JP2002513389A - Method and apparatus for treating Parkinson's disease - Google Patents

Abstract

  (57) [Summary] Pharmaceutical compositions for the treatment of Parkinson's disease contain a levodopa compound dissolved in a non-denaturing solvent, which allows for the transdermal administration of levodopa. The levodopa compound 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

Description: FIELD OF THE INVENTION The present invention relates to a method and a device for treating Parkinson's disease. BACKGROUND OF THE INVENTION Parkinson's disease (PD) is one of the most common neurodegenerative diseases affecting the elderly. The following is a list of representative articles discussing Parkinson's disease and its treatment. 1.De Rijk MC, Breteler MMB, Graveland GA, etc., Prevalence of Parkinson's disease in the elderly: The Rotterdam study, Neurol., 1995; 45: 2143-2146 2. Prevalence of Parkinsonian signs and associated mortality in a community population of older people, such as Bennet DA, Beckett LA, and Murray AM, in an elderly community population, N. Engl .J. Med., 1996; 334 (2): 71-76 3. Hornykiewicz O, Kish SJ, Biochemica l pathophysiology of Parkinson's disease, Adv. Neurol., 1986; 45: 19-34 4. The nigrostriatal dopaminergic system evaluated in vivo by positron emission tomography in healthy volunteers and patients with Parkinson's disease, such as Leenders KL, Salmon EP, and Tyrrel P assessed in vivo by posit ron emission tomography in healthy volunteers ubjects and patients with Parkinson's disease), Arch.Neurol., 1990; 47: 1290-1298 5.LeWitt PA, Levodopa therapy: New treatment strategies, Neurology, 1993; 43 (Supplement 6): S31-S37 6.Risk factors for motor response complications in Parkinson's syndrome patients treated with Peppe A, Dambrosia JM, Chase TN, L-Dopa L-Dopa treated parkinsonian patients), Adv. Neurol., 1993; 60: 698-702 7.Chase TN, Mouradian MM, EngberTM, motor response complications and striatal centrifugal function (Motor response complications and the functions of striatal efferent sy stems), Neurology, 1993; 43 (Supplement 6): S23-S27 8.Doller HJ, Connor JD, Changes in neostriatal dopamine concentrations in response to levodopa infusion (Changes in neostriatal dopamine concentrations in response) to levod opainfusions), J. Neurochem., 1980; 34: 1264-1269 9.Spencer SE, Wooten GF, dopaminergic nerve support Altered pharmacokinetics of L-dop a metabolism in rat striatum deprived of dopaminergic innervation in rat striatum lacking, Neurology, 1984; 34: 1105-1108 10 The pharmacologic effects of Spencer SE, Wooten GF, L-dopa are not strictly temporally related to striatal dopamine levels (Pharmacologic effects of L-dopa are not c losely linked temporally to striatal dopamine concentration), Neurology, 1 984; 34: 1609-1611 11.Dynamic pharmacokinetics of intravascular and oral levodopa in patients with Parkinson's disease showing on-off fluctuations such as Hardie RJ, Malcolm SL, Lees AJ (The pharmacokinetics) of int ravenous and oral levodopa in Parkinson's patients who exhibit on-off fl uctuations), Br.J.Clin.Pharmacol., 1986; 22: 421-436 12.Fabbrini G, Juncos J, Mouradian MM, etc. Of the dynamic pharmacological mechanism and motility of levodopa pharmacokinetic mechan isms and mo Tor fluctuations in Parkinson's disease), Ann. Neurol., 1987; 21: 370-376 13. Nutt JG, Woodwars WR, Hammerstad JP, et al. "On-off" phenomena in Parkinson's disease: Implications for levodopa absorption and transport (The “On-off” phenomenon in Parkinson's disease: relation to levodopa absorption and transport), N.EnglJMed., 1984; 310: 483-488 14.Shoulson I, Glaubiger GA, Chase TN, On-off response: Parkinson syndrome patients -On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients in Neurology, 1975: 25: 1144-1148 15. Quinn N, Parkes JD, Marsden CD, Control of on / off phenomenon by continuous intravenous in fusion of levodopa, Neurology, 1984; 34: 1131-1136 16 .Schuh LA, Bennet JP, Motor abnormalities in advanced Parkinson's disease Suppression. I. Continuous intravascular levodopa infusion shifts the dose dependence for the development of dyskinesias, but not the reduction of Parkinsonism in patients with advanced Parkinson's disease (Suppression of dyskinesias in advanced Parkinson's disease.I. Continuous intravenous levodopa shifts dose -response for production of dyskinesias but not for relief of parkinsoni sm 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 com plex 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 (146): 46-49 19.Nutt JG, Woodward WR, Levodopa pharmacodynamics and pharmacodynamics in patients with fluctuating Parkinsonism. and pharmacodynamics in flu ctuating parkinsonian patients), Neurology, 1986; 36: 739-744 20. Nelson MV, Berchou RC, LeWitt PA, etc., after controlled carbidopa / levodopa (Sinemet CR-4) release in Parkinson's disease Modeling of concentration-effect relation ship after controlled-release carbidopa / levodopa (Sinemet CR-4) in Parkin son'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 thera peutic effect in sever Parkinson's disease) , Eur. J. Clin. Pharmacol., 1993; 4 5: 117-122 22.Mouradian MM, Juncos JL, Fabbrini G et al., Motor fluctuations in Parkinson's disease: a central pathophysiological mechanism (Motor fluctuations in Parkinson's diseas) e: central pathophysiological mechanisms), Part II, Ann. Neurol., 1988; 24: 372 -378 23. Sage JI, Mark MH, Rationale for continuous dopaminergic stimulation in patients with Parkinson's disease. For continuous dopaminergic s timulation in patients with Parkinson's disease), Neurology, 1992: 42 (Supplement 1): 23-28 24. Chase TN, Baronti F, Fabbrini G, etc. Rationality for continuous dopamine therapy for Parkinson's disease (Rational for continuous dopaminometic therapy of Parkinson's disease), Neurology, 1989; 39 (Supplement 2): 7-10 25. Sage JI, Mark MH, Basic mechanisms of mot or fluctuations, Neurology, 1994; 44 (Appendix 6): S10-S14 26. Suffering from progressive Parkinson's disease, such as Sage JL, Trooskin S, Sonsalla PK Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson's disease), Neurology, 1989; 36 (Supplement 2): 60- 63 27. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease, such as Mouradian MM, Heuser IJE, Baronti F, etc. Neurol., 1990; 27: 18-23 28.Bravi D, Mouradian MM, Roberts JW, et al., End-of-dose dystonia in Parkinson's disease in Parkinson's disease, Neurology, 1993; 43: 2130-2. 131 29.Tanner CM, Melamed E, Lees AJ, Managing motor fluctuations, dyskinesias and o ther adverse effects in Parkinson's disease in Parkinson's disease, Neurology, 1994; 44 ( Addendum 1): S1 2-S16 30.Josep h Kiug Ching Tsui, Future Treatment of Parkinson's disease, Can. J. Neurol. Science, 1992; 19: 160-162 31. Djaldetti R, Atlas D, Melamed E, levodopa-ethyl ester Subcutaneous injections of levodopa-ethylester: A potential novel rescue therapy for response fluctuations in patients with Parkins on's disease (Abst.) , Neurology, 1995; 45 (Supplement 4): 4155 32.LeWitt PA, described in Levodopa controlled-release pre parations, Neurology, 1993; 43 (Supplement 6): S38-S40. Article 33.Koner WC & Pahwa R, Treating motor fluctuations wit h controlled-release levodopa preparations, Neurology, 1994: 44 (Supplement 6): S23-S28 55 years or older The prevalence of diagnosed PD in this population is approximately 1.4%, Increases with age (Reference 1). Furthermore, it has been estimated that Parkinsonism in the elderly occurs in 30% of the population over the age of 65 (2). PD is a multisystem disease, primarily a motility disorder caused by continuous, prolonged alteration of dopaminergic neurons located in the mesencephalic substantia nigra pars compacta. is there. PD becomes a syndrome only after about 60-80% degeneration of these dopaminergic neurons or after about 90% loss of striatal dopamine (3,4). Dopamine (DA) produced in the substantia nigra reaches the striatum via the nigro-striatal tract and is released at the striatal synapse. Deficiency of PD in the DA striatum due to alteration of the dopaminergic neurons in the substantia nigra is believed to be responsible for PD. Consequently, the most effective treatment of PD is with levodopa (LD), which is converted to DA by enzymatic decarboxylation. Inhibition of peripheral aromatic amino acid decarboxylase by carbidopa (an inhibitor that cannot penetrate the blood-brain barrier) significantly improves the outcome of this treatment. However, generally man-made LD formulations are only effective for a relatively short period of time and can be even harmful under some conditions (discussed below). Administration of LD is particularly advantageous in the early stages of the disease. The adverse effects of LD, such as dyskinesias and hallucinations that occur early in the disease, are dose-dependent. These adverse effects are due to hypersensitivity of denervated striatal dopaminergic receptors to exogenous dopamine (Reference 5). In the late stages of the disease, ancillary types of adverse effects appear as the