WO1998016208A1 - Methods and apparatus for treatment of parkinson's disease - Google Patents
Methods and apparatus for treatment of parkinson's disease Download PDFInfo
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- WO1998016208A1 WO1998016208A1 PCT/IL1997/000327 IL9700327W WO9816208A1 WO 1998016208 A1 WO1998016208 A1 WO 1998016208A1 IL 9700327 W IL9700327 W IL 9700327W WO 9816208 A1 WO9816208 A1 WO 9816208A1
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- Prior art keywords
- levodopa
- parkinson
- pharmaceutical composition
- disease
- transdermal
- Prior art date
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- 208000018737 Parkinson disease Diseases 0.000 title claims abstract description 33
- 238000011282 treatment Methods 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims description 14
- 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 81
- 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 80
- 229960004502 levodopa Drugs 0.000 claims abstract description 79
- NULMGOSOSZBEQL-QMMMGPOBSA-N etilevodopa Chemical compound CCOC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 NULMGOSOSZBEQL-QMMMGPOBSA-N 0.000 claims abstract description 31
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Classifications
-
- 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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to methods and apparatus for treatment of
- Parkinson's disease is one of the most common neuro-degenerative diseases which affect the elderly
- Parkinson's disease - new modes of dopamine substitution Acta neurol Scand 1993, 87(suppl
- PD Parkinsonian signs in the elderly are estimated to occur in 30% of the population over the age of 65 (Ref 2)
- PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta PD becomes symptomatic only after degeneration of about 60- 80% of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine (Refs 3, 4)
- Dopamine (DA) which is produced within the substantia nigra, reaches the striatum via the nigro-striatal tract and is released at the striatal synapses DA deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to be the cause of PD.
- LD Levodopa
- carbidopa an inhibitor that cannot penetrate the blood-brain-barrier
- LD Adverse effects of LD, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine (Ref 5) At late stages of the disease additional types of adverse effects appear as the response to LD becomes unpredictable, fluctuative and the duration of the response is reduced " Motor fluctuations appear after about 4 - 5 years from the introduction of LD therapy in 24%-84% of the patients (Ref. 6) The most common and disabling motor complications are 1) “wearing-off” fluctuations, 2) “on-off” fluctuations and 3) peak-dose dyskinesias (Ref 7)
- the "wearing-off effect means a reduction in the duration of the beneficial effect after each administration of LD During this period, LD must be administered more frequently than before, a problem which severely affects the quality of life of the patient Complications such as “wearing off” may arise due to limitation of storage capacity of DA in the CNS (Refs 5, 8-10) When neuronal DA storage is reduced, the clinical state of the patients becomes fully dependent on the fluctuating blood level of LD Since the normal half- life of LD in the circulation is 1-2 hours (Refs 1 1-13), LD should be administered at this stage more frequently and the effect is fluctuative Moreover, with the currently available oral preparations, the blood level of LD is a function of the rate of absorption from the gastrointestinal tract, which is irregular and uncontrollable The resulting fluctuations of the LD blood levels contribute further to the instability of the effect A continuous drug delivery, which maintains a constant blood level of LD, has been shown to improve significantly the clinical state of the fluctuating parkinsonian patients (Refs 13-18
- Peak-dose dyskinesia is a common advanced motor complication which occurs when the blood level of LD rises to its peak This complication is observed in advanced stages of the disease when patients show a very steep dose-response curve Under such circumstances, small shifts in circulating LD levels, and thus in cerebral DA, induce major swings in the clinical state (Ref 7) In this stage of the disease, a continuous administration that keeps the circulating LD level constant, may prevent the dyskinesias Moreover, these kinds of dyskinesias, like the "on-off dyskinesia, may not develop during a continuous administration of LD (Refs 7, 16, 17, 28, 29)
- the CR preparations do not provide the same favorable effect which was demonstrated by a continuous administration of LD such as an IV infusion (e g , Refs 5, 15, 18) 5. Sclerosis of the peripheral veins occurs frequently during an IV infusion of LD (Ref. 5).
- transdermal delivery of LD could be the best substitution for the methods of continuous invasive infusions, free of disadvantages of the currently available strategies.
- the present invention constitutes a solution to most of the problems associated with the currently available treatments, and thus provides a safer and more effective treatment for PD.
- the invention describes a novel route of administration of levodopa dissolved in a formulation which is designed to maintain stability of the drug in solution and enables continuous penetration of the drug through the skin
- This method is suggested as a treatment of Parkinson's patients, especially at advanced stages of the disease
- the currently available LD preparations cause side effects and deterioration in the clinical state of the disease
- the present invention helps overcome these disadvantages.
- an alkyl- ester of LD such as levodopa-ethyl-ester (LDEE) is administered transdermally.
- the alkyl-ester of LD is dissolved in an appropriate formulation.
- the formulation consists of propylene glycol, a fatty acid and a detergent.
- the LD-alkyl-ester and the formulation (the solvent) are kept separately and mixed just before the beginning of the drug application.
- a transdermal device which includes a container connected to a patch via a narrow plastic tube is used for the transdermal delivery
- the container is re-filled every 24 h
- the patch is fed with the LD-alkyl-ester solution preferably by gravity, or alternatively by pump, the solution then being spread on the skin area covered by the patch
- the patient ingests tablets of carbidopa (25 - 50 mg/tablet) three times a day
- the patient could receive a supplemental treatment such as oral anti-parkinson's drug
- FIG. 1 is a simplified pictorial illustration of apparatus for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention.
