WO2006006929A1 - Infusion and injection solution of levodopa - Google Patents
Infusion and injection solution of levodopa Download PDFInfo
- Publication number
- WO2006006929A1 WO2006006929A1 PCT/SE2005/001135 SE2005001135W WO2006006929A1 WO 2006006929 A1 WO2006006929 A1 WO 2006006929A1 SE 2005001135 W SE2005001135 W SE 2005001135W WO 2006006929 A1 WO2006006929 A1 WO 2006006929A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- levodopa
- infusion
- injection solution
- inhibitor
- physiologically acceptable
- Prior art date
Links
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 157
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 157
- 229960004502 levodopa Drugs 0.000 title claims abstract description 157
- 239000000243 solution Substances 0.000 title claims abstract description 103
- 238000001802 infusion Methods 0.000 title claims abstract description 81
- 238000002347 injection Methods 0.000 title claims abstract description 49
- 239000007924 injection Substances 0.000 title claims abstract description 49
- 239000003112 inhibitor Substances 0.000 claims abstract description 39
- 102000004190 Enzymes Human genes 0.000 claims abstract description 31
- 108090000790 Enzymes Proteins 0.000 claims abstract description 31
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims abstract description 20
- 239000008103 glucose Substances 0.000 claims abstract description 20
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000000872 buffer Substances 0.000 claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003381 stabilizer Substances 0.000 claims abstract description 3
- 238000001990 intravenous administration Methods 0.000 claims description 19
- 229960004205 carbidopa Drugs 0.000 claims description 14
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 claims description 9
- 108010035075 Tyrosine decarboxylase Proteins 0.000 claims description 9
- 102000006378 Catechol O-methyltransferase Human genes 0.000 claims description 7
- 108020002739 Catechol O-methyltransferase Proteins 0.000 claims description 7
- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical group OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 claims description 7
- 238000007920 subcutaneous administration Methods 0.000 claims description 7
- 229960000911 benserazide Drugs 0.000 claims description 5
- 102000010909 Monoamine Oxidase Human genes 0.000 claims description 4
- 108010062431 Monoamine oxidase Proteins 0.000 claims description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 claims description 4
- 102000004316 Oxidoreductases Human genes 0.000 claims description 3
- 108090000854 Oxidoreductases Proteins 0.000 claims description 3
- 239000003543 catechol methyltransferase inhibitor Substances 0.000 claims description 2
- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 claims description 2
- 229960003337 entacapone Drugs 0.000 claims description 2
- 229940117803 phenethylamine Drugs 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 claims description 2
- 229960003946 selegiline Drugs 0.000 claims description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 238000011282 treatment Methods 0.000 description 44
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 22
- 208000018737 Parkinson disease Diseases 0.000 description 15
- 230000000694 effects Effects 0.000 description 11
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 11
- 229960003638 dopamine Drugs 0.000 description 10
- 239000003978 infusion fluid Substances 0.000 description 10
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- 230000007935 neutral effect Effects 0.000 description 7
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 7
- 235000010262 sodium metabisulphite Nutrition 0.000 description 7
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 239000011550 stock solution Substances 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 5
- 229930195725 Mannitol Natural products 0.000 description 5
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- CFFZDZCDUFSOFZ-UHFFFAOYSA-N 3,4-Dihydroxy-phenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C(O)=C1 CFFZDZCDUFSOFZ-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
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- FZWBNHMXJMCXLU-UHFFFAOYSA-N 2,3,4,5-tetrahydroxy-6-[3,4,5-trihydroxy-6-[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-yl]oxyhexanal Chemical compound OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OCC(O)C(O)C(O)C(O)C=O)O1 FZWBNHMXJMCXLU-UHFFFAOYSA-N 0.000 description 3
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- QRMZSPFSDQBLIX-UHFFFAOYSA-N homovanillic acid Chemical compound COC1=CC(CC(O)=O)=CC=C1O QRMZSPFSDQBLIX-UHFFFAOYSA-N 0.000 description 2
- 230000009610 hypersensitivity Effects 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
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- DIVQKHQLANKJQO-UHFFFAOYSA-N 3-methoxytyramine Chemical compound COC1=CC(CCN)=CC=C1O DIVQKHQLANKJQO-UHFFFAOYSA-N 0.000 description 1
- ZKDHZGMUMZUPLV-UHFFFAOYSA-N C(CCO)O.NC(CO)(CO)CO Chemical compound C(CCO)O.NC(CO)(CO)CO ZKDHZGMUMZUPLV-UHFFFAOYSA-N 0.000 description 1
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
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- 229940080381 levodopa 100 mg Drugs 0.000 description 1
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- DXGIRFAFSFKYCF-UHFFFAOYSA-N propanehydrazide Chemical compound CCC(=O)NN DXGIRFAFSFKYCF-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Definitions
- the present invention relates to an infusion or injection solution of Levodopa which optionally comprises at least one inhibitor of a Levodopa-metabolising enzyme.