response to LD becomes unpredictable and variable, and the duration of the response decreases. Motility variability appears in approximately 24% -84% of the patients about 4-5 years after the start of LD treatment (6). The most common and disabling motor complications are 1) `` wearing-off '' variation, 2) `` on-off '' variation, and 3) peak-dose ) Motor abnormalities (Reference 7). The "extinguishing" effect means a decrease in the duration of the beneficial effect after each administration of LD. During this period, LD needs to be administered more frequently than before, which creates certain problems that have a significant impact on the quality of life of the patient. Complexity such as "extinction" is thought to be caused by limitations in the storage capacity of DA in the CNS (Refs. 5, 8-10). If neuronal DA stores are reduced, the patient's clinical state becomes completely dependent on the fluctuating blood levels of LD. Since the normal half-life of LD in the circulatory system is 1-2 hours (11-13), LD should be administered more frequently at this point, and its effects are variable. In addition, using commonly available oral formulations, blood levels of LD are a function of the irregular and uncontrollable rate of absorption from the gastrointestinal tract. The observed fluctuations in the LD blood concentration further contribute to the instability of the effect. Continuous drug release, maintaining a constant blood concentration of LD, has been shown to significantly improve the clinical status of the fluctuating Parkinson's disease patients (13-18). In this regard, it has been reported that the therapeutic effect of LD was seen when the plasma concentration of LD reached 300-800 ng / ml (References 19-21). The "on-off" fluctuation is the conflicting transition between a hypokinetic Parkinson syndrome state (the "off" state) and a hypermotor state (the "on" state). The clinical status of these patients is highly correlated with the plasma concentration of LD (5,20). These fluctuations may be due to narrowing the therapeutic window for LD. Intermittent administration of LD performed over a long period of time is considered to be one of the main causes of the decrease in the number of treatment windows (References 22 and 23), and as a result, leads to the motility fluctuation (References 23 to 25) . On the other hand, continuous infusion of LD has been shown to widen the therapeutic window and reduce the "on-off" variability (25-27). Furthermore, during continuous administration, the blood concentration of LD required to keep the patient in the "on" state gradually decreases (Ref. 21). Peak dose dyskinesia is a common advanced motor complication, which occurs when blood levels of LD reach their peak. This complication is observed in the advanced stages of the disease when the patient shows a very steep dose-response curve. Under these circumstances, a slight shift in the concentration of circulating LD and consequently DA in the brain induces major oscillations in the clinical condition (7). At this stage of the disease, continuous administration that maintains a constant circulating LD concentration may prevent this dyskinesia. Furthermore, these types of dyskinesias, such as the "on-off" dyskinesia, cannot develop during continuous administration of LD (7,16,17,28,29). All of these findings and observations clearly suggest that continuous release of LD is more advantageous than intermittent dosing. Enduring attempts have been made in efforts to develop sustained release LDs (30, 31). Methods for improving the clinical outcome of intermittent LD administration include controlled release (CR) formulations and pump release of LD. However, existing formulations and devices have several disadvantages, as described below. 1. CR formulations are delayed acting. The peak effect of Symmet CR (commercially available from Merck Sharp and Dome Research Laboratories) was shown to occur one hour later than the known Symmet peak effect ( References 18, 32). 2. The bioavailability of the CR formulation is low (References 18, 32). This low bioavailability is explained by the variable properties of the gastrointestinal tract (33). 3. Low reliability and predictability of the clinical response (References 32, 33). 4. According to many studies, the CR formulation does not give the same favorable results as revealed by continuous administration of LD, for example IV infusion (eg 5,15,18). 5. Peripheral sclerosis often occurs during IV infusion of LD (Reference 5). 