BG61200B2 - CONTROLLED SEPARATOR/LEVATOR COMBINATION - Google Patents

Abstract

1. A controlled-release orally doseable formulation containing a uniform dispersion of 25 to 100 mg of sarvidor, 100 to 400 mg of levodore, 1 to 10 mg of a substance improving the sliding properties of the tablet, and mixed with them a pharmaceutically acceptable dye in a polymeric carrier containing from 5 to 25 mg of a water-soluble copolymer of polyvinyl acetate and crotonic acid, and according to administration, the sarvidor and levodor are released slowly and together from the formulation. 4 claims

Description

This is a separate application cep.No 223 861, filed July 25, 1988, now U.S. Pat. No. 4,832,957, which is a partial extension of pending application cep.No 131 061, filed December 11, 1987, now abandoned, which in part is continuation of pending application cep.No 874 988, filed June 16, 1986, now abandoned.

The present invention relates to a controlled release formulation for the simultaneous delivery of carbidopa and levodopa in the treatment of Parkinson's disease, with adverse reactions and insufficient efficacy in the treatment with the standard combination of carbidopa and levodopa being minimized.

Sinemet ^R (Merck & Co.Inc., Rahway, NJ) is a trademark for therapeutic agent used in the treatment of idiopathic Parkinson's disease. It is a combination of levodopa and carbidopa and is a tablet of 10 mg carbidopa / 100 mg levodopa; 25 mg carbidopa / 250 mg levodopa; and 25 mg carbidopa / 100 mg levodopa. The usual dose is 3 to 4 tablets daily.

Prior to the manufacture of Sinemet in 1975, Parkinson's disease was treated with levodopa only. To achieve adequate control of Parkinson's syndrome, large doses of the drug are required, causing some adverse reactions, especially emesis. In order to reduce side effects, attempts have been made to introduce levodopa in a form that ensures its long-term release. The Brocadopa Temtabs product is known. Studies have been performed that do not prove the advantage of the sustained release formulation over the standard one. (Eckstein et al., The Lancet, 24 Feb. 1973, p.431-432]; Curzon et al., The Lancet, 7 April 1973, p.781).

Sinemet therapy is widely used to treat idiopathic Parkinson's disease, but it is accompanied by an on-off wearigoff. After two to three years, tremor motor oscillations are observed in many patients causing progressive crippling. The main sign is the shift from mobility to immobility, which can happen several times a day. The expected decline in the therapeutic effect following each dose of Sinemet is known as "wearing-off" and may occur for the first time in stages II - III of the disease. Such variations in response occur in 15 to 40% of patients after two to three years from the start of treatment and in a larger percentage with longer illness. Fluctuations in levodopa levels that accompany Sinemet therapy may contribute to the development of clinical tremor.

The clinical manifestation of on-off involves rapid and unpredictable deviations from mobility to immobility. "On" periods can usually correlate with high or increasing levels of levodopa in plasma and are often associated with various abnormal involuntary movements (dose-dependent dyskinesia), while "off" periods are usually but not always associated with low or decreasing levels. levels in the plasma of levodopa. The association of “off” periods with low plasma levels of levodopa and the finding that apomorphine treatment during the “off” periods can restore function suggests that most such periods are due to cerebral dopamine deficiency. Frequent dosing helps to alleviate clinical tremor effects, but dyskinetic and bradykinetic episodes may still be observed.

Levodopa is administered intravenously to provide stable levels of 2000 to 5000 ng / ml in plasma in patients with advanced Parkinson's disease. This procedure reduces motor oscillations, but the optimal effect in some patients still includes either tremor and bradykinesia or mobility with dyskinesia. Foods with high protein content exacerbate the effect of treatment without affecting plasma levodopa levels, possibly inhibiting the transport of levodopa into the brain.

The above considerations indicate that a dosage administration of Sinemet, which has slower degradation and provides a more stable profile of plasma levdopa levels, would be effective in alleviating some but not all therapeutic tremor effects.

If clinical shaking depends on the variable level of levopoda, a controlled release formulation can also prevent the risk of wearing-off and on-off phenomena.

The present invention provides a controlled release form of a carbidopa / levodopa combination intended to eliminate or at least reduce problems associated with standard combination therapy. Dyskinesia and other central nervous system side effects and gastrointestinal side effects may be reduced in patients sensitive to high levels of levodopa in the plasma. Patients with tremor symptoms would respond to persistent plasma levels of levodopa with a more consistent clinical response. In addition, controlled-release Sinemet is also expected to be a more appropriate dosage form (ie, allowing for less frequent dosing) for many patients who require standard Sinemet four or more times a day. Taking the medicine twice a day may also be applicable to some patients.