- the invention also relates to a disposable syringe as well as an infusion pump cassette containing a therapeutically effective amount of an infusion or injection solution of Levodopa, optionally further containing at least one inhibitor of a Levodopa-metabolising enzyme.
- Parkinson's Disease is very common and is contracted by approximately 15 out of 10,000 people in the Western world. The age of debut is usually between 55 and 60 years. The disease is characterised by rigidity and tremors caused by a massive loss of nigrostratial neurones and subsequently a lack of dopamine [ 3,4-dihydroxyphenylethyl- amine] (1 ). The symptoms of Parkinson's Disease appear upon a loss of approximately 80% of dopamine neurones.
- DDC dopadecarboxylase
- Dopamine is metabolised into 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine and Homovanilic acid (HVA) by the two enzymes monoamino oxidase (MAO) and catechol-o- methyltransferase (COMT) (3).
- DOPAC 3,4-dihydroxyphenylacetic acid
- HVA Homovanilic acid
- MAO monoamino oxidase
- CAT catechol-o- methyltransferase
- Levodopa is still the most important treatment for Parkinson's disease and intermittent oral Levodopa treatment achieves good relief of the symptoms at early stages of the disease. In spite of the massive loss of neurones there still is an adequate storage capacity, which makes possible an even release of dopamine into the synaptic Suitem during interval dosage. Levodopa given orally is, however, metabolised to 90% in the first passage before reaching the brain.
- Bioavailability can be increased by simultaneous administration of DDC-inhibitors, such as carbidopa [L-2-hydrazino-3-(3,4-dihydroxyphenyl)- 2-methylpropanoic acid] or benserazide [2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl) propionohydrazide], which both compete with Levodopa for the metabolising DDC- and thus allow more of the administered Levodopa to reach the brain before it is metabolised into dopamine .
- DDC-inhibitors such as carbidopa [L-2-hydrazino-3-(3,4-dihydroxyphenyl)- 2-methylpropanoic acid] or benserazide [2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl) propionohydrazide]
- Levodopa is a neutral amino acid, which must pass the blood-brain barrier before it reaches the central nervous system. This transport is energy consuming.
- the half-life of Levodopa is short, 30 to 60 minutes.
- DDC dopadecarboxylase
- the greater part of Levodopa is metabolised into dopamine. This enzyme is found in a number of organs but above all in muscles, red blood cells and in the skin where it is an important component in the formation of melanin pigment (5).
- DDC dopadecarboxylase
- Levodopa is therefore given in combination with a decarboxylase inhibitor (benserazide or carbidopa) in the same oral dosage form.
- a decarboxylase inhibitor benserazide or carbidopa
- Levodopa has to compete for the enzyme transport with other amino acids from, for example, protein-rich meals (7).
- the absorption of Levodopa takes place primarily in the proximal third part of the small intestine (8). Variations in the emptying of the ventricle can, therefore, result in large variations in the serum concentration in the same patient despite intake of the same amount of Levodopa.
- Levodopa belongs to the group of neutral amino acids and is absorbed by oral administration only in the proximal third of the small intestine via competitive active transport. It has been shown that approximately 10% of the total dose enters the blood circulation. By avoiding protein-rich meals during the daytime, and in close proximity to the individual times of dosage, it is possible to facilitate Levodopa absorption from the intestine and to a certain degree relieve clinical fluctuations. There is not always a direct correlation between the serum concentration of Levodopa and clinical fluctuations. This is probably due to the fact that the passage over the blood-brain barrier also takes place through active transport and even there competes with other neutral amino acids. An overview of the analysis methods for Levodopa has been published (11)
- Levodopa for treatment of Parkinson's disease have been used since the 1960ies and the progress of the disease and the treatment thereof follows the description above.
