BG61201B2 - Controlled release combination of carbidopa/levodopa - 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, such that sarvidor and levodor are slowly and co-released from the formulation. 3 claims

Description

This is a continuation-in-part of pending application serial no. 131,601, filed on December 11, 1987, which in turn is a continuation-in-part of pending application serial no. 874,988, filed on June 16, 1986, now abandoned.

The invention relates to a controlled release formulation for simultaneous delivery of salicyclic acid and levodopa in the treatment of Parkinson's disease, whereby adverse reactions and insufficient efficacy in treatment with a standard salicyclic acid/levodopa combination are minimized.

5-Septel ^K (McK & Co. Ltd., Carrollton, N.Y.) is a trademarked brand name for a therapeutic agent used in the treatment of idiopathic Parkinson's disease. It is a combination of levodopa and sibutramine and is available as tablets of 10 mg levodopa/100 mg levodopa; 25 mg levodopa/250 mg levodopa; and 25 mg levodopa/100 mg levodopa. The usual dose is 3 to 4 tablets daily.

Until the introduction of Zestrel in 1975, Parkinson's disease was treated only with levodopa in large doses to adequately control the Parkinson's syndrome. Some side effects, especially emesis, were noted. In order to minimize these, attempts were made to introduce levodopa in a form that provided for its prolonged release. This product was called Brescia TenNa3. Several studies were conducted, which did not prove the advantage of the prolonged release formulation over the standard one. Escalade et al., The Lancet 24 Feb. 1973, p. 431, stating on p. 432, "For most Parkinson's patients in our study, prolonged release levodopa did not show any definite advantage over the standard preparation." Also from Sigron et al., The Lancet, 7 Apr. 1973, p. 781, we read: “These results suggest that no practical benefit would be obtained by using an oral sustained-release preparation of yuuoyora.

Therapy with dynesine is widely accepted as the starting point in the treatment of idiopathic Parkinson's disease. On the other hand, the phenomena of "^eam^-oC" and "op-oίί" have emerged as major problems in the long-term treatment of Parkinson's disease. After two to three years, many patients experience tremor-like motor fluctuations that cause progressive disability. The main sign is the transition from mobility to immobility, which may occur several times a day. The expected decrease in the therapeutic effect following each dose of §1petel is known as "\ueapp£οίί" and may first appear during stages II-III of the disease. Such fluctuations occur in 15 to 40% of patients after two to three years from the start of treatment and in a higher percentage with longer disease. Fluctuations in serum levels that accompany 51NEMAT treatment may themselves contribute to the development of clinical tremor.

The clinical presentation of “on-off” involves rapid and unpredictable shifts from mobility to immobility. “On” periods are usually associated with high or increasing plasma levodopa levels and are often associated with a variety of abnormal involuntary movements (dose-dependent dyskinesias), whereas “off” periods are usually, but not always, associated with low or decreasing plasma levodopa levels. The association of “off” periods with low plasma levodopa levels and the finding that treatment with apomorphine during the “off” period can restore function suggest that most such periods are due to cerebral dopamine deficiency. Frequent dosing helps to alleviate the clinical tremor effects, but dyskinetic and bradykinetic episodes may still occur.

Intravenous levodopa is administered to provide steady-state plasma levels of 2000 to 5000 ηβ/ml in patients with advanced Parkinson's disease. This procedure reduces motor oscillations, but the optimal effect in some patients still involves either tremor and bradykinesia or mobility with dyskinesia. High-protein meals impair the effect of treatment without affecting plasma levodopa levels, probably by inhibiting levodopa transport into the brain.

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

If the development of clinical tremor is aided by the variable level of levothyroxine, a controlled release formulation may also help to avoid the danger of the “whee-oh” and “whee-oh” phenomena.