SUMMARY OF THE INVENTION

The new controlled-release carbidopa / levodopa tablet according to the invention is a matrix or monolithic drug delivery system comprising carbidopa and levodopa as active ingredients. The system consists of two drugs equally dispersed in the polymeric carrier at a concentration higher than the solubility of each of the drugs in the polymeric carrier, which in turn is one or a combination of several polymers.

The new introduction system provides slow separation of the two drug components by erosion or by a diffusion-controlled mechanism, depending on the specificity of the polymeric carrier.

Erosion is effected by slowly decomposing the surface of the tablet and by diffusion either through the space between the macromolecular polymer chains or through a porous network filled with an aqueous medium. Optimal erosion or diffusion conditions can be achieved by controlling the crystalline phase of the porous structure, the degree of swelling, the type of polymer, the ratio of polymers, the drug concentration and other characteristic parameters.

DESCRIPTION OF THE FIGURES Attached

FIG. 1. is a cross-sectional view of a homogeneous polymeric matrix shaped as a tablet showing the drug components 1 evenly dispersed in the matrix;

Figure 2 is a schematic representation of the same polymer matrix 1 after part of the drug is separated by fluid intrusion into the curved capillary ducts 2, followed by separation of the drug solution along the same path. This matrix remains intact until its medicinal content is removed;

Figure 3 is a cross-sectional view of the schematically represented polymeric matrix 1 after part of the drug is separated by erosion from liquids, where polymer 1 and the active ingredients 2 are dispersed in the liquid as a solution or suspension;

Figure 3a is a schematic representation of polymer matrix 1 after all drug 2 has been separated by erosion. This matrix completely degrades when its drug content is released.

The polymeric carrier is a monopolymer or copolymer or a combination thereof and is selected from water-soluble polymers such as hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, starch, methylcellulose; and less water soluble polymers such as copolymer of polyvinyl acetate and crotonic acid, polyvinyl chloride, polyethylene, cellulose acetate, polyvinyl alcohol, ethylene vinyl acetate copolymer, polyvinyl acetate, polymethyl methacrylate, ethyl cellulose and the like. The preferred solvent is a combination of a water-soluble polymer, hydroxypropyl cellulose and a less water-soluble copolymer of polyvinyl acetate and crotonic acid.

Other components of the invention are optional colorants and substances that enhance the sliding properties of the tablet, such as metal salts of acids, including aluminum, calcium, magnesium, sodium and zinc stearate, fatty acids, hydrocarbons and fatty alcohols, acid stearic acids paraffin, stearic alcohol and palmityl alcohol; fatty acid esters including glyceryl monostearate, glyceryl (mono- or di-) stearate, triglycerides, glyceryl (palmityl stearate) ester, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate and sodium stearyl fumarate; alkyl sulfates, including sodium lauryl sulfate and magnesium lauryl sulfate, polymers including 5 polyethylene glycols, polyoxyethylene glycols and polytetrafluoroethylene (Teflon); and inorganic materials such as talc. The preferred substance that enhances the sliding properties of the tablets is magnesium stearate.

In a typical formulation, the components are represented in the following amounts:

Amount (mg)

Component

It varies

Preferred reach

Levodopa 20-1200 100-400 Carbidopa 5-300 25-100 Water soluble polymer 0-120 < ² ' 5-25 Less water- soluble polymer 0-120 <» 20-50 Lubricant 0-25 1-10

^{(|) The} preferred carbidopa to levodopa ratios are from about 1 carbidopa / 10 levodopa to 1 carbidopa / 4 levodopa.

⁽²⁾ In the given formulation, both polymers cannot be in amounts equal to 0 mg.

The method of preparing the new formulation involves mixing levodopa, carbidopa and colorants with hydroalcohols or other suitable solvent, dispersing the polymer (s), drying, grinding, blending with a lubricant (a substance that improves gliding properties) and compression into tablets.

Alternatively, the formulation may be prepared by mixing levodopa, carbidopa and colorants and adding hydroxypropylcellulose and / or polyvinyl acetate / crotonic acid copolymer, or drying or dispersing in a solvent such as water, alcohol or hydroalcohol. The mixture was dried, mixed with a lubricant and compressed into tablets.

Examples of implementation

Specific examples of the novel controlled release formulation in this invention are as follows:

Example 1

Contents Per 1 tablet (mg)

Levodopa USP 200

30 Carbidopa Hydrous USP Cellulose acetate Fine magnesium stearate Powder NF FD & C Blue No.l 54 50 5.5 1.0 35 Example 2 Contents For 1 tablet 40 (mg) Levodopa USP 200 Carbidopa Hydrous USP 54 Vinyl acetate / Croton k-copolymer ^(I> 6.5 45 Hydroxypropylcellulose NF ⁽²⁾ 17,0 Fine magnesium stearate 3.0 Powder NF Order 347 Mapico 0.4 Yellow D&C No. 10 Aluminum 1.0 50 Lake HT

^ω Vinac ASB-516 ^R contains about 5% crotonic acid; molar viscosity 15-17 cps;

Contents Per 1 tablet (mg)

Example 6

molecular weight 95000; Availability from Air Products and Chemicals, Inc., Box 538, Allentown,

PA 18105, USA.

^<21 Klucel LF ^R , molecular weight 75000, viscosity of 5% aqueous solution 75-150 cps, available from Hercules, Incorporated, Wilmington, Delawere, 19894, USA.

Example 3.

Contents Per 1 tablet (mg)

Levodopa USP 200 Carbidopa Hydrous USP 54 Carboxyvinyl polymer 60 Microcrystalline cellulose 20 Fine magnesium stearate 5.5 Powder NF FD & C Red No.3 1.0

Example 4.

Contents Per 1 tablet (mg)

Levodopa USP 200 100 Carbidopa Hydrous USP 54 27 Vinyl acetate / croton 5.0 2.5 copolymer ^(υ Hydroxypropylcellulose NF ^<2) 17,0 8.5 Fine magnesium stearate 3.0 1.5 Powder NF Order 347 Mapico 0.3 0.15 Yellow D&C No. 10 Aluminum 1.1 0.55

Lake NT ¹¹¹ See the remarks of Example 2. ^<2) See the remarks of Example 2.

Example 5

Contents Per 1 tablet (mg)

Levodopa USP200

Carbidopa Hydrous USP54

Hydroxypropylcellulose NF ⁽ ”90

Fine magnesium stearate 8.0

Powder NF

Order 347 Mapico0,4

Yellow D&C No.10 Aluminum1.0

Lake HT ^<n See Note ^<2> of Example 2.

Levodopa USP 400 Carbidopa HydrouS USP 108 Polymethyl methacrylate 120,0 Fine magnesium stearate 5.5 Powder NF FD & C Red No.3 0.4 Yellow D&C No.10 Aluminum 1.0 Lake HT

Example 7. Contents Per 1 tablet (mg) Levodopa USP 100 Carbidopa Hydrous USP 54 Ethyl cellulose 20,0 Methylcellulose 5.0 Fine magnesium stearate 5.5 Powder NF FD & C Red No.3 0.4 Yellow D&C No. 10 Aluminum 1.0

Lake NT

Controlled release formulations No.l and No.2 were compared with standard Sinemet in 20 patients with uncomplicated Parkinson's disease. The observed weakness was similar for about two weeks in patients taking No.l or standard Sinemet and in patients taking No.2 or standard Sinemet. (The design of this study is that the two groups of 10 patients taking Nos. 1 and 2 are different, but both groups are treated with standard Sinemet).

Per 1 tablet (mg)

Content No.l Mo.2 CR-2 CR-3 Levodopa 100 200 Carbidopa 50 50 Polyvinyl acetate 3 20 Crotonic acid copolymer ⁰⁾ Magnesium stearate 1.7 5.5

Hydroxypropylcellulose3aNF ^<2) 10

See the remarks of Example 2. ^<2 'See the remarks of Example 2.

The pharmacological profiles of the sustained release formulation are clearly differentiated from those of the standard Simenet. In patients with No.l, the highest plasma concentrations of Levodopa reached 2.8 ± 1.2 h after dosing, compared to a T- _inhalation of 1.1 ± 0.33 h after standard Simenet. For formulation No.2, T _max is 3.1 ± 2.2 h compared to 1.4 ± 0.5 h with standard Sinemet. At eight hours, the bioavailability of No.l and No.2, relative to the standard Simenet, was estimated at 86% and 75%, respectively.

Although the highest plasma concentrations of levodopa for No.l and No.2 are only about half of those obtained from standard Simenet after 8 hours, the levels of No.l or No.2 exceed those of Simenet, proving continuous the separating properties of the two CR formulas.