- new treatment approaches have been developed such as dopamine agonists and enzyme inhibitors.
- dopamine agonists and enzyme inhibitors have not been able to solve all the problems encountered with the traditional Levodopa treatment.
- a new Levodopa formulation comprising carbidopa in the form of a viscous gel
- Duodopa® has recently become available from NeoPharma AB, Uppsala, Sweden, for treatment of Parkinson's disease. This treatment is given directly to the duodenum with a nasoduodenal probe or with a percutaneous probe. With this system a continuous administration of Levodopa is possible but the limitations of the gastric transport barrier remains.
- the present invention provides an infusion or injection solution that is therapeutically effective in lower daily volumes. This is achieved by first dissolving the Levodopa in a physiologically acceptable acid and then adding an organic buffer and small portions of a physiologically acceptable sugar, such as glucose, at a time, ensuring that no precipitation of Levodopa occurs.
- a physiologically acceptable sugar such as glucose
- the bioavailability of Levodopa can be increased by simultaneous administration of an inhibitor of a Levodopa-metabolising enzyme. Therefore, the concentration of Levodopa in the infusion or injection solution of the invention can be as low as 5 mg/mL of Levodopa as long as the solution also comprises at least 0.5 mg/mL of at least one inhibitor of a Levodopa-metabolising enzyme.
- the present invention is directed to an infusion or injection solution of Levodopa containing a1 ) at least 10 mg/mL of Levodopa, or a2) at least 5 mg/mL of Levodopa together with at least 0.5 mg/mL of at least one inhibitor of a Levodopa-metabolising enzyme, b) a buffer, c) a physiologically acceptable sugar, and d) a physiologically acceptable acid, the pH of the solution being lower than or equal to 6.
- Examples of the buffer in the solution of the invention are 2-amino-2-hydroxymethyl-
- the solution further comprises a stabilizer, such as sodium pyrosulphite,
- the volume of the solution is adapted for a single or continuous intravenous and/or subcutaneous and/or intrathekal administration.
- infusion pumps are used for administration of solutions to patients, and these are also possible to use with the infusion or injection solution of Levodopa of the invention.
- the PCA pump CADD system from Smiths Medical Sverige AB, Sollentuna, Sweden, is used for administering the Levodopa infusion solution according to the invention.
- This system can be used both for infusion with the infusion solution in cassettes (maximum 100 ml_) and with the infusion solution in a bottle connected with an adapter to the pump system.
- Disetronic pump system from Disetronic Medical Systems AB, Sweden, can be used.
- the advantage with this system is the small size of the pump and the possibilities using it during different activities without interference.
- Maximum infusion solution is 20 ml_.
- the Medtronic pump system from Medtronic AB, Jarfalla, Sweden, can be used. The pump is placed subcutaneously and refilled regularly by medical staff.
- the physiologically acceptable sugar is selected from dextran, e.g. dextran 70, 60 or 40, mannitol and glucose, and glucose is presently preferred.
- the pH of the infusion or injection solution of the invention is in the range of 3 to 6.
- the amount of Levodopa in a2) is selected from the range 5 mg/mL to 25 mg/mL and the amount of the inhibitor of a Levodopa- metabolising enzyme is selected from the range 0.5 mg/mL to 6.25 mg/mL.
- the inhibitor of a Levodopa-metabolising enzyme in the infusion or injection solution is selected from the group consisting of dopa decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, and enzymes monoamino oxidase (MAO-B) inhibitors.
- DDC dopa decarboxylase
- COMP catechol-o-methyltransferase
- MAO-B enzymes monoamino oxidase
- the DDC-inhibitor is L-2-hydrazino-3-(3,4-dihydroxy- phenyl)-2-methylpropanoic acid (carbidopa) or 2-amino-3-hydroxy-N'-(2,3,4-trihydroxy- benzyl) propionohydrazide (benserazide).
- the COMT inhibitor is (E)-2-cyano-3-(3,4- dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propane amide (entacapone).
- the MAO-B inhibitor is (R)-N, ⁇ -dimethyl-N-(2- propynyl)phenethyl amine (selegiline).
- the physiologically acceptable acid comprised by a preferred infusion or injection solution of Levodopa according to the invention is hydrochloric acid or acetic acid.