- Fig. 2 is a simplified sectional illustration of apparatus of Fig. 1, taken along the lines II - II in Fig. 1.
- the formulation is designed to dissolve a treating drug (alkyl-ester of LD) and maintain it stable in solution for the period during which a continuous transdermal penetration takes place.
- a treating drug alkyl-ester of LD
- the formulation provides the drug with stability and transdermal permeation properties.
- the formulation preferably contains several components as follows:
- Non-aqueous solvent LD and its derivatives are more stable in non-aqueous solution than in aqueous solution.
- a preferred solvent is propylene glycol which is non-toxic, does not produce skin irritation and provides the proper constituency for dermal application.
- Other non-aqueous solvents with similar properties may also be used for this purpose.
- Transdermal enhancer and stabilizer A preferred transdermal enhancer and stabilizer is carboxylic acid.
- the alkyl- esters of LD are quite soluble and much more stable in an acidic environment than in a neutral environment.
- the carboxylic acid also keeps the LD derivative uncharged and helps permeability through the skin.
- Figs. 1 and 2 illustrate apparatus 10 for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention.
- Apparatus 10 preferably includes a storage compartment 12 which is in fluid communication with a dermal patch 14, preferably via a flexible plastic tube 16 Patch 14 may be made of any suitable material, such as cloth or plastic Storage compartment 12 is preferably flexible and compressible by mechanical pressure Storage compartment 12 preferably contains a fluid 18 (Fig. 2) which is a treating drug, such as an alkyl-ester of LD, dissolved in a formulation, such as described hereinabove in accordance with a preferred embodiment of the present invention
- the alkyl- ester of LD is kept pre-weighed as a dried powder Carbidopa (25 - 50 mg/tablet) is preferably ingested two hours before the beginning of the transdermal delivery of the LD derivative and then three times a day throughout the entire treatment
- Carbidopa 25 - 50 mg/tablet
- the alkyl-ester of LD is placed in storage compartment 12 and a sufficient amount of formulation is added therein, and the constituents are thoroughly mixed together.
- Storage compartment 12 is then preferably tied to an arm or any other suitable location on a patient, such as with a strap 20, and connected to patch 14 via tube 16
- Flow of fluid 18 from storage compartment 12 to patch 14 is preferably controlled by a regulating valve 22.
- Patch 14 is preferably attached to the skin along an adhesive periphery 24, and a central portion 26 is preferably adapted to receive and maintain a quantity of fluid 18 Fluid 18 spreads under patch 14 preferably via a system of hollow capillaries 28 (Fig 2), and penetrates the skin of a patient
- fluid 18 flows from storage compartment 12 to patch 14 by gravity, or alternatively by a miniature pump (not shown) When necessary, flow of fluid 18 may be increased by exerting mechanical pressure on storage compartment 12 or by increasing the pump rate.
- Apparatus 10 is preferably disposable The location of apparatus 10 on the patient's skin may be changed periodically Supplemental oral treatment may be given during the transdermal delivery according to clinical needs
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- Bioinformatics & Cheminformatics (AREA)
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- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
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Abstract
A pharmaceutical composition for treatment of Parkinson's disease comprising a compound of levodopa dissolved in a non-degradative solvent which allows transdermal administration of levodopa. The compound of levodopa is an alkyl-ester of levodopa and the solvent is a formulation comprising a substantially non-aqueous solvent, a transdermal enhancer and a detergent. The alkyl-ester of levodopa is preferably levodopa-ethyl-ester (LDEE).
Description
METHODS AND APPARATUS FOR TREATMENT OF PARKINSON'S DISEASE
FIELD OF THE INVENTION
The present invention relates to methods and apparatus for treatment of
Parkinson's disease BACKGROUND OF THE INVENTION
Parkinson's disease (PD) is one of the most common neuro-degenerative diseases which affect the elderly
The following is a representative list of references which discuss Parkinson's disease and therapeutic strategies 1 de Rijk MC, Breteler MMB, Graveland GA, et al Prevalence of Parkinson's disease in the elderly The Rotterdam study Neurol 1995, 45 2143-2146
2 Bennet DA, Beckett LA, Murray AM, et al Prevalence of Parkinsonian signs and associated mortality in a community population of older people N Engl J Med 1996,
334(2) 71-76 3 Hornykiewicz O, Kish SJ Biochemical pathophysiology of Parkinson's disease Adv
Neurol 1986, 45 19-34
4 Leenders KL, Salmon EP, Tyrrel P, et al The nigrostπatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease Arch Neurol 1990, 47 1290-1298 5 LeWitt PA Levodopa Therapeutics New treatment strategies Neurology 1993,
43(suppl 6) S31-S37
6 Peppe A, Dambrosia JM, Chase TN Risk factors for motor response complications in L-Dopa treated parkinsonian patients Adv Neurol 1993, 60 698-702
7 Chase TN, Mouradian MM, Engber TM Motor response complications and the function of striatal efferent systems Neurology 1993, 43 (suppl 6) S23-S27
8 Doller HJ, Connor ID Changes in neostriatal dopamine concentrations in response to levodopa infusions J Neurochem 1980, 34 1264-1269
9 Spencer SE, Wooten GF Altered pharmacokinetics of L-dopa metabolism in rat striatum deprived of dopaminergic innervation Neurology 1984, 34 1 105-1 108 10 Spencer SE, Wooten GF Pharmacologic effects of L-dopa are not closely linked temporally to striatal dopamine concentration Neurology 1984, 34 1609-161 1