6. Gastric fistula formation-Duodenal tubes or esophageal catheters are extremely uncomfortable. To overcome these drawbacks and to administer LD in a continuous manner, alternative methods of drug release are needed. SUMMARY OF THE INVENTION In the present invention, we find that transdermal release of LD may be the best alternative to the continuous invasive infusion method without showing the disadvantages of the commonly available methods Argue that. The present invention constitutes a solution to most of the above problems associated with commonly available therapies, and thus provides a safer and more effective treatment for PD. The present invention describes a novel method for administering levodopa dissolved in a formulation. The formulation is designed to maintain the stability of the drug in solution, and allows for continuous penetration of the drug through the skin. This method is suggested as a treatment for patients with Parkinson's disease, especially those with advanced disease. The commonly available LD formulations cause side effects and exacerbations in the clinical state of the disease. The present invention helps overcome these disadvantages. According to a preferred embodiment of the present invention, an alkyl ester of LD, such as levodopaethyl ester (LDEE), is administered transdermally. For this purpose, the alkyl ester of the LD is dissolved in a suitable formulation. The formulation consists of propylene glycol, a fatty acid and a detergent. The LD-alkyl ester and the formulation are kept separate and mixed just before application of the drug. A transdermal administration device that includes a container connected to the patch via a thin plastic tube is used for this transdermal release. The container is refilled every 24 hours. The patch is supplied with the LD-alkyl ester solution, preferably by gravity or alternatively by a pump, and the solution is then spread on the skin surface covered with the patch. During treatment, the patient takes tablets of carbidopa (25-50 mg / tablet) three times a day. According to clinical needs, the patient may receive supplemental treatment, for example, orally an antiparkinsonian drug. BRIEF DESCRIPTION OF THE DRAWINGS The invention will be better understood from the following detailed description given in connection with the accompanying drawings. FIG. 1 is a simplified diagram of a device for transdermal administration of levodopa, constructed and operated in accordance with a preferred embodiment of the present invention. And FIG. 2 is a simplified cross-sectional view of the device shown in FIG. 1, taken along line II-II of FIG. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Formulations (solvents) useful in the percutaneous treatment of Parkinson's disease, according to preferred embodiments of the present invention, are first described below. The formulation is engineered to dissolve the therapeutic drug (alkyl ester of LD) and to maintain the stability of the drug in solution during periods of continuous transdermal penetration. Designed for Preferably, the formulation confers stability and transdermal permeability to the drug. To achieve these objectives, the formulation preferably contains several components, such as: 1) Non-aqueous solvent: LD and its derivatives are more stable in non-aqueous solutions than in aqueous solutions. A preferred solvent is propylene glycol, which is non-toxic, does not cause skin irritation and provides a suitable consistency for application to the skin. Other non-aqueous solvents with similar properties can also be used for this purpose. 2) Transdermal enhancers and stabilizers: Preferred transdermal enhancers and stabilizers are carboxylic acids. The alkyl esters of the LD are much more soluble and more stable in acidic environments than in neutral environments. The carboxylic acid also keeps the LD derivative intact and aids its penetration through the skin. 3) Detergents: Detergents have been shown to be transdermal enhancers. The detergent must not interfere with the chemical stability of the penetrating drug and must not be toxic. We have found that sodium lauryl sulfate and sodium deoxycholate are sufficient detergents for transdermal release of LD. In addition, other cleaning agents are suitable for this purpose. Referring to FIGS. 1 and 2, these figures show a device 10 constructed and operated in accordance with a preferred embodiment of the present invention for transdermal administration of levodopa. The