- Acid solutions are often used for intravenous infusion. pH below 3 is known to give vessel irritations and trombophlebitis. Glucose solutions can however have a low pH (3.5) without any side effects. Weak acids as hydrochloric acid and acetic acid are tolerated for intravenous infusion in pH above 3. Levodopa is easily soluble at low pH. However it is crystallized at higher pH although the crystallization doesn't appear instantly.
- Another aspect of the invention is directed to a disposable syringe containing a therapeutically effective amount of an infusion or injection solution of Levodopa dissolved in a physiologically acceptable acid, containing a buffer and a physiologically acceptable sugar and having a pH of lower than or equal to 6.
- the therapeutically effective amount is decided empirically based on the condition of the patient, or a standard dose is recommended by the manufacturer, and it is preferably made up of a solution having a concentration of at least 10 mg/mL of Levodopa, and the physiologically acceptable sugar is preferably selected from dextran, e.g. dextran 70, 60 or 40, mannitol or glucose, preferably glucose, and the solution having a pH of lower than or equal to 6, is preferably a solution having a pH in the range of 3 to 6.
- the infusion or injection solution in the disposable syringe further comprises at least one inhibitor of a Levodopa-metabolising enzyme in an amount that together with an amount of Levodopa gives a therapeutically effective amount of the solution.
- the therapeutically effective amount is preferably made up of a solution having at least 5 mg/mL of Levodopa together with at least 0.5 mg/mL of at least one inhibitor of a Levodopa-metabolising enzyme, such as Levodopa in the range of 5 mg/mL to 25 mg/mL and the amount of inhibitor(s) of a Levodopa-metabolising enzyme in the range 0.5 mg/mL to 6.25 mg/mL.
- a syringe of the invention will typically hold 1 to 10 mL of an infusion or injection solution according to the invention.
- Still another aspect of the invention is directed to an infusion pump cassette containing a therapeutically effective amount of an infusion or injection solution of Levodopa, dissolved in a physiologically acceptable acid, containing a buffer, a physiologically acceptable sugar, and having a pH of lower than or equal to 6.
- the therapeutically effective amount is decided empirically based on the condition of the patient, or a standard dose is recommended by the manufacturer, and it is preferably made up of a solution having a concentration of at least 10 mg/mL of Levodopa, and the physiologically acceptable sugar is preferably selected from dextran, e.g. dextran 70, 60 or 40, mannitol or glucose, preferably glucose, and the solution having a pH of lower than or equal to 6, is preferably a solution having a pH in the range of 3 to 6.
- the infusion pump cassette further comprises at least one inhibitor of a Levodopa-metabolising enzyme in an amount that together with an amount of Levodopa gives a therapeutically effective amount of the solution.
- the therapeutically effective amount is preferably made up of a solution having at least 5 mg/mL of Levodopa together with at least 0.5 mg/mL of at least one inhibitor of a Levodopa-metabolising enzyme, such as Levodopa in the range of 5 mg/mL to 25 mg/mL and the amount of inhibitor(s) of a Levodopa-metabolising enzyme in the range 0.5 mg/mL to 6.25 mg/mL.
- the size and shape of the cassette will vary depending on the actual infusion pump system that will be used for the administration of the infusion or injection solution of the invention.
- Addex®-Tham that is used in the preparation of the infusion solutions, is a concentrated infusion solution sold by Fresenius Kabi AB, Uppsala Sweden.
- the active ingredient is Trometamol, 2-amino-2-hydroximetylpropan-1,3-diol (Tris-Hydroximetyl-Amino- Metan), also named TRIS or THAM, and it is an organic buffer.
- THAM functions as a proton acceptor, i.e. a weak base.
- the Levodopa is dissolved in the HCI solution in a 100 mL flask.
- the sodium pyrosulfite is weighed into a 10 mL injection vial and 2 mL of sterile water is added for dissolution. Water in an amount of 50 mL is added to the flask containing Levodopa, followed by addition of the sodium pyrosulfite solution.
- the mixture is poured into a 100 mL measuring flask and water for injection is added up to the 100 mL mark.
- the resulting solution is sterile filtered into a 100 mL injection flask.
- a Sterivex GV-filter 0.22 ⁇ m was used.