1 1 Hardie RJ, Malcolm SL, Lees AJ, et al The pharmacokinetics of intravenous and oral levodopa in Parkinson's patients who exhibit on-off fluctuations Br J Clin Pharmacol 1986, 22 421-436
12 Fabbrini G, Juncos J, Mouradian MM, et al Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson's disease Ann Neurol 1987, 21 370-376
13 Nutt JG, Woodward WR, Hammerstad JP, et al The "on-off" phenomenon in Parkinson's disease relation to levodopa absorption and transport N Engl J Med 1984, 310 483-488
14 Shoulson I, Glaubiger GA, Chase TN On-off response clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients
Neurology 1975, 25 1144-1148
15 Quinn N, Parkes JD, Marsden CD Control of on/off phenomenon by continuous intravenous infusion of levodopa Neurology 1984, 34 1131-1136
16 Schuh LA, Bennet JP Suppression of dyskinesias in advanced Parkinson's disease I Continuous intravenous levodopa shifts dose-response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson's disease Neurology 1993, 43.1545-1550
17 Sage JI, McHale DM, Sonsulla P, et al Continuous levodopa infusion to treat complex dystonia in Parkinson's disease Neurology 1989, 39 888-891 18 Schelosky L, Poewe W Current strategies in the drug treatment of advanced
Parkinson's disease - new modes of dopamine substitution Acta neurol Scand 1993, 87(suppl
146) 46-49
19 Nutt JG, Woodward WR Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients Neurology 1986, 36 739-744 20 Nelson MV, Berchou RC, LeWitt PA, et al Pharmacodynamic modeling of concentration-effect relationship after controlled-release carbidopa/levodopa (Sinemet CR-4) in Parkinson's disease Neurology 1990, 40 70-74
21 Bredberg E, Nilson D, Johansson K, et al Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in sever Parkinson's disease Eur J Clin Pharmacol 1993, 45 117-122
22 Mouradian MM, Juncos JL, Fabbrini G, et al Motor fluctuations in Parkinson's disease central pathophysiological mechanisms Part II Ann Neurol 1988, 24,372-378
23 Sage JI, Mark MH The rationale for continuous dopaminergic stimulation in patients with Parkinson's disease Neurology 1992, 42(Suppl 1) 23-28
24 Chase TN, Baronti F, Fabbrini G, et al Rational for continuous dopaminometic therapy of Parkinson's disease Neurology 1989, 39(Suppl 2) 7-10 25 Sage JI, Mark MH Basic mechanisms of motor fluctuations Neurology 1994,
44(Suppl 6) S10-S14
26 Sage JL, Trooskin S, Sonsalla PK, et al Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson's disease Neurology 1989,
39(Suppl 2) 60-63 27 Mouradian MM, Heuser IJE, Baronti F, et al Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease Ann Neurol
1990, 27 18-23
28 Bravi D, Mouradian MM, Roberts JW, et al End-of-dose dystonia in Parkinson's disease Neurology 1993, 43 2130-2131 29 Tanner CM, Melamed E, Lees AJ Managing motor fluctuations, dyskinesias and other adverse effects in Parkinson's disease Neurology 1994, 44(Suppl 1) S12-S16
30 Joseph King Ching Tsui Future Treatment of Parkinson's disease Can J Neurol Science 1992, 19 160-162
31 Djaldetti R, Atlas D, Melamed E Subcutaneous injections of levodopa-ethylester A potential novel rescue therapy for response fluctuations in patients with Parkinson's disease
(Abst) Neurology 1995, 45(Suppl 4) 415S
32 LeWitt PA In Levodopa controlled-release preparations Neurology 1993, 43 (Suppl 6)S38-S40
33 Roller WC, and Pahwa R Treating motor fluctuations with controlled-release levodopa preparations Neurology 1994, 44(Suρpl 6) S23-S28
The prevalence of diagnosed PD in the population above the age of 55 is about 1 4% and it increases with age (Ref 1) Moreover, Parkinsonian signs in the elderly are estimated to occur in 30% of the population over the age of 65 (Ref 2) Although PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta PD becomes symptomatic only after degeneration of about 60- 80% of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine (Refs 3, 4) Dopamine (DA), which is produced within the substantia nigra, reaches the
striatum via the nigro-striatal tract and is released at the striatal synapses DA deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to be the cause of PD. Consequently, the most effective treatment of PD is Levodopa (LD), which is converted to DA by enzymatic decarboxylation Inhibition of the peripheral aromatic amino acid decarboxylase by carbidopa (an inhibitor that cannot penetrate the blood-brain-barrier) improves dramatically the results of the treatment However, the currently available LD preparations are effective only for a relatively short period and may be even deleterious, under certain conditions (as will be explained below)
Administration of LD is especially successful during early stages of the disease Adverse effects of LD, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine (Ref 5) At late stages of the disease additional types of adverse effects appear as the response to LD becomes unpredictable, fluctuative and the duration of the response is reduced " Motor fluctuations appear after about 4 - 5 years from the introduction of LD therapy in 24%-84% of the patients (Ref. 6) The most common and disabling motor complications are 1) "wearing-off" fluctuations, 2) "on-off" fluctuations and 3) peak-dose dyskinesias (Ref 7)
The "wearing-off effect means a reduction in the duration of the beneficial effect after each administration of LD During this period, LD must be administered more frequently than before, a problem which severely affects the quality of life of the patient Complications such as "wearing off" may arise due to limitation of storage capacity of DA in the CNS (Refs 5, 8-10) When neuronal DA storage is reduced, the clinical state of the patients becomes fully dependent on the fluctuating blood level of LD Since the normal half- life of LD in the circulation is 1-2 hours (Refs 1 1-13), LD should be administered at this stage more frequently and the effect is fluctuative Moreover, with the currently available oral preparations, the blood level of LD is a function of the rate of absorption from the gastrointestinal tract, which is irregular and uncontrollable The resulting fluctuations of the LD blood levels contribute further to the instability of the effect A continuous drug delivery, which maintains a constant blood level of LD, has been shown to improve significantly the clinical state of the fluctuating parkinsonian patients (Refs 13-18) In this regard, it has been reported that therapeutic effects of LD were noticed when LD plasma levels reached 300-800 ng/ml (Refs 19-21)
