CA2022552A1

CA2022552A1 - Antiparkinsonian compositions

Info

Publication number: CA2022552A1
Application number: CA002022552A
Authority: CA
Inventors: James W. Tetrud; J. William Langston
Original assignee: DEPRENYL RESEARCH Ltd
Current assignee: DEPRENYL RESEARCH Ltd
Priority date: 1990-08-02
Filing date: 1990-08-02
Publication date: 1992-02-03

Abstract

ABSTRACT

A pharmaceutical composition, the function of which is to slow the rate of progression of Parkinson's disease, is described. The composition comprises selegiline, the chemical name of which is (-)-N,.alpha.-dimethyl-N-2-propynylbenzene-ethanamine, or a pharmaceutically acceptable salt thereof.

Description

2~2~2 The present invention relates to a pharmaceutical composition capable of slowing the progression of Parkinson's disease in a patient.

Parkinson's disease, also known as shaking palsy, is a chronic, progressive d~sease of the nervous system characterized by muscular weakness, tremor and muscular rigidity. Drugs are available for symptomatic treatment; however, there were no drugs heretofore understood or recognized to slow the progression of the disease.

At present, the preferred method of treating Parkinson's disease involves administration of L-dopa, the chemical name of which is (-)-3-(3,4-dlhydroxyphenyl)-L-alanine. Unfortunately, such treatment can often result in one or more of compllcations, toxicity problems and decreased efficacy of L-dopa upon prolonged treatment. Furthermore, L-dopa does not appear to hinder the progression of Parkinson's dlsease, but rather provides merely symptomatic treatment. Thus, there would appear to be a need for a drug which reduces or eliminates progression of the disease, preferably without the onset of the undesirable results of L-dopa therapy as discussed above.

Canadian patent 871,155, issued May 18, 1971, teaches a group of compounds, and methods for the preparation of such compounds, the general formula of which is as follows:

2~22~2 R3 ~ CH2 -CH - N - R2 wherein, R3 is hydrogen, halogen, nitro or amino, R4 is hydrogen, halogen, nitro or amino, R is a lower alkyl group; and R2 is a hydrogen or an unsubstituted propyl, propenyl or propynyl group or such a group substituted by a halogen atom or a hydroxy group.

Deprenyl, which is the racemic mixture of the dextrorotatcry and levorotatory optical isomers of N,~-dimethyl-N-2-propynylbenzeneethanamine, is encompassed by this group of chemical compounds. Selegillne is the levorotary optical lsomer of deprenyl.
It would be desirable to have a pharmaceutical composition which could decelerate the progression rate of the disease while mitigating the complications, toxicity and declining long-term effects (discussed above) of known pharmaceutical compositions.

It is an ob~ect of the present invention to provide a pharmaceutical composition, the functlon of which is to decelerate the progression of Parkinson's disease.

Accordingly, in one of its aspects, the present invention provides an antiparkinsonian pharmaceutical composition comprising a therapeutically effective amount of an active ingredient of the formula:

2~2~

R3 ~ CH2- CH - N - R2 or a pharmaceutically acceptable acid addition salt thereof, wherein, R3 is selected from the group comprising hydrogen, halogen, nitro and amino, R4 is selected from the group comprising hydrogen, halogen, nltro or amino, R is a lower alkyl group; and R2 is a hydrogen or is selected from the group comprising a propyl group, a propenyl group and a propynyl group unsubstituted or substituted by at least one of a halogen atom and a hydroxy group, together with at least one pharmaceutically acceptable excipient.

In another of its aspects, the present invention provide~ an antiparkinsonian pharmaceutical composition, substantially free of L-dopa, comprising an active ingredient of the formula:

R3 ~ CH2 CH - N R2 2~22 ~2 or 2~ pharmaceutically acceptable acid addition salt thereof, wherein, R3 is selected from the group comprising hydrogen, halogen, nltro and amino, R4 is selected from the group comprising hydrogen, halogen, nitro or amlno, R is a lower alkyl group; and R2 is a hydrogen or is selected from the group comprising a propyl group, a propenyl group and a propynyl group unsubstituted or substituted by at least one of a halogen atom and a hydroxy group;
together with at least one pharmaceutically acceptable excipient.

In yet another of its aspects, the present invention provides an antiparkinsonian pharmaceutical composition, susbstantially free of L-dopa, comprising a therapeutically effective amount of selegiline or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutically acceptable excipient.

In yet another of its aspects, the present invention provides a pharmaceutical composition, substantially free of L-dopa, comprising a therapeutically effective amount of selegiline or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutically acceptable excipient, for the use of decelerating the progression of Parkinson's disease in a patient.