- the Levodopa is dissolved in the HCI solution in a 100 mL flask.
- the sodium pyrosulfite is weighed into a 10 mL injection vial and 2 mL of sterile water is added for dissolution. Water in an amount of 50 mL is added to the flask containing Levodopa, followed by addition of the sodium pyrosulfite solution.
- the mixture is poured into a 100 mL measuring flask and water for injection is added up to the 100 mL mark.
- the resulting solution is sterile filtered into a 100 mL injection flask.
- a Sterivex GV-filter 0.22 ⁇ m was used.
- Levodopa 5 mg/mL - solution containing Carbidopa 0.5 mg/mL Levodopa, 20 mL of the 50 mg/mL stock solution 2
- Glucose 50 mg/mL add to 200 mL
- Addex-Tham was added to the Levodopa solution.
- Glucose 50 mg/mL, was added up to a total volume of 200 mL.
- the pH of the solution was 3.5 - 4 and the shelf-life was > 3 days.
- Addex-Tham was added to the Levodopa stock solution 2.
- Glucose 50 mg/mL, was added slowly in portions of approximately 1O mL with stirring up to a total volume of 200 mL.
- the pH of the solution was 3.5 - 4 and the shelf-life was > 3 days.
- Levodopa can be dissolved in HCI up to 100 mg/mL without any precipitation.
- HCI water
- the steps of producing the solutions of the invention are made rather quickly up to the addition of glucose. Initially, approximately half of the volume of the glucose solution is added, followed by a drop by drop addition of the rest of the volume at approximately 10 min intervals and constant stirring until the pH is acceptable (e.g. pH 3-6).
- a solution of 5 mg/mL Levodopa and 0.5 mg Carbidopa has been heated to 6O 0 C and left to stand for 36 hours, and then at room temperature for 1 week, without any sign of discoloration or precipitation.
- Mannitol can be used instead of glucose in the Levodopa solutions of the invention, but it is much more unstable and a precipitate is formed in a few hours.
- Intravenous Levodopa infusion or injection continuously or intermittently during 12 hours for 10 days is an effective treatment of clinical fluctuations.
- the effect is due to a widening of the therapeutic interval for Levodopa.
- the treatment has also a long-lasting effect of at least 5 months.
- Levodopa solutions according to the invention can be given as an infusion or injection into different tissues or to the blood.
- Addition of inhibitor of a Levodopa-metabolising enzyme is at a concentration of 0.5 mg/mLor more, such as dopadecarbolyxyase inhibitor, into the Levodopa solution which enables simultaneous administration of the two active ingredients to even an unconscious patient.
- Levodopa solutions of the invention doesn't need any surgical intervention since it can be given as an infusion through a standard needle (Venflon®), which is used for all types of intravenous infusions.
- Infusion or injection to the subcutaneous tissue, of the abdomen, is given trough a needle of a syringe, which can be placed by the patient.
- the same infusion or injection method that is used for treatment with the dopamine agonist Apomorfin and for treatment with Insulin can be used with the infusion or injection solution of the invention.
- the invention comprises a disposable syringe containing a therapeutically effective amount of an infusion or injection solution of Levodopa solved in a physiologically acceptable acid, containing a buffer, glucose and having a pH in the range of 3 to 6 and optionally further containing an inhibitor of a Levodopa-metabolising enzyme.
- the Levodopa solution of the invention is significantly improved by the addition of at least one inhibitor of a Levodopa-metabolising enzyme, e.g. dopadecarbolyxyase inhibitor, into the solution. This simplifies the treatment and oral treatment with dopadecarbolyxyase inhibitor becomes unnecessary.
- the increased concentration of Levodopa decreases the volume necessary for infusion or injection of the daily Levodopa dose enabling the use of smaller infusion pump and a subsequent increased mobility for the patient.
- the treatment can be given both in ward and as policlinic treatment.
- Levodopa solutions of the invention can be delivered in ready-to-use cassettes adapted for the infusion pump used by the patient.
- Parkinson's disease is diagnosed by clinical symptoms in combination with therapeutic response to treatment with Levodopa.
- PD Parkinson's disease
- oral treatment has been provided to the patients. This means that the therapeutic response of the patient has been seen after a treatment period of 2-3 months.
- the therapeutic response is often discrete, and a certain positive effect is hard to evaluate, especially when the difference from day to day is very small.