The "on-off fluctuations are inconsistent transitions between a hypokinetic parkinsonian state (the "off" state) and a hyperkinetic state (the "on" state) The clinical state of these patients is highly correlated with the plasma concentration of LD (Refs 5, 20) It is thought that these fluctuations result from a narrowing of the therapeutic window of LD An intermittent administration of LD, given for a long period, is considered to be one of the major causes of the reduction of the therapeutic window (Refs 22, 23) and consequently leads to the motor fluctuations (Refs 23-25) On the other hand, a continuous infusion of LD has been shown to increase the therapeutic window and to reduce the "on-off fluctuations (Refs 25-
27) Moreover, during a continuous administration, the blood levels of LD which are needed to keep the patient at the "on" state gradually decrease (Ref 21)
Peak-dose dyskinesia is a common advanced motor complication which occurs when the blood level of LD rises to its peak This complication is observed in advanced stages of the disease when patients show a very steep dose-response curve Under such circumstances, small shifts in circulating LD levels, and thus in cerebral DA, induce major swings in the clinical state (Ref 7) In this stage of the disease, a continuous administration that keeps the circulating LD level constant, may prevent the dyskinesias Moreover, these kinds of dyskinesias, like the "on-off dyskinesia, may not develop during a continuous administration of LD (Refs 7, 16, 17, 28, 29)
All these findings and observations clearly suggest that a continuous delivery of LD is advantageous over an intermittent administration Persistent attempts have been made in effort to develop a sustained delivery of LD (Refs 30, 31) Strategies to improve the clinical results of intermittent LD administration include controlled release (CR) preparations and pump-delivery of LD However, the existing preparations and devices suffer from several disadvantages as follows 1 CR preparations have a delayed onset The peak effect of Sinemet CR (commercially available from Merck Sharp and Dohme Research Laboratories) was shown to occur an hour later than that of the conventional Sinemet (Refs 18, 32)
2 The bioavailability of the CR preparations is low (Refs 18, 32) The low bioavailability is explained by the variable properties of the gastro-intestinal tracts (Ref 33) 3 Reduced reliability and predictability of the clinical response (Refs 32, 33)
4 According to many investigators, the CR preparations do not provide the same favorable effect which was demonstrated by a continuous administration of LD such as an IV infusion (e g , Refs 5, 15, 18)
5. Sclerosis of the peripheral veins occurs frequently during an IV infusion of LD (Ref. 5).
6. A gastrostom-duodenal tube or an esophageal catheter is very unpleasant
To overcome these disadvantages, and yet to administer LD in a continuous manner, an alternative method of drug delivery is needed SUMMARY OF THE INVENTION
In the present invention, we claim that transdermal delivery of LD could be the best substitution for the methods of continuous invasive infusions, free of disadvantages of the currently available strategies.
The present invention constitutes a solution to most of the problems associated with the currently available treatments, and thus provides a safer and more effective treatment for PD.
The invention describes a novel route of administration of levodopa dissolved in a formulation which is designed to maintain stability of the drug in solution and enables continuous penetration of the drug through the skin This method is suggested as a treatment of Parkinson's patients, especially at advanced stages of the disease The currently available LD preparations cause side effects and deterioration in the clinical state of the disease The present invention helps overcome these disadvantages.
In accordance with a preferred embodiment of the present invention, an alkyl- ester of LD such as levodopa-ethyl-ester (LDEE) is administered transdermally. For this purpose, the alkyl-ester of LD is dissolved in an appropriate formulation. The formulation consists of propylene glycol, a fatty acid and a detergent. The LD-alkyl-ester and the formulation (the solvent) are kept separately and mixed just before the beginning of the drug application. A transdermal device which includes a container connected to a patch via a narrow plastic tube is used for the transdermal delivery The container is re-filled every 24 h The patch is fed with the LD-alkyl-ester solution preferably by gravity, or alternatively by pump, the solution then being spread on the skin area covered by the patch During treatment, the patient ingests tablets of carbidopa (25 - 50 mg/tablet) three times a day According to the clinical needs, the patient could receive a supplemental treatment such as oral anti-parkinson's drug
BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which-
Fig. 1 is a simplified pictorial illustration of apparatus for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention; and
Fig. 2 is a simplified sectional illustration of apparatus of Fig. 1, taken along the lines II - II in Fig. 1.
DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT A formulation (solvent) useful in transdermal treatment of Parkinson's disease, in accordance with a preferred embodiment of the present invention, is now described.