Thus, an aspect of the present invention resides in the discovery that seleglline may be used, as an active ingredient, in the absence of other active 2~2~

compounds such as L-dopa, to decelerate the progression of Parkinson's disease. Accordingly, the undesirable shortcomings (discussed above) associated with the use of L-dopa may be obviated or mltigated by use of the lnstant antiparkinsonian pharmaceutical composltion.

As used throughout this specification, the term "pharmaceutical composition" refers to a regimen of treatment as regards Parkinson's disease and not necessarily to a single uni~ dosage of any particular active ingredient. Such a composition may comprise one or more units containing the same or different active ingredient or ingredients administrable to a patient for the purpose of treating Parkinson's disease in that patient. As used herein, "antiparkinsonian pharmaceutical composltion" refers to a pharmaceutical composition administrable to a patient for the purpose of decelerating the progression of Parkinson's disease in that patient relative to the progression rate of the disease in an untreated patient.

The term "therapeutically effective amount", as used with respect to the present invention, means a pharmaceutically acceptable amount effective to attain deceleration of the progression of Parkinson's disease.
The term "pharmaceutically acceptable", as throughout this specification, means non-toxic and applies to compositions otherwise suitable for administration to a patient.
As used throughout this specification, the term "acid addition salt" refers to a salt formed by reaction with an organic or inorganic acid. Non-limiting examples of organic acids include acetic acid, citric acid, fumaric acid and the like, while non-limiting examples of inorganic acids include hydrochloric acid, sulphurlc acld, phosphoric acid and the like. A preferred pharmaceutically acceptable acid addition salt- i8 selegiline hydrochloride, which is also known as ELDEPRYL (trade-mark).

The term "pharmaceutlcally acceptable exclpient~ refers to those ~xclpients normally empl~yed in the formatlon of pharmaceutlcal composltions intended for administration by the known routes of administration of pharmaceutlcals. For example, for composltlons lntended for oral admlnlstratlon, sultable pharmaceutlcal exciplents include the non-toxic pharmaceutically acceptable carriers such as starch, glucose, lactose, dextrose, sucrose, mannitol, sorbltol, gelatin, malt, rlce, flour, chalk, silica gel, magnesiu~
carbonate, magnesium stearate, sodium stéarate, glyceryl, monostearate, sodium chlorlde, talc, drled sklm milk, glycerol, propylene glycol, water, ethanol and the llke. Mixtures of one or more of such carriers may also be used.

The composition o the present inventlon may be adapted for admlnlstratlon by accepted methods of admlnlstratlon lncludlng oral and parenteral (including transdermal) means. Such oral composltions may take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.

Accordlng to a preferred embodlment of the invention, the dosage unit ls for oral admlnlstratlon and comprlses from about 4 tD about 8 mg of selegillne hydrochloride. More preferably, the oral dosage unit ls about 5 mg seleglline hydrochlorlde. However, lt will 2 ~ 2 be appreciated that the invention is not limited to unit;s of this dosage or method of administration.

Preferably, the therapeutically effective oral daily dosage in respect of the present composition is 10 mg/day. This oral daily dosage may be varied as required depending on the welght of the patient and the extent to which the patient is afflicted with the disease.
Aspects of the invention are further described for illustrative purposes only in the following specific, non-limiting Example. In the Example, reference will be made to the accompanying Figure which i8 a Kaplan-Meier survival curve for a Placebo Group and a Selegiline Group.

Exam~le In the ~xample, a double-blind, placebo-controlled study of patients with early, untreated Parkinson's disease was conducted in order to determine the effectiveness of selegiline hydrochloride in retarding the advancement of Parkinson's disease.
1. Patient Selection Patients with Parkinson's disease for less than 5 years, and having at least 2 of the 3 cardinal features typical of the disease (i.e. rigidity, bradykinesia and rest tremor) were considered for the study. Further evaluation of prospective patients included development of medical history, physical examination, and the Mini-Mental State Examination (MMSE). Further, prospect$ve patients were screened using five assessment scales to measure the severity of parkinsonism, as follows:

2~2,?~2 (1) Unified Parkinson's Disease Rating Scale (UPDRS) Motor Examination. The scoring method included rating each of 13 different motor features on a 5-point scale (0, normal; 4, severely affected). The ratings for each motor feature were then summed for a total score for each patient.

(2) Hoehn and Yahr Staging scoring method, as described by Hoehn and Yahr in Neurology 17, 427 (1967).
The test was modified as follows: stage 1, unilateral disease; stage 1.5, unilateral disease with neck rigidity; stage 2, bilateral disease without impaired balance; stage 2.5, bilateral disease with impaired balance after being pushed, but able to regain balance without assistance.