- the Levodopa solution of the invention with or without the inhibitor of a Levodopa- metabolising enzyme, enables intravenous administration of Levodopa and makes it possible to register a positive response within one to two days!
- a predetermined dose of Levodopa is administered to the patient intravenously.
- the dose is successively increased e.g. starting from 6 mL per hour and increasing by 1 mL every 30 minutes of a solution containing 5 mg/mL of Levodopa - or half the amounts of a solution containing 10 mg/mL Levodopa.
- a positive response is seen as an effect on clinical symptoms.
- a test for determining the plasma concentration of Levodopa is taken (see e.g. Ref. 11 , 13, 14 or 15) and this value can be used for establishing the therapeutic threshold value.
- the infusion velocity is increased further until side effects are noticed.
- a new plasma concentration value is taken, and the interval between therapeutic threshold value and side effect value is called therapeutic interval.
- the magnitude of the therapeutic interval can be used for diagnostic purposes, and for evaluating any previously given Levodopa therapy.
- intravenous Levodopa test is suitable for 1 ) de novo patients with suspected PD
- DBS Deep Brain Stimulation
- the patient partially needed help with hygiene and dressing but ate by herself and walked with the Zimmerframe. At follow-up six months later the patient could walk without any means of assistance indoors, but used the wheel chair outdoors for reasons of self-confidence. She managed dressing and hygiene herself and could even manage lighter household chores. The patient had, at the check-up, some remaining rigidity but accepted this as it was not disabling. She had not suffered from dyskinesia since the infusion. The other patients showed, as did the patient described above, a clear improvement in the symptoms of Parkinson's disease during and after the treatment with continuous intravenous Levodopa. Individual variations did occur and this pilot study is not comprehensive enough to securely assess the length of the effect of treatment.
- Intravenous treatment with Levodopa makes it possible to ascertain these patients a normal motor function and more effective and faster mobilisation. Patients with PD are sometimes considered not to be suitable for surgery, because of postoperative rehabilitation difficulties. Peroperative intravenous Levodopa treatment increases the therapeutic possibilities in these cases. Subcutaneous infusion
- Tests have been made with subcutaneous infusion. They showed a fast distribution of Levodopa to the blood with measurable concentrations and a positive clinical effect for the patient.
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Abstract
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Priority Applications (20)
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AU2005262918A AU2005262918B2 (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of Levodopa |
MX2013006111A MX349829B (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of levodopa. |
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US11/631,602 US20080255235A1 (en) | 2004-07-12 | 2005-07-08 | Infusion and Injection Solution of Levodopa |
CN200580029688.5A CN101022784B (en) | 2004-07-12 | 2005-07-08 | Levodopa transfusion and injection |
CA2574437A CA2574437C (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of levodopa |
SI200531958T SI1773297T1 (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of levodopa |
EA200700020A EA012415B1 (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of levodopa |
JP2007521433A JP2008505966A (en) | 2004-07-12 | 2005-07-08 | Infusion and injection of levodopa |
DK05757066T DK1773297T3 (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of Levodopa |
PL05757066T PL1773297T3 (en) | 2004-07-12 | 2005-07-08 | Infusion and injection solution of levodopa |
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IL180650A IL180650A (en) | 2004-07-12 | 2007-01-11 | Infusion and injection solution of levodopa |
HK08101908.1A HK1111347A1 (en) | 2004-07-12 | 2008-02-21 | Infusion and injection solution of levodopa |
US13/208,628 US8735382B2 (en) | 2004-07-12 | 2011-08-12 | Infusion and injection solution of levodopa |
US14/251,967 US9248113B2 (en) | 2004-07-12 | 2014-04-14 | Infusion and injection solution of Levodopa |
HRP20150384TT HRP20150384T1 (en) | 2004-07-12 | 2015-04-02 | Infusion and injection solution of levodopa |
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DE10261808A1 (en) | 2002-12-19 | 2004-07-08 | Turicum Drug Development Ag | Use of L-DOPA, its derivatives and medicaments containing these compounds for the prophylaxis of psychotic diseases |
JP5160786B2 (en) | 2003-08-29 | 2013-03-13 | トランスフォーム・ファーマシューティカルズ・インコーポレイテッド | Pharmaceutical composition and method of using levodopa and carbidopa |
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