The present invention provides a controlled release form of a combination of sabsiclovir/levoxil designed to eliminate or at least reduce the problems associated with standard combination therapy. Dyskinesia and other central nervous system and gastrointestinal side effects may be reduced in patients sensitive to high plasma levosulfur. Patients with tremor symptoms respond to sustained plasma levosulfur levels with a more durable clinical response. Furthermore, the controlled release form is expected to be a more convenient dosage form (i.e., allowing less frequent dosing) for many patients who require standard SINEMET four or more times daily. Twice daily dosing may also be appropriate for some patients.

DETAILED DESCRIPTION OF THE INVENTION

The novel controlled release tablet of carbamide/iodine according to the invention is a matrix or monolithic drug delivery system containing carbamide and iodine as active ingredients. The system consists of two drugs equally dispersed in the polymer carrier, at a concentration higher than the solubility of each of the drugs in the polymer carrier, which in turn is one or a combination of several polymers.

The new delivery system provides slow release of the two drug components through erosion or through a diffusion-controlled mechanism, depending on the specificity of the polymer carrier.

The drug is released by erosion through slow degradation of the tablet surface. Drug release by diffusion occurs either through the space between the macromolecular polymer chains or through the porous network filled with aqueous medium. Optimal conditions for erosion or diffusion 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.

Fig. 1 shows a cross-section of the homogeneous polymer matrix, shaped as a tablet, showing the drug components 1 evenly dispersed in the matrix.

Fig. 2 schematically shows the same polymer matrix 1 after a portion of the drug has been separated by the entry of liquid into the curved capillary channels 2, followed by the release of the drug solution along the same path. This matrix remains intact while its drug content is released.

Fig. 3 is a cross-section of the schematically represented polymer matrix 1 after a portion of the drug has been separated by erosion from liquids, where the polymer 1 and the active ingredients 2 are dispersed in the liquid as a solution or suspension.

Fig. 3a schematically represents the polymer matrix 1 after all the drug 2 has been released by erosion. This matrix completely degrades when its drug content is released.

The polymeric carrier is a monopolymer or copolymer or a combination thereof selected from: water-soluble polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol, starch, methylcellulose; and less water-soluble polymers such as polyvinyl acetate-crotonic acid copolymer, 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 the water-soluble polymer, hydroxypropylcellulose, and the less water-soluble copolymer of polyvinyl acetate and crotonic acid.

Other components of the invention are optional colorants and substances improving the sliding properties of the tablet such as metal salts of acids including aluminum, calcium, magnesium, sodium and zinc.

610201 stearate; fatty acids, hydrocarbons and fatty alcohols including stearic and palmitic acid, liquid paraffin, stearic and palmityl alcohol; fatty acid esters including glyceryl monostearate, glyceryl (mono- and di-) stearate, triglycerides, glyceryl (palmitylstearate) ester, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate and sodium stearyl fumarate; alkyl sulphates including sodium lauryl sulphate and magnesium lauryl sulphate; polymers including polyethylene glycols, polyoxyethylene glycols and polytetrafluoroethylene (Teflon); and inorganic materials such as talc. The preferred glidant for tablets is magnesium stearate.

In the typical formulation, the components are presented in the following amounts:

Quantity Component Varies, (ιηβ) Preferred range (m) Leuodora 20-1200' 100-400 SagUmora Water-soluble 5-300' 25-100 polymer Less water soluble 0-120® 5-25 polymer 0-120® 20-50 Lubricant 0-25 1-10

Preferred ratios of carbon monoxide to hydrogen are from about 1 carbon monoxide/10 hydrogen to 1 carbon monoxide/4 hydrogen.

^<2) In the given formulation, both polymers cannot be present in amounts equal to 0 wt.

The method for preparing the new formulation includes mixing the leucovorin, carbohydrin and colorants with a hydroalcoholic or other suitable solvent, dispersing the polymer(s), drying, grinding, mixing with the lubricant (the substance improving the sliding properties) and compressing into tablets.

Alternatively, the formulation can be prepared by mixing the hydrogen peroxide, sulfite 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 is dried, mixed with a lubricant and compressed into tablets.

Specific examples of the novