometry (GC-MS) method.
- GC-MS gas chromatography-mass spectrometry
- the formulation has less than about 0.1 ⁇ g/ml (0.1 ppm) or less than about 0.05 ⁇ g/ml (0.05 ppm) of hydrazine, or from about 0.1 ⁇ g/ml to about 0.5 ⁇ g/ml (from about 0.1 to about 0.5 ppm) of hydrazine.
- a contemplated formulation may further include levodopa, a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof.
- a disclosed formulation comprises less than 4% (e.g., less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.05%, or less than 0.01%) by weight of levodopa and/or a levodopa prodrug or a pharmaceutically acceptable salt thereof.
- a disclosed formulation does not include a levodopa prodrug, or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition includes: from about 0.1% to about 10% by weight of the compound of formula (I); from about 0.1% to about 10% by weight, ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.001% to about 5% by weight L-cysteine or a pharmaceutically acceptable salt thereof, from about 0.001% to about 5% by weight NAC, or about 0.01% to about 2% by weight sodium bisulfite; from about 1% to about 20% by weight levodopa and/or a levodopa prodrug, or a pharmaceutically acceptable salt or an ester thereof; optionally, from 0% to about 42% by weight arginine, meglumine, or a combination thereof; and, optionally from about 0.01% to about 5% by weight polysorbate 80.
- the composition comprises less than about 10 ⁇ g/ml (10 ppm), less than about 5 ⁇ g/ml (5 ppm), or less than about 1 ⁇ g/ml (1 ppm)
- a disclosed pharmaceutical composition may comprise: from about 0.5% to about 6%, from about 1% to about 4%, about 0.75%, about 1.4%, about 3%, or about 3.3% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof; from about 0.2% to about 2%, from about 0.4% to about 1.3%, about 0.5%, about 1.2%, or about 1.3% by weight ascorbic acid or a pharmaceutically acceptable salt thereof; from about 0.01% to about 1% or from about 0.1% to about 0.6% by weight L-cysteine or a pharmaceutically acceptable salt thereof; and either from about 0.01% to about 3% or from about 0.1% to about 2% by weight NAC, or from about 0.075% to about 0.75% by weight sodium bisulfite; from about 2% to about 16%, about 4%, about 6%, about 12%, or about 13.2% by weight levodopa, a levodopa prodrug, or a pharmaceutically acceptable salt thereof; optionally, from about 0.5% to about 6%,
- a disclosed formulation comprises: from about 2% to about 8% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II); from about 0.1% to about 3% by weight of carbidopa prodrug such as a compound of formula (I); from 0% to about 25% by weight arginine; from about 0.1% to about 10% (e.g., from about 0.3% to about 2%) by weight ascorbic acid or salts thereof; and from about 0.001% to about 5% by weight of one of L-cysteine or a salt thereof, NAC, glutathione or diacetylcysteine or a salt thereof.
- a disclosed formulation comprises: from about 8% to about 16% by weight of levodopa and/or a levodopa prodrug such as a compound of formula (II); form about 1% to about 4% by weight of carbidopa prodrug such as a compound of formula (I); optionally, from 0% to about 40% by weight of a component selected from the group consisting of arginine, meglumine, and a combination thereof; from about 0.1% to about 10% by weight ascorbic acid or a salt thereof; and from about 0.001% to about 1 % by weight of one of L-cysteine or a salt thereof, NAC, glutathione or diacetylcysteine or a salt thereof.
- any one of the formulations described above may be in a liquid form.
- a liquid formulation comprising form about 4% to about 8% (e.g., about 6%) by weight of levodopa and/or a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof; from about 0.1% to about 1.5% (e.g., from about 0.6% to about 1.4%, about 0.75%, or about 1.4%) by weight of a carbidopa prodrug thereof, for example a compound of formula (I) or a pharmaceutically acceptable salt thereof; optionally, from 0% to about 20% (e.g., 0%, from about 10% to about 16%, about 15.2%, or about 15.6%) by weight arginine; and from about 0.1% to about 1.5% (e.g., from about 0.4 to about 1%, from about 0.4% to about 0.6%, or about 0.5%) by weight ascorbic acid or a salt thereof; and, optionally, from about 0.1% to about 0.7% (e.g., about a compound of formula (
- a disclosed formulation for example, a liquid formulation, includes (a) from about 0.4% to about 3% or from about 0.4 to about 2% by weight ascorbic acid or a salt thereof; and (b) from about 0.1% to about 3% by weight of L-cysteine or NAC.
- the formulation may further include from about 0.1% to about 0.5% (e.g., about 0.3%) by weight Tween®-80.
- a liquid formulation comprising form about 8% to about 16% (e.g., from about 12% to about 15%, about 12%, or about 13.2%) by weight of a levodopa and/or a levodopa prodrug, for example, a compound of formula (II) or a pharmaceutically acceptable salt thereof; from about 1% to about 4% (e.g., about 3.0% or about 3.3%) by weight of carbidopa prodrug, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof; optionally, from about 0% to about 42% (e.g., 0%, from about 32% to about 42%, about 32%, or about 36%) by weight of arginine, meglumine, or a combination thereof; from about 0.1% to about 1.5% (e.g., from about 1.0% to about 1.4%, about 1.2%, or about 1.3%) by weight ascorbic acid or a salt thereof (e.g., sodium ascorbic acid or a salt thereof (e
- the formulation after, for example, 1, 2, 3, 4, 6, 8, 10, 12, 15, 18, 20, 24 or 48 hours; 1, 2, 3, 5, 7, 10, 14, 21, 28, or 30 days; 1, 2, 3, 4, 6, 9, or 12 months; or 1, 1.5, 2, 2.5, or 3 years at 25°C, has less than about 1.0 ⁇ g/ml (1.0 ppm), less than about 0.75 ⁇ g/ml (0.75 ppm), less than about 0.5 ⁇ g/ml (0.5 ppm), less than about 0.2 ⁇ g/ml (0.2 ppm), less than about 0.1 ⁇ g/ml or (0.1 ppm) hydrazine as determined by GC-MS.
- Contemplated pharmaceutical compositions may have varying pH values or pH values that fall within a pH range.
- a disclosed pharmaceutical composition has a pH of from about 9.1 to about 10.0, from about 7.0 to about 10.0, from about 8.0 to about 10.0, from about 8.0 to about 9.0, from about 9.0 to about 9.5, from about 9.5 to about 10.0, from about 9.1 to about 9.3, from about 9.3 to about 9.6, from about 9.5 to about 9.7, or a pH from about 9.7 to about 10.0.
- a pharmaceutical composition may have a pH of about 7.0, about 7.5, about 8.0, about 8.5, about 9.0, about 9.1, about 9.2, about 9.3, about 9.4, about 9.5, about 9.6, about 9.7, about 9.8, about 9.9, about 10.0, or about 11.0.
- a contemplated formulation may comprise, for example, a carbidopa prodrug or a pharmaceutically acceptable salt thereof, one or toe antioxidants and, optionally, a surfactant, and the pH of the formulation may be within the range of from about 9.1 to about 10.0 or from about 9.6 to about 9.8.
- any of the formulation described herein may further comprise other active agents.
- a non-limiting example is catechol-O-methyl transferase (COMT) inhibitor, such as tolcapone or entacapone, or a pharmaceutically acceptable salt thereof.
- CCT catechol-O-methyl transferase
- Contemplated pharmaceutical formulations may be formulated in different media.
- a pharmaceutical composition may be formulated as a liquid, a gel, a cream, a solid, a film, an emulsion, a suspension, a solution, a lyophilisate, or an aerosol.
- Formulations comprising a carbidopa prodrug such as a compound of formula (I), or a pharmaceutically acceptable salt thereof, one or more antioxidants, and, optionally further comprising levodopa and/or a levodopa prodrug such as a compound of formula (II), or a pharmaceutically acceptable salt thereof, may be prepared by mixing these ingredients, each in its powdered form, to form a powder mixture. Water can be added to the mixture to dissolve the mixture. Specific methods of preparation are described in the Examples below.
- a procedure wherein the ingredients of the formulation are first mixed together as powders and then a solution is formed by the addition of water, may result in a more stable solution, as compared to a preparation that includes a stepwise preparation of individual water solutions of the ingredients and later combination thereof.
- N 2 may be provided to the stirred suspension or solution.
- Disclosed formulations may be sterilized, e.g., by using 0.2 ⁇ filters such as filters with nylon or PVDF membranes.
- a method of treatment of a subject inflicted with neurological disease or disorder comprising administrating to the subject an effective amount of a formulation comprising a carbidopa prodrug or a pharmaceutically acceptable salt thereof and optionally further comprising levodopa and/or a levodopa prodrug or a pharmaceutically acceptable salt thereof, thereby threating the subject.
- the method of treatment provided herein comprises the administration of a provided formulation as described herein, optionally in a liquid form.
- the formulation administered comprises a compound of formula (I) and/or a compound of formula (II) as described herein.
- the neurological disease or disorder being treated by a contemplated method may be a neurological disorder such as a disorder associated with reduced dopamine or loss of dopaminergic neurons, or a movement disorder.
- a neurological disorder such as a disorder associated with reduced dopamine or loss of dopaminergic neurons, or a movement disorder.
- diseases and disorders include, for example, neurological or movement disorders including restless leg syndrome, Parkinson's disease, secondary parkinsonism, Huntington's disease, Shy-Drager syndrome, and conditions resulting from brain injury including carbon monoxide or manganese intoxication.
- the disease to be treated is Parkinson's disease.
- Treating a disease means ameliorating, inhibiting the progression of, delaying worsening of, and even completely preventing the development of a disease, for example inhibiting the development of neurological manifestations in a person who has neurological disease or disorder.
- Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or a pathological condition after it has begun to develop. In particular examples, however, treatment is similar to prevention, except that instead of complete inhibition, the development, progression or relapse of the disease is inhibited or slowed.
- administering is introduction of the formulation described herein into a subject by a chosen route.
- Administration of the active compound or pharmaceutical composition can be by any route known to one of skill in the art, and as appropriate for the particular condition and location under treatment.
- Administration can be local or systemic. Examples of local administration include, but are not limited to, topical administration, subcutaneous administration, intramuscular administration, intrathecal administration, intrapericardial administration, intra-ocular administration, topical ophthalmic administration, or administration to the nasal mucosa or lungs by inhalational administration.
- local administration includes routes of administration typically used for systemic administration, for example by directing intravascular administration to the arterial supply for a particular organ.
- local administration includes intra-arterial administration, subcutaneous administration, intraduodenally administration, and intravenous administration when such administration is targeted to the vasculature supplying a particular organ.
- Local administration also includes the incorporation of active compounds and agents into implantable devices or constructs, such as vascular stents or other reservoirs, which release the active agents and compounds over extended time intervals for sustained treatment effects.
- Systemic administration includes any route of administration designed to distribute an active compound or composition widely throughout the body via the circulatory system.
- systemic administration includes, but is not limited to, intra-arterial and intravenous administration.
- Systemic administration also includes, but is not limited to, topical administration, subcutaneous administration, intraduodenally administration, intramuscular administration, or administration by inhalation, when such administration is directed at absorption and distribution throughout the body by the circulatory system.
- An effective amount of a compound for example, of a compound of formula (I) or a compound of formula (II), is a quantity of compound sufficient to achieve a desired effect in a subject being treated.
- An effective amount of a compound can be administered in a single dose, or in several doses, for example daily, during a course of treatment. However, the effective amount of the compound will be dependent on the compound applied, the subject being treated, the severity and type of the affliction, and the manner of administration of the compound.
- Contemplated formulations may be administered to a patient in need thereof via one or more routes such as, but not limited to, parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.
- parenteral routes selected from subcutaneous, transdermal, intradermal, intratracheal, intraocular, intramuscular, intraarterial, intraduodenally or intravenous.
- formulations as described herein are administered continuously, for example by a designated pump.
- formulations may be administered non-continuously, e.g., as bolus, injection, or eye drops.
- a provided formulation is administered subcutaneously and substantially continuously.
- substantially continuous administration is meant that a dose of the formulation being administered is not administered as a bolus, e.g., a pill taken orally or a bolus injection.
- substantially continuous administration can involve administration of a dosage at over a period of at least 10 minutes, 30 minutes, 1 hour, 2 hours, 4, hours, 6 hours, 8 hours, 12 hours, 15 hours, 18 hours, 21 hours, or 24 hours to administer a single dose.
- Substantially continuous administration can be achieved using a transdermal patch or a pump device that continuously administers the formulation to a patient over time.
- administration include acute and immediate administration such as inhalation or injection.
- compositions comprising e.g., levodopa or a compound of formula (II) and/or a compound of formula (I), or a pharmaceutically acceptable salt thereof (e.g. a disclosed liquid composition) may be administered at a rate of from about 0.16 ml/hour/site to about 0.24 ml/hour/site, or, e.g., from about 0.01 ml/hour/site to about 0.4 ml/hour/site.
- rates may be constant throughout the day and night or varied according to patient's need, for example, may reflect a patient resting or sleeping schedule and waking or higher activity level schedule.
- liquid compositions such as those disclosed herein (e.g., including a compound of formula (I) and/or levodopa and/or a compound of formula (II) or a pharmaceutically acceptable salt thereof) may be administered at a rate of about 0.32 ml/hour/site in the morning (e.g., for about 2-4 hours before waking), about 0.24 ml/hour/site during the daytime or activity time (e.g., for about 10 to about 12 hours), and/or about 0.08 ml/hour/site at rest or at night.
- liquid composition such as those disclosed herein may be administered, e.g., intraduodenally, at a rate of about 1.0 ml/hour during the daytime or activity time (e.g., for about 2-3 hours before waking and for about 10 to about 12 hours thereafter), and 0 to about 0.5 ml hour at rest or at night.
- liquid compositions such as disclosed herein may be administered at a rate of about 1.25 ml/hour (e.g., about 1.25 ⁇ 0.5 ml/hour during the daytime or activity time (e.g., for about 2-3 hours before or after waking and for about 10 to about 14 hours thereafter), and 0 to about 0.5 ml/hour (e.g. about 0.5 ⁇ 0.25 ml hour) at rest or night.
- a rate of about 1.25 ml/hour e.g., about 1.25 ⁇ 0.5 ml/hour during the daytime or activity time (e.g., for about 2-3 hours before or after waking and for about 10 to about 14 hours thereafter
- 0 to about 0.5 ml/hour e.g. about 0.5 ⁇ 0.25 ml hour
- compositions may be administered at a rate of about 0.1 to about 1000 ⁇ /hour/site; or at a volume of about 2 to about 10 ml/24 hour/site, preferably about 4 to about 6 ml/24 hour/site; or at a dose of about 80 to about 800 mg of levodopa and/or a levodopa prodrug (e.g., a compound of formula (II) or a pharmaceutically acceptable salt thereof)/day and about 20 to about 200 mg of a carbidopa prodrug (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof)/day; or at a rate of about 240 to about 360 mg of levodopa and/or a levodopa prodrug and about 60 to about 90 mg of a carbidopa prodrug/day/site.
- a levodopa prodrug e.g., a compound of formula (II) or a pharmaceutically acceptable salt
- Contemplated administration typically can be carried out over a defined time period, usually weeks, months, or years, by any of the administration routes and means defined herein.
- substantially continuously administering using, e.g., a liquid formulation can be via a pump for subcutaneous infusion (insulin pump) at an average rate of about 10-1000 ⁇ /hour (e.g., 10-250 ⁇ /hour), about 300 ⁇ 100 ⁇ /hour, or about 200 ⁇ 40 ⁇ /hour continuously for 24 hours; about 440 ⁇ 200 ⁇ /hour or about 200 ⁇ 50 ⁇ /hour continuously for 16 hours (during waking hours), and at night (e.g., for 8 hours), about 0 to 80 ⁇ /hour or 0 to 200 ⁇ hour.
- Substantially continuously administering the formulation into a patient can be doubled or tripled by using more than one pump or site of infusion.
- substantially continuously administering using, e.g., a liquid formulation can be at an average rate of about 0.2- 2 ⁇ /hour, or about 1 ⁇ 0.5 ⁇ /hour continuously for 24 hours; about 1.0 ⁇ 0.5 ⁇ hour continuously for 16 hours (during waking hours) and at night (e.g., for 8 hours), about 0 to 0.5 ⁇ /hour via a pump or transdermal patch, or combination of delivery devices that are suitable for, e.g., subcutaneous, intravenous, intrathecal, and/or via the duodenum.
- a patch suitable for transdermal or subcutaneous administration of an active agent in a formulation as disclosed herein for example, including levodopa or a levodopa prodrug such as a compound of formula (II) or a pharmaceutically acceptable salt thereof; and/or carbidopa prodrug such as a compound of formula (I) or a pharmaceutically acceptable salt thereof.
- Such patches can have one or more compartments that can have the same or different formulations, for example, one compartment can have a disclosed formulation and another compartment a different disclosed formulation, or a different active agent.
- a dermal patch refers to any device that is capable of delivering one or more of the active agents contained in a disclosed formulation, through the skin or mucous membrane, into a patient.
- liquid formulations e.g., comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a compound of formula (II) or a pharmaceutically acceptable salt thereof thereof
- a pre-filled cartridge or vial suitable for use by a patient or physician.
- kits comprising a prefilled cartridge wherein a disclosed liquid formulation is disposed within the cartridge (e.g., a pre-filled cartridge having a single dose of a disclosed formulation or a dose suitable for a single or multiple administration to a patient, and optionally instructions for use).
- a container, vial, pre-filled syringe or the like that can include about 1-10 ml of a disclosed formulation.
- a contemplated kit can include one, two, or more pre-filled vials, containers or syringes having an amount of a disclosed liquid formulation suitable for filling a syringe pump or patch pump, e.g., a vial, container, or syringe having about 1-6 ml, 2-5 ml, 1-2 ml, or 4-10 ml of a disclosed formulation.
- kits that include formulations disclosed herein, taking advantage of an increased stability of the disclosed formulations.
- kits can include a supply of a formulation sufficient for at least 1, 2, 3, 4, or 5 days; 1, 2, 3 or 4 weeks; 1, 2, 3, 4, 6, or 9 months; or 1 or 1.5 years of administration to a patient, which can be packaged, for example, into suitable dosage (e.g., unit dosage) formulations.
- suitable dosage e.g., unit dosage
- kits can optionally include instructions for their use.
- a kit for daily use for example, can include one, two or more containers or vials of a disclosed formulation, an infusion set, and a disposable delivery unit (e.g. syringe).
- (a) Solutions The following solutions were prepared: (i) internal standard stock solution (ISTD) was prepared by dissolving 10 ⁇ of toluene-dB (density 0.87 g/ml) in 1 -methyl- 2-pyrrolidone to obtain a 870 ⁇ g/ml toluene-dB solution; (ii) reagent solution was prepared by mi ing: 125 ml of l-methyl-2-pyrrolidone, 25 ml of cyclobexane, 1.25 ml of formic acid. 1 .25 ml of acetone-d6, and 10 ⁇ of ISTD, and agitating to mix the phases.
- ISD internal standard stock solution
- reagent solution was prepared by mi ing: 125 ml of l-methyl-2-pyrrolidone, 25 ml of cyclobexane, 1.25 ml of formic acid. 1 .25 ml of acetone-d6, and 10 ⁇ of
- Toluene-dB concentration 0.06 ⁇ g/ml;
- NaOH solution was prepared by diluting 2.5 ml of sodium hydroxide solution 50% in 100 ml water deionized;
- EDTA solution was prepared by dissolving and diluting to volume 0. 1 g of ethylenediamine tetra acetic acid disodium salt dihydrate ( EDTA ) with water deionized.
- Reference stock solution 1 (RSS 1) was prepared by dissolving 20 mg to 25 mg of hydrazine sulfate with EDTA solution by agitating overhead at approx. 40 rpm for 20 to 30 min, and then diluting to volume with EDTA solution. Concentration of hydrazine: 277 ⁇ g/ml;
- Reference stock solution 2 (RSS2) was prepared by diluting 900 ⁇ of reference stock solution 1 (RSS1 ) with EDTA solution. Concentration of hydrazine: 24.9 u /ml: and Reference stock solution 3 (RSS3) was prepared by diluting 400 ⁇ RSS2 with EDTA solution. Concentration of hydrazine: 1.0 .ug/ml.
- Blank solution A blank solution was prepared by mixing 5000 ⁇ of reagent solution with 100 ⁇ of EDTA and solution and agitating shortly to mix the phases. The solution was left for derivatization for 10 min. Derivatization was ended by addition of 2 ml of sodium hydroxide solution, mixing for phase separation, and centrifugation. The clear upper phase was separated and analyze by GC-MS. Seven blank solutions were prepared and remained stable for at least 12 hours when stored at room temperature.
- test solutions An exemplary test solution was prepared in duplicates, by mixing 100 ⁇ of a test formulation with 5000 ⁇ of reagent solution, agitating shortly to mix the phases, and leaving the solutions for derivatization for 8 min. Derivatization was ended by addition of 2 ml of sodium hydroxide solution, agitating shortly, and mixing for phase separation. The test solutions was centrifuged (3000 rpm for 5 min), and the clear upper phase was separated and analyze by GC-MS. The test solutions remained stable for at least 12 hours when stored at room temperature.
- Formulations comprising a compound of formula (I) (FI) and/or a compound of formula (II) (FII) were prepared using the powder mixing method, as follows: powders of the FII, and/or FI, ascorbic acid (or sodium ascorbate) and, optionally sodium bisulfite (Na-Bis) and N- acetylcysteine (NAC) were weighed, mixed together and water was added.
- powders of the FII, and/or FI, ascorbic acid (or sodium ascorbate) and, optionally sodium bisulfite (Na-Bis) and N- acetylcysteine (NAC) were weighed, mixed together and water was added.
- formulations were prepared for two separate sets of measurements. In the first set, formulation F1-F4 did not contain LD-p, were prepared in N 2 atmosphere and kept at RT for up to 48 hours; in the second set, formulationsF5, F6 contained LD-p, were prepared without N 2 and kept at RT. The formulations and the relative amounts of ingredients are indicated in Tables 6. Table 6. Formulations F1-F6
- formulations F7 and F8 containing both CD-p and LD-p were prepared with increasing concentrations of ascorbic acid and NAC, without N 2 , and kept at -20°C.
- Formulation F7 comprised 1.36% by weight of CD-p, 5.64% by weight LD-p, 1% by weight ascorbic acid, and 1% by weight NAC.
- Formulation F8 comprised 1.36% by weight of CD-p, 5.64% by weight LD-p, 1.5% by weight ascorbic acid, and 1.5% by weight NAC.
- These formulations presented lower level of hydrazine as compared to formulations without antioxidants. Increased amounts of two antioxidants was manifested in decreased hydrazine release (results not shown).
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Abstract
La présente invention concerne des formulations contenant un promédicament de carbidopa et/ou un promédicament de lévodopa, et un, deux ou plusieurs antioxydants, présentant des taux réduits d'impuretés et de toxines, en particulier des produits de dégradation par oxydation tels que l'hydrazine. Ces formulations sont utiles dans le traitement de maladies ou d'états pathologiques associés à une perte de dopamine ou de neurones dopaminergiques, tels que la maladie de Parkinson.
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