device 10 preferably includes a storage compartment 12, which is in fluid communication with a skin patch 14, preferably via a plastic tube 16. The patch 14 can be made of any suitable material, such as cloth or plastic. The storage compartment 12 is preferably flexible and compressible by mechanical pressure. The storage compartment 12 preferably contains a fluid 18 (FIG. 2), which is a therapeutic drug, eg, an alkyl ester of LD, dissolved in a formulation as described above in accordance with a preferred embodiment of the present invention. In a preferred embodiment of the present invention, the alkyl ester of LD is pre-weighed as a dry powder. Carbidopa (25-50 mg / tablet) is preferably taken 2 hours before the onset of transdermal release of the LD derivative and then 3 times per day throughout the treatment. Preferably, just prior to the start of the transdermal administration, the alkyl ester of the LD is placed in the storage compartment 12, where a sufficient amount of the formulation is added and the components are thoroughly mixed together. The storage compartment 12 is then tied to the patient's arm or any other suitable location, such as by a strap 20, and connected to the patch 14 via a tube 16. The flow of the fluid 18 from the storage compartment 12 to the patch 14 is preferably regulated by a regulating valve 22. The patch 14 is preferably applied along an adhesive perimeter 24 and the central portion 26 is preferably adapted to receive and retain a quantity of the fluid 18. The fluid 18 deploys to the lower portion of the patch 14 and penetrates the patient's skin, preferably via a system having a hollow capillary 28 (FIG. 2). In a normal application mode, the fluid 18 flows from the storage compartment 12 to the patch 14 by gravity or alternatively by a miniature pump (not shown). If necessary, the flow of the fluid 18 can be increased by applying mechanical pressure to the storage compartment 12 or by increasing the speed of the pump. The device 10 is preferably disposable. The position of the device 10 on the patient's skin can be changed periodically. Supplemental oral treatments can be applied during the transdermal release, depending on the clinical need. We have tested various formulations of LD. The experimental results are shown below. LDEE Solubility : The solubility of LD, LD methyl ester (LDME) and LD ethyl ester (LDEE) was studied using several potential solvents. Increasing amounts of these three LD derivatives were added to a volume of 5% aqueous propionic acid or 10% propionic acid in propylene glycol. We have found that only negligible amounts of LD or LDME are soluble in these two solvents, while at least 660 mg of LDEE is soluble in 1 ml of both these solvents. The addition of 33% glycerol to the aqueous solvent did not significantly alter the solubility of these three derivatives, but a higher concentration of propionic acid (10%) was required for the aqueous solution. Met. LDEE stability: LDEE stability was tested for several combinations of the possible components of the formulation. For this purpose, 500 mg of LDEE was dissolved in 1 ml of 5% propionic acid just before the start of the stability experiment. In parallel, 500 mg of LDEE was dissolved in 1 ml of propylene glycol containing 10% propionic acid. These LDEE formulations were used as mother liquors for the following several tested formulations. 1) A solution in which LDEE prepared as described above is dissolved in a 5% aqueous solution of propionic acid 2) The solution of No. 1 above + 5% sodium deoxycholate 3) The solution of No. 1 above + 5% sodium dodecyl sulfate 4) No. 1 solution + 5% Tween-20 5) No. 1 solution + 5% triton X100 6) No. 1 solution + glycerol (mixing ratio 1: 1) 7) The above No. 1 solution + propylene glycol (mixing ratio 2: 1) 8) LDEE dissolved in propylene glycol containing 10% propionic acid 9) The above No. 8 solution + 5% sodium deoxycholate 10 ) No. 8 solution + 5% sodium dodecyl sulfate The above LDEE formulation was purified by thin layer chromatography (silica gel (Merck Art. 5735) and cellulose) for qualitative detection of LDEE and its degradation products. (Merc Art.5574)). The various LDEE formulations were left at room temperature for several days, and the separation of the LDEE and its degradation products on the thin layer chromatography was repeated at various times after dissolution of the LDEE. The following were used as developing solvents for the thin layer chromatography. a) propanol: butanoic acid: water (20: 4: 10) b) dichloromethane: acetone: ethyl acetate: methanol (35: 15: 1: 0.25) Immediately after preparation, LDEE is applied as a single spot on thin layer chromatography. Appeared. At this time, no decomposition products were observed. Degradation products appeared in formulations containing Triton X100 24 hours after dissolving the LDEE. Other formulations did not show significant degradation 24 hours after dissolution of the LDEE. Forty-eight hours after dissolution of the LDEE, it appeared in all aqueous solutions in the following decomposition order: Formulations containing Triton X100> Formulations containing Tween-20> Formulations containing sodium dodecyl sulfate = Formulations containing deoxycholic acid. In the propylene glycol based formulation, the LDEE was stable for over 48 hours. Dynamic pharmacological study : In a pilot study of dermal release, two human volunteers were treated with LDEE 10% propionic acid and 5% sodium deoxycholate (one volunteer) or dodecyl for 24 hours. Exposure to LDEE dissolved in propylene glycol containing sodium sulfate (1 volunteer). At various times after application of the LDEE to the skin, blood samples were taken, and the LDEE in the serum was separated on high performance liquid chromatography and measured with an electrochemical detector. Details of this protocol and this pilot study are provided in the attached Appendix. These results indicated that the blood concentration of LDEE after application to the skin using the above formulation could reach about 200 ng / ml. These concentrations are believed to be sufficient to achieve a therapeutic effect in Parkinson's disease patients. Those skilled in the art will understand that the present invention is not limited in any way by what has been particularly shown and described above. On the contrary, the scope of the invention is not limited to the features described herein, but also to combinations and modifications thereof that will occur to those skilled in the art upon reading the above description and are not included in the prior art. The combination includes both.

[Procedure amendment] [Submission date] April 14, 1999 (1999.4.1.14) [Correction contents] The scope of the claims 1． A pharmaceutical composition for the treatment of Parkinson's disease, wherein the composition comprises a levodopa compound Wherein the compound is dissolved in a non-decomposable solvent and the process of the levodopa compound is carried out. The above pharmaceutical composition, which is capable of transdermal administration. 2． The levodopa compound is substantially stable at room temperature for at least 48 hours. And the therapeutic concentration of levodopa in the bloodstream following transdermal release. 2. A pharmaceutical composition according to claim 1 in an amount sufficient to achieve 3． The levodopa compound is an alkyl ester of levodopa, and preferably levodopa. The pharmaceutical composition according to claim 1, which is dopaethyl ester (LDEE). Four. The non-degrading solvent includes a non-toxic or non-toxic solvent including polyethylene glycol. Non-irritating at least one non-aqueous solvent consisting of propionic acid and butanoic acid A transdermal enhancer, which is a stabilizer, comprising a carboxylic acid selected from the group; and lauryl From the group consisting of sodium sulfate, sodium deoxycholate and its derivatives The pharmaceutical composition according to claim 3, comprising a selected detergent. Five. A device for transdermally releasing a therapeutic substance effective in treating a disease, , A storage compartment containing a therapeutic fluid therein, and a skin in fluid communication with the storage compartment A skin patch, wherein the skin patch is attached to a portion of the skin to be treated, The fluid flows from the storage compartment to the skin patch and from there transdermally to the therapeutic agent. The above device, wherein the device is discharged to an elephant. 6． The therapeutic fluid is levodopa alone or in combination with a second therapeutic substance; The skin patch includes a plurality of hollow capillaries, wherein the hollow capillaries are Through the storage compartment for flowing the fluid through the skin to be treated. Is compressible by mechanical pressure, and the device further comprises a storage compartment for the fluid. Claims also including a regulating valve for controlling flow from the skin patch to the skin patch. Item 6. The device according to item 5.

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Claims (1)

[Claims] 1． Levodopa compound dissolved in a non-degradable solvent that allows dermal administration of levodopa A pharmaceutical composition for treating Parkinson's disease, comprising a substance. 2． The levodopa compound 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 pharmaceutical composition according to claim 1. 3． The alkyl ester of levodopa is levodopa ethyl ester (LDEE), The pharmaceutical composition according to claim 2. Four. The non-aqueous solvent has at least one of non-toxic and non-irritating properties The pharmaceutical composition according to claim 2, wherein Five. 3. The medical device according to claim 2, wherein the non-aqueous solvent is propylene glycol. Drug composition. 6． 3. The pharmaceutical composition according to claim 2, wherein said transdermal enhancer is also a stabilizer. 7． The pharmaceutical composition according to claim 2, wherein the transdermal enhancer is a carboxylic acid. . 8． The carboxylic acid is selected from the group consisting of propionic acid and butanoic acid; A pharmaceutical composition according to claim 7. 9． The detergent is sodium lauryl sulfate, sodium deoxycholate and 3. The pharmaceutical composition according to claim 2, which is selected from the group consisting of its derivatives. Ten. A device for transdermally delivering a substance for treating Parkinson's disease, comprising: A storage compartment containing a fluid for percutaneous treatment of Kinson's disease; A skin patch in a continuous state, wherein the skin patch is applied to a portion of the patient's skin. The fluid flows from the storage compartment to the skin patch, and thereby the fluid The device as described above, wherein the device is transdermally released to the patient. 11． The skin patch has a plurality of passages for the fluid to flow through the patient's skin. 11. The device according to claim 10, comprising an empty capillary. 12． Claims 10 and wherein the storage compartment is compressible by mechanical pressure. Item 12. The device according to any one of items 11 to 12. 13. An adjustment valve for controlling the flow of the fluid from the storage compartment to the skin patch Apparatus according to any one of claims 10-12, comprising a probe. 14. Comprising the step of transdermally administering a levodopa drug in a stable solution. How to treat Parkinson's disease. 15． Transdermally administering the levodopa drug comprises a substantially continuous transdermal administration of levodopa. 15. The method of claim 14, comprising objective infiltration. 16． 15. The levodopa drug, wherein the levodopa drug is an alkyl ester of levodopa. The method described in. 17． Claims wherein the solution comprises a substantially non-aqueous solvent, a transdermal enhancer and a cleanser. Item 15. The method according to Item 14. 18． The levodopa drug and the solution are stored separately and the drug is applied transdermally. 15. The method according to claim 14, wherein the method is mixed immediately before use. 19. In addition, carbidopa may be taken prior to initiating the transdermal release of the levodopa drug. 15. The method of claim 14, further comprising the step of: 20. Further, a step of ingesting carbidopa during the transdermal release of the levodopa drug is also included. 15. The method of claim 14, comprising: twenty one. Further comprising the step of receiving an oral antiparkinsonian drug. 15. The method according to claim 14, wherein