Based on these results and the preferred 1: 4 ratio for No.2 tablets, four formal clinical and pharmacological studies have been conducted in patients with motor tremor. Among the thirty patients (22 with wearing-off and 8 with unpredictable on-off), only a few showed noticeable improvement with a reduced off-period and a mild effect throughout the day. Many others have nighttime improvements, consisting of better sleep and mobility, combined with restored morning function. High persistent plasma levels of levodopa have been found but associated with unpredictable variability.

Formulation No.2 is extremely difficult to use due to the marked delay in response at the beginning after each dosage, due to the requirement for very high daily doses (150 - 400% of standard Sinemet) and the very poor correlation between drug delivery time (dosing ) and elevation of plasma levels of levodopa. In fact, at night and early in the morning, levodopa plasma levels are slightly higher than during the day, although the drug is taken during the day rather than at night. Severe, persistent and unpredictable periods of dyskinesia and similar persistent "off" periods are observed. The dosed B.LD. treatment was unsuccessful in 9 of 9 patients with mild to moderate tremor. Formulation No.2 is given almost as frequently as the satemetric Sinemet in most patients.

The results of these studies strongly indicate that the release rate and bioavailability of tablet No.2 are quite low in vivo and are likely to be too sensitive to food and gastric pH. In many patients, the daily dose has been found to persist in the stomach and is not excreted at night. A fragmenting tablet with faster solubility characteristics, such as No.l, has the potential to eliminate some of these problems.

These considerations lead to the development of formulation No.3 (Example 4), which in vitro has the same solvent characteristics as No. 1 but contains 50 mg of carbidopa and 200 mg of levodopa. Fifty patients were enrolled in studies No.3 and preliminary clinical and / or pharmacokinetic data were appropriate for approximately 40 of them.

All four researchers find formulation No.3 much easier to apply than No.2, which is the length:

1) the predictability of the beginning of the answer,

2) the required doses are comparable or slightly higher than standard Sinemet and 3) the longer therapeutic action throughout the day. Most patients who complete the initial phase of Study No.3 want long-term treatment due to clinical improvement. In general, the dosage frequency can be reduced by up to 25-50% with No.3 compared to standard Sinemet. Clinical shivering is reduced throughout the day and sometimes completely eliminated. Patients with mild to moderate tremors (especially at the end of the wearing-off period) are most at risk, although half of the more severely ill are also improving. Pharmacokinetic data indicate that plasma levels of levodopa are stable for 3 to 6 hours after dosing of No.3 compared to 1 to 2 hours of standard Sinemet.

The onset of response after a single dose of Formulation No.3 is slightly delayed compared to standard Sinemet and may start after 45 min. In patients with advanced disease, nocturnal and early morning reactions with No.3 were better than those of standard Sinemet but significantly lower than with No.2. Plasma 5 L-Dopa levels correlate well with the results of the observations, as early in the morning LDopa levels are usually higher with No.3 than with standard Sinemet but much lower than with No.2.

Dyskinesia, mental distress, and psychosis are observed at higher doses in patients _? which have similar side effects to standard Sinemet. Prolonged dyskinesia or “off” periods do not present significant problems.

Another formulation (Example 2) having solvent properties intermediate to those of No.2 and No.3 is also being developed. This formulation provides night improvements in severely ill patients compared to formulation No.3.

Claims (4)

1. A controlled release orally dosage formulation comprising a uniform dispersion of 25 to 100 mg of carbidopa, 100 to 400 mg of levodopa, 1 to 10 mg of a tablet-enhancing substance and a pharmaceutically acceptable dye mixed therewith in a polymeric carrier comprising 5 to 25 mg of a water-soluble copolymer of polyvinyl acetate and crotonic acid are released slowly and co-formulated according to the administration of carbidopa and levodopa. A formulation according to claim 1 comprising 200 mg of levodopa and 50 mg of carbidopa or 100 mg of levodopa and 25 mg of carbidopa. A formulation according to claim 1 comprising 200 mg of levodopa, 50 mg of carbidopa, 5-6.5 mg of a copolymer of vinyl acetate and crotonic acid and about 17 mg of hydroxypropylcellulose. A formulation according to claim 1 comprising 100 mg of levodopa, 25 mg of carbidopa, 2.5 mg of a vinyl acetate-crotonic acid copolymer and about 8.5 mg of hydroxypropylcellulose.