The formulation is designed to dissolve a treating drug (alkyl-ester of LD) and maintain it stable in solution for the period during which a continuous transdermal penetration takes place. Preferably, the formulation provides the drug with stability and transdermal permeation properties. To achieve these goals, the formulation preferably contains several components as follows:
1) Non-aqueous solvent LD and its derivatives are more stable in non-aqueous solution than in aqueous solution. A preferred solvent is propylene glycol which is non-toxic, does not produce skin irritation and provides the proper constituency for dermal application. Other non-aqueous solvents with similar properties may also be used for this purpose.
2) Transdermal enhancer and stabilizer A preferred transdermal enhancer and stabilizer is carboxylic acid. The alkyl- esters of LD are quite soluble and much more stable in an acidic environment than in a neutral environment. The carboxylic acid also keeps the LD derivative uncharged and helps permeability through the skin.
3) Detergent Detergents have been shown to be transdermal enhancers. The detergent should not interfere with the chemical stability of the penetrating drug and should not be toxic. We found that sodium laurylsulphate and sodium deoxycholate are adequate detergents for the purpose of transdermal delivery of LD. Yet, other detergents may also be appropriate for this purpose. Reference is now made to Figs. 1 and 2 which illustrate apparatus 10 for transdermal administration of levodopa, constructed and operative in accordance with a preferred embodiment of the present invention.
Apparatus 10 preferably includes a storage compartment 12 which is in fluid communication with a dermal patch 14, preferably via a flexible plastic tube 16 Patch 14 may be made of any suitable material, such as cloth or plastic Storage compartment 12 is preferably flexible and compressible by mechanical pressure Storage compartment 12 preferably contains a fluid 18 (Fig. 2) which is a treating drug, such as an alkyl-ester of LD, dissolved in a formulation, such as described hereinabove in accordance with a preferred embodiment of the present invention
In accordance with a preferred embodiment of the present invention, the alkyl- ester of LD is kept pre-weighed as a dried powder Carbidopa (25 - 50 mg/tablet) is preferably ingested two hours before the beginning of the transdermal delivery of the LD derivative and then three times a day throughout the entire treatment Preferably just before the beginning of the dermal application, the alkyl-ester of LD is placed in storage compartment 12 and a sufficient amount of formulation is added therein, and the constituents are thoroughly mixed together. Storage compartment 12 is then preferably tied to an arm or any other suitable location on a patient, such as with a strap 20, and connected to patch 14 via tube 16
Flow of fluid 18 from storage compartment 12 to patch 14 is preferably controlled by a regulating valve 22. Patch 14 is preferably attached to the skin along an adhesive periphery 24, and a central portion 26 is preferably adapted to receive and maintain a quantity of fluid 18 Fluid 18 spreads under patch 14 preferably via a system of hollow capillaries 28 (Fig 2), and penetrates the skin of a patient
In a normal mode of application, fluid 18 flows from storage compartment 12 to patch 14 by gravity, or alternatively by a miniature pump (not shown) When necessary, flow of fluid 18 may be increased by exerting mechanical pressure on storage compartment 12 or by increasing the pump rate. Apparatus 10 is preferably disposable The location of apparatus 10 on the patient's skin may be changed periodically Supplemental oral treatment may be given during the transdermal delivery according to clinical needs
Various preparations of LD have been tested by the inventors and the experimental results are now presented Solubility of LDEE The solubility of LD, LD methyl ester (LDME) and LD ethyl ester (LDEE) was examined in several potential solvents, with increasing amounts of the three LD derivatives being added to a constant volume of 5% propionic acid in water or 10% propionic acid in propylene glycol We found that only negligible amounts of LD or LDME
were soluble in the two solvents, whereas at least 660 mg LDEE were soluble in 1 ml of both solvents Adding 33% glycerol to the aqueous solvent did not significantly alter the solubility of the three derivatives, although a higher concentration of propionic acid ( 10%) was needed in the case of the aqueous solutions Stability of LDEE The stability of LDEE was tested in several combinations of potential components of the formulation For this purpose, 500 mg LDEE was dissolved in 1 ml 5% propionic acid just before the beginning of the stability experiment In parallel, 500 mg LDEE was dissolved in 1 ml propylene glycol containing 10% propionic acid These preparations of LDEE were used as stock solutions for several tested formulations as follows 1) LDEE in aqueous solution of 5% propionic as prepared above
2) Same solution as in No 1 above + 5% sodium deoxycholate
3) Same solution as in No 1 above + 5% sodium dodecylsulfate
4) Same solution as in No 1 above + 5% Tween-20
5) Same solution as in No 1 above + 5% tritonXlOO 6) Same solution as in No 1 above + glycerol at a ratio of 1 1
7) Same solution as in No 1 above + propylene glycol at a ratio of 2 1
8) LDEE in propylene glycol containing 10% propionic acid
9) Same solution as in No 8 above + 5% sodium deoxycholate
10) Same solution as in No 8 above + 5% sodium dodecylsulfate The above LDEE formulations were run on a thin layer chromatography (on silica gel - Merk Art 5735, and on cellulose - Merk Art 5574) for a qualitative detection of LDEE and its degradative products The various LDEE formulations were kept at room temperature for several days and separation of the LDEE and its degradative products on the thin layer chromatography were repeated at various times after dissolving the LDEE The running solvents for the thin layer chromatography were a) Propanol Butanoic Acid Water (20 4 10) b) Dichloromethane Acetone Ethyl- Acetate Methanol (35 15 1 0 25)
Immediately after the preparation, LDEE appeared on the thin layer chromatography as a single spot No degradative products were seen at this stage Degradative products appeared in formulations that contained tritonXlOO 24 h after dissolving the LDEE Other formulations did not show significant degradation 24 h after dissolving the LDEE At 48 h after dissolving the LDEE, degradative products appeared in all the aqueous solutions with the following order of degradation formulation containing tritonXlOO > formulation
containing Tween-20 > formulation containing sodium dodecylsulfate = formulation containing sodium deoxycholate. In the propylene glycol-based formulations, the LDEE was stable for more than 48 h.