(3) The Webster Step-Second Test as described by Webster in Mod. Treat. 5, 257 (1968). The scoring method included measuring the time (in seconds) to stand and walk a prescribed course and to sit again.

(4) UPDRS Activities of Daily Living (ADL).
The scoring method included reviewing with the patient 13 different ADL's and rating the degree of dysfunction for each ADL on a 5-point scale (0, normal; 4, severely disabled). The ratings were then summed for a total score for each patlent.

(5) The Schwab and England ADL (Schwab and England, Third Sympos~um on Parkinson's D~sease, 152-157 ~1969)). The scoring method included estimating by the patient of the percentage of normal function to the nearest 5%.

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Depression in the prospective patients was also assessed. The scoring method used was the UPDRS
subscale for depression (0, none; 4, severe).

Laboratory tests included a complete blood count, urine analysis, a standard blood chemistry panel including liver enzymes (Sequential Method Analysis no.
18) and an electrocardiogram.

Upon completing the evaluation, 54 patients were chosen for the study. The patients were randomly divided into 2 groups: the Selegiline Group and the Placebo Group. The data ~enerated from the evaluation of prospective patients is provided in Table 1.

2. Treatment Selegillne Group tablets (5 mg selegiline hydrochloride together with excipient) and Placebo Group tablets (excipient only) were prepared. A dosage of two tablets daily per patient was selected for both Groups in the study. Both patient and clinic personnel were blinded as to treatment status.
3. Follow-up Evaluation One month following initiation of treatment (wa~h-in study), follow-up evaluations were conducted, and continued routinely at 5-month intervals thereafter _ g _ 20~2~i C
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until patients reached the "end point" defined as the earlier of the patient requiring L-dopa therapy or 3 years of selegiline hydrochloride treatment. Threatened 1085 or significant change in employability or the abllity to handle domestic responsibilities, or failing postural reflexes were used as indicators of the requirement for L-dopa therapy. Upon reaching the end point, treatment was discontinued and a final follow-up examination was conducted 1 month later (wash-out study). Follow-up evaluations consisted of all five assessment measures and a depression rating - the results these evaluations are provided in Table 2.

A wash-out period of 1 month was chosen since this was believed to be an adequate amount of time to detect a transient dopaminomimetic effect, if there had been one. This is due to the fact that selegiline hydrochloride and lts metabolites are typically cleared from the body wlthin 24 to 48 hours after cessatlon of treatment. Moreover, during treatment, any effect of selegiline hydrochloride on enzyme activity would be substantially reversed within 2 to 3 weeks after cessation of treatment.

As described above, half of the patients were assigned to each arm of the study, baseline characteristics being comparable in each Group (Table 1). A wash-in examination was performed on all 54 patients. Further analysis of 3 patients (2 in Placebo Group (PG), 1 in Selegiline Group (DG)) was discontinued because they were unable to remain off antiparkinsonian medication for more than one month. Seven patlents dropped out for the following reasons: lost to follow-up (2 in DG); insomnia (1 in DG); euphoria-intoxicated sensation (1 in PG); transient elevation in liver enzymes (1 in PG); dysphagia (1 in DG); and incidental 2 ~ 2 ~ ~o ~ o a N N O O .~ O O O ~ O
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4. Analysis of Data Survivorship was analyzed by calculating a Kaplan-Meier curve for each Group by using time to end point (excluding 3 drop-outs, n=51). The 2 curves were compared using the log rank test (see R. Miller, Survival Analysis (Wiley, New York, 1981)). The Kaplan-Meler survlval curves for each Group are lllustrated ln the attached Figure and indicate that selegiline hydrochloride delayed the time to end point (P<0.002).
The average time to end point was 312.1 days (44.47 +
SEM) for patients in the Placebo Group and 548.9 days (61.01 + SEM) for patients ln the Selegiline Group. One patient in the Selegiline Group reached end point by staying on selegiline for 3 years.
The rate of disease progression was determined by fitting a separate line for each assessment score versus time by least squares for each patient who reached end polnt (n-44) wlth all of the data points available (Note: two patients ln PG had less than four data polnts). Thereafter, the slope of the llnes were averaged for each assessment measure in the Selegiline Group and the Placebo Group by a two-tailed Wilcoxon test. The wash-in (n=54) and wash-out (n=38) studies were assessed for statistical significance by using the Wilcoxon signed rank test (see Table 2). As illustrated - 13 ~

2~ 2~i~2 in Table 2, only the change in the Webster Step-Second Test in the Placebo Group at wash-out is statistically slgnificant. The disease status was remarkably similar at end point in both Groups, indlcating that (i) the declslon to admlnlster L-dopa had been consistently applied between Groups and was therefore not biased in favour of either Group, and (ii) patients in the Selegiline Group were taking nearly twlce as long to reach this stage of disability as those in the Placebo Group. The scores did not change appreciably after treatment was stopped (wash-out) in either Group, indicating that the delay to end point in the Selegiline Group was not due to a transient therapeutic effect on parkinsonian signs or symptoms or signs at wash-in.
Moreover, there was no dlfference in the depresslon scores at wash-in or wash-out in either the Selegiline Group or the Placebo Group, indlcatlng that an antidepressant effect did not interfere with the declslon to administer subse~uently L-dopa.
The rate of disease progression, on an annual basis, for Parkinson's disease patients ln both the Selegiline Group and the Placebo Group (n=44) was assessed. The results of this assessment are provided in Table 3 and illustrate that the rate of progression was slowed by 40 to 83~ per year as measured by the five assessment scales. Only the Webster Step-Second Test failed to reach a statistical slgnificance (P ~ 0.07).

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Claims

1. An antiparkinsonian pharmaceutical composition comprising a therapeutically effective amount of an active ingredient of the formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein, R3 is selected from the group comprising hydrogen, halogen, nitro and amino, R4 is selected from the group comprising hydrogen, halogen, nitro or amino, R is a lower alkyl group; and R2 is a hydrogen or is selected from the group comprising a propyl group, a propenyl group and a propynyl group unsubstituted or substituted by at least one of a halogen atom and a hydroxy group;
together with at least one pharmaceutically acceptable excipient.

2. The composition defined in claim 1, wherein said active ingredient is selegiline, or a pharmaceutically acceptable acid addition salt thereof.

3. The composition defined in claim 1, wherein the active ingredient is selegiline hydrochloride.

4. The composition defined in claims 1, 2 or 3, wherein said composition is provided in a form suitable for oral administration.

5. The composition defined in claims 1, 2 or 3, wherein said composition is provided in a form suitable for parenteral administration.

6. The composition defined in claims 1, 2 or 3, wherein said composition is provided in oral unit dosage forms each comprising 5 mg of active ingredient.

7. An antiparkinsonian pharmaceutical composition, substantially free of L-dopa, comprising an active ingredient of the formula:

or a pharmaceutically acceptable acid addition salt thereof, wherein, R3 is selected from the group comprising hydrogen, halogen, nitro and amino, R4 is selected from the group comprising hydrogen, halogen, nitro or amino, R is a lower alkyl group; and R2 is a hydrogen or is selected from the group comprising a propyl group, a propenyl group and a propynyl group unsubstituted or substituted by at least one of a halogen atom and a hydroxy group;
together with at least one pharmaceutically acceptable excipient.

8. The composition defined in claim 7, wherein said active ingredient is selegiline, or a pharmaceutically acceptable acid addition salt thereof.

9. The composition defined in claim 7, wherein said active ingredient is selegiline hydrochloride.

10. The composition defined in claim 7, wherein said composition is provided in a form suitable for oral administration.

11. The composition defined in claim 7, wherein said composition is provided in a form suitable for parenteral administration.

12. The composition defined in claims 7, 8 or 9, wherein said composition is provided in oral unit dosage forms comprising 5 mg of said active ingredient.

13. An antiparkinsonian pharmaceutical composition, susbstantially free of L-dopa, comprising a therapeutically effective amount of selegiline or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutically acceptable excipient.

14. The composition defined in claim 13, wherein said composition is provided is unit dosage form.

15. The composition defined in claim 14, wherein said dosage unit is suitable for oral administration.

16. The composition defined in claim 14, wherein said dosage unit form is suitable for parenteral administration.

17. The composition defined in claims 13 or 14, wherein said dosage unit is suitable for oral administration and comprises 5 mg of selegiline or a pharmaceutically acceptable acid addition salt thereof.

18. A pharmaceutical composition, substantially free of L-dopa, comprising a therapeutically effective amount of selegiline or a pharmaceutically acceptable acid addition salt thereof, together with at least one pharmaceutically acceptable excipient, for the use of decelerating the progression of Parkinson's disease in a patient.

19. The composition defined in claim 18, wherein said composition is provided is unit dosage form.

20. The composition defined in claim 19, wherein said dosage unit is suitable for oral administration.

21. The composition defined in claim 19, wherein said dosage unit form is suitable for parenteral administration.

22. The composition defined in claims 18 or 19, wherein said dosage unit is suitable for oral administration and comprises 5 mg of selegiline or a pharmaceutically acceptable acid addition salt thereof.

23. The composition defined in claim 18, comprising selegiline hydrochloride.