Pharmacolanetic study: In a pilot experiment of transdermal delivery, two human volunteers were exposed for 24 h to LDEE dissolved in propylene glycol containing 10%) propionic acid and 5% of either sodium deoxycholate (one volunteer) or sodium dodecylsulfate (one volunteer). Blood samples were taken at various times after the application of the LDEE on the skin and LDEE in the serum was separated on high performance liquid chromatography and determined with an electrochemical detector. The protocol and the details of this pilot study are described in the enclosed appendix. The results showed that blood levels of LDEE after dermal application using the above mentioned formulations could reach about 200 ng/ml. These levels are considered appropriate for obtaining therapeutic effect in Parkinson's patients.
It will be appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention includes both combinations and subcombinations of the features described hereinabove as well as modifications and variations thereof which would occur to a person of skill in the art upon reading the foregoing description and which are not in the prior art.
Claims
C L A I M S What is claimed is
1 A pharmaceutical composition for treatment of Parkinson's disease comprising a compound of levodopa dissolved in a non-degradative solvent which allows transdermal administrtion of levodopa
2 A pharmaceutical composition according to claim 1 and wherein said compound of levodopa is an alkyl-ester of levodopa and said solvent is a formulation comprising a substantially non-aqueous solvent, a transdermal enhancer and a detergent
3 A pharmaceutical composition according to claim 2 wherein said alkyl-ester of levodopa is levodopa-ethyl-ester (LDEE)
4 A pharmaceutical composition according to claim 2 wherein said non-aqueous solvent has at least one of the following properties non-toxic and non-irritant
5 A pharmaceutical composition according to claim 2 wherein said non-aqueous solvent is propylene glycol 6 A pharmaceutical composition according to claim 2 wherein said transdermal enhancer is also a stabilizer
7 A pharmaceutical composition according to claim 2 wherein said transdermal enhancer is a carboxylic acid
8 A pharmaceutical composition according to claim 7 wherein said carboxylic acid is selected from the group consisting of propionic acid and butanoic acid
9 A pharmaceutical composition according to claim 2 wherein said detergent is selected from the group consisting of sodium laurylsulphate, sodium deoxycholate and their derivatives
10 Apparatus for transdermal delivery of a substance for treatment of Parkinson's disease, said apparatus comprising a storage compartment containing therein a fluid for transdermal treatment of Parkinson's disease, and a dermal patch in fluid communication with said storage compartment, said dermal patch being attached to a portion of skin of a patient, wherein said fluid flows from said storage compartment to said dermal patch and is thence transdermally delivered to said patient
11 Apparatus according to claim 10 wherein said dermal patch comprises a plurality of hollow capillaries for flow of said fluid therethrough to the skin of said patient
12. Apparatus according to either of claims 10 and 1 1 and wherein said storage compartment is compressible by mechanical pressure.
13. Apparatus according to any of claims 10 - 12 and comprising a regulating valve for controlling flow of said fluid from said storage compartment to said dermal patch. 14. A method for treatment of Parkinson's disease, comprising the step of transdermally administering a levodopa drug in a stable solution.
15. A method according to claim 14 wherein said step of transdermally administering said levodopa drug comprises substantially continuous transdermal penetration of levodopa. 16. A method according to claim 14 and wherein said levodopa drug comprises an alkyl-ester of levodopa.
17. A method according to claim 14 and wherein said solution comprises a substantially non-aqueous solvent, a transdermal enhancer and a detergent.
18. A method according to claim 14 and wherein said levodopa drug and said solution are stored separately and mixed just before transdermally applying said drug.
19. A method according to claim 14 and further comprising the step of ingesting carbidopa before commencing transdermal delivery of said levodopa drug.
20. A method according to claim 14 and further comprising the step of ingesting carbidopa during transdermal delivery of said levodopa drug. 21. A method according to claim 14 and further comprising the step of receiving an oral anti-parkinson's drug.
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002268455A CA2268455C (en) | 1996-10-13 | 1997-10-09 | Methods and apparatus for treatment of parkinson's disease |
| JP51815198A JP2002513389A (en) | 1996-10-13 | 1997-10-09 | Method and apparatus for treating Parkinson's disease |
| AU45702/97A AU4570297A (en) | 1996-10-13 | 1997-10-09 | Methods and apparatus for treatment of parkinson's disease |
| EP97944077A EP1011644A4 (en) | 1996-10-13 | 1997-10-09 | Methods and apparatus for treatment of parkinson's disease |
| US09/287,951 US6166081A (en) | 1997-10-09 | 1999-04-07 | Methods and apparatus for treatment of Parkinson's disease |
| US09/711,709 US6746688B1 (en) | 1996-10-13 | 2000-11-13 | Apparatus for the transdermal treatment of Parkinson's disease |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL119417 | 1996-10-13 | ||
| IL11941796A IL119417A (en) | 1996-10-13 | 1996-10-13 | Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US09/287,951 Continuation US6166081A (en) | 1996-10-13 | 1999-04-07 | Methods and apparatus for treatment of Parkinson's disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1998016208A1 true WO1998016208A1 (en) | 1998-04-23 |
Family
ID=11069375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IL1997/000327 WO1998016208A1 (en) | 1996-10-13 | 1997-10-09 | Methods and apparatus for treatment of parkinson's disease |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1011644A4 (en) |
| JP (2) | JP2002513389A (en) |
| AU (1) | AU4570297A (en) |
| CA (1) | CA2268455C (en) |
| IL (1) | IL119417A (en) |
| WO (1) | WO1998016208A1 (en) |
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| WO1999030702A1 (en) * | 1997-12-17 | 1999-06-24 | Sekisui Chemical Co., Ltd. | Percutaneously absorbable levodopa-containing preparation |
| JP2003503442A (en) * | 1999-07-05 | 2003-01-28 | イデア アクチェンゲゼルシャフト | Methods to improve transport across adaptive semi-permeable barriers |
| JP2003321350A (en) * | 2002-02-28 | 2003-11-11 | Lintec Corp | Percutaneously absorbable preparation and method for percutaneously absorbing drug using the same |
| US6746688B1 (en) | 1996-10-13 | 2004-06-08 | Neuroderm Ltd. | Apparatus for the transdermal treatment of Parkinson's disease |
| AT500095A1 (en) * | 2004-01-23 | 2005-10-15 | Braun Werner Mag | TRANSDERMAL DELIVERY SYSTEM |
| WO2007114697A1 (en) * | 2006-03-31 | 2007-10-11 | Erasmus University Medical Center Rotterdam | Novel composition for tumor growth control |
| US7858112B2 (en) | 2002-02-28 | 2010-12-28 | Lintec Corporation | Percutaneous absorption system and percutaneous absorption method |
| US8815950B2 (en) | 2003-08-29 | 2014-08-26 | Janssen Biotech, Inc. | Pharmaceutical compositions and method of using levodopa and carbidopa |
| EP2648716A4 (en) * | 2010-12-10 | 2015-05-20 | Synagile Corp | Subcutaneously infusible levodopa prodrug compositions and methods of infusion |
| EP3075723A1 (en) * | 2015-03-30 | 2016-10-05 | Berlirem GmbH | Highly soluble L-DOPA glycerol esters |
| WO2016155888A1 (en) * | 2015-03-30 | 2016-10-06 | Berlirem Gmbh | Water-soluble l-dopa esters |
| US9901561B2 (en) | 2015-05-06 | 2018-02-27 | Synagile Corporation | Pharmaceutical suspensions containing drug particles, devices for their administration, and methods of their use |
| US10624839B2 (en) | 2014-03-13 | 2020-04-21 | Neuroderm, Ltd. | Dopa decarboxylase inhibitor compositions |
| US10813902B2 (en) | 2014-03-13 | 2020-10-27 | Neuroderm, Ltd. | DOPA decarboxylase inhibitor compositions |
| US11213502B1 (en) | 2020-11-17 | 2022-01-04 | Neuroderm, Ltd. | Method for treatment of parkinson's disease |
| US11331293B1 (en) | 2020-11-17 | 2022-05-17 | Neuroderm, Ltd. | Method for treatment of Parkinson's disease |
| US11844754B2 (en) | 2020-11-17 | 2023-12-19 | Neuroderm, Ltd. | Methods for treatment of Parkinson's disease |
| US12161612B2 (en) | 2023-04-14 | 2024-12-10 | Neuroderm, Ltd. | Methods and compositions for reducing symptoms of Parkinson's disease |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL119417A (en) * | 1996-10-13 | 2003-02-12 | Moshe Kushnir | Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease |
| DE10261807A1 (en) * | 2002-12-19 | 2004-07-01 | Turicum Drug Development Ag | Deuterated catecholamine derivatives and medicinal products containing these compounds |
| WO2012066538A1 (en) * | 2010-11-15 | 2012-05-24 | Neuroderm Ltd | Continuous administration of l-dopa, dopa decarboxylase inhibitors, catechol-o-methyl transferase inhibitors and compositions for same |
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| US5354885A (en) * | 1992-12-24 | 1994-10-11 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Process for preparing ethyl ester of L-DOPA |
| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
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| DE252290T1 (en) * | 1986-06-10 | 1988-06-09 | Chiesi Farmaceutici S.P.A., Parma | LEVODOPA METHYL ESTER CONTAINING PHARMACEUTICAL COMPOSITIONS, THEIR PRODUCTION AND THERAPEUTIC USE. |
| GB8807504D0 (en) * | 1988-03-29 | 1988-05-05 | Sandoz Ltd | Improvements in/relating to organic compounds |
| US4927408A (en) * | 1988-10-03 | 1990-05-22 | Alza Corporation | Electrotransport transdermal system |
| JPH04261119A (en) * | 1991-02-13 | 1992-09-17 | Lintec Corp | Percutaneous absorption-type pharmaceutical preparation |
| IL111240A (en) * | 1993-10-18 | 2001-10-31 | Teva Pharma | Salts of r(+) - enantiomers of n- propargyl-1-aminoindan and pharmaceutical compositions comprising them |
| IL119417A (en) * | 1996-10-13 | 2003-02-12 | Moshe Kushnir | Pharmaceutical composition for transdermal administration of levodopa for parkinson's disease |
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1996
- 1996-10-13 IL IL11941796A patent/IL119417A/en not_active IP Right Cessation
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1997
- 1997-10-09 WO PCT/IL1997/000327 patent/WO1998016208A1/en active Application Filing
- 1997-10-09 EP EP97944077A patent/EP1011644A4/en not_active Withdrawn
- 1997-10-09 CA CA002268455A patent/CA2268455C/en not_active Expired - Fee Related
- 1997-10-09 JP JP51815198A patent/JP2002513389A/en active Pending
- 1997-10-09 AU AU45702/97A patent/AU4570297A/en not_active Abandoned
-
2008
- 2008-08-11 JP JP2008207049A patent/JP2009001588A/en active Pending
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| US5474783A (en) * | 1988-03-04 | 1995-12-12 | Noven Pharmaceuticals, Inc. | Solubility parameter based drug delivery system and method for altering drug saturation concentration |
| US5354885A (en) * | 1992-12-24 | 1994-10-11 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Process for preparing ethyl ester of L-DOPA |
Non-Patent Citations (1)
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| See also references of EP1011644A4 * |
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| US6746688B1 (en) | 1996-10-13 | 2004-06-08 | Neuroderm Ltd. | Apparatus for the transdermal treatment of Parkinson's disease |
| WO1999030702A1 (en) * | 1997-12-17 | 1999-06-24 | Sekisui Chemical Co., Ltd. | Percutaneously absorbable levodopa-containing preparation |
| JP2003503442A (en) * | 1999-07-05 | 2003-01-28 | イデア アクチェンゲゼルシャフト | Methods to improve transport across adaptive semi-permeable barriers |
| JP2003321350A (en) * | 2002-02-28 | 2003-11-11 | Lintec Corp | Percutaneously absorbable preparation and method for percutaneously absorbing drug using the same |
| US7858112B2 (en) | 2002-02-28 | 2010-12-28 | Lintec Corporation | Percutaneous absorption system and percutaneous absorption method |
| JP4608187B2 (en) * | 2002-02-28 | 2011-01-05 | リンテック株式会社 | Transdermal preparation |
| US8815950B2 (en) | 2003-08-29 | 2014-08-26 | Janssen Biotech, Inc. | Pharmaceutical compositions and method of using levodopa and carbidopa |
| AT500095A1 (en) * | 2004-01-23 | 2005-10-15 | Braun Werner Mag | TRANSDERMAL DELIVERY SYSTEM |
| AT500095B1 (en) * | 2004-01-23 | 2006-05-15 | Braun Werner Mag | TRANSDERMAL DELIVERY SYSTEM |
| WO2007114697A1 (en) * | 2006-03-31 | 2007-10-11 | Erasmus University Medical Center Rotterdam | Novel composition for tumor growth control |
| EP2389930A1 (en) * | 2006-03-31 | 2011-11-30 | Erasmus University Medical Center Rotterdam | Novel composition for tumor growth control |
| EP2648716A4 (en) * | 2010-12-10 | 2015-05-20 | Synagile Corp | Subcutaneously infusible levodopa prodrug compositions and methods of infusion |
| US10624839B2 (en) | 2014-03-13 | 2020-04-21 | Neuroderm, Ltd. | Dopa decarboxylase inhibitor compositions |
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| US11046640B2 (en) | 2015-03-30 | 2021-06-29 | Berlirem Gmbh | Water-soluble L-DOPA esters |
| WO2016155888A1 (en) * | 2015-03-30 | 2016-10-06 | Berlirem Gmbh | Water-soluble l-dopa esters |
| EP3075723A1 (en) * | 2015-03-30 | 2016-10-05 | Berlirem GmbH | Highly soluble L-DOPA glycerol esters |
| US9901561B2 (en) | 2015-05-06 | 2018-02-27 | Synagile Corporation | Pharmaceutical suspensions containing drug particles, devices for their administration, and methods of their use |
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| US11135191B2 (en) | 2015-05-06 | 2021-10-05 | Synagile Corporation | Devices for the administration of pharmaceutical suspensions |
| US11426376B2 (en) | 2015-05-06 | 2022-08-30 | Synagile Corporation | Devices for the administration of pharmaceutical suspensions |
| US11213502B1 (en) | 2020-11-17 | 2022-01-04 | Neuroderm, Ltd. | Method for treatment of parkinson's disease |
| US11331293B1 (en) | 2020-11-17 | 2022-05-17 | Neuroderm, Ltd. | Method for treatment of Parkinson's disease |
| US11458115B2 (en) | 2020-11-17 | 2022-10-04 | Neuroderm, Ltd. | Method for treatment of Parkinson's disease |
| US11844754B2 (en) | 2020-11-17 | 2023-12-19 | Neuroderm, Ltd. | Methods for treatment of Parkinson's disease |
| US12161612B2 (en) | 2023-04-14 | 2024-12-10 | Neuroderm, Ltd. | Methods and compositions for reducing symptoms of Parkinson's disease |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2268455A1 (en) | 1998-04-23 |
| CA2268455C (en) | 2007-05-15 |
| IL119417A (en) | 2003-02-12 |
| EP1011644A4 (en) | 2006-02-08 |
| IL119417A0 (en) | 1997-01-10 |
| AU4570297A (en) | 1998-05-11 |
| JP2002513389A (en) | 2002-05-08 |
| JP2009001588A (en) | 2009-01-08 |
| EP1011644A1 (en) | 2000-06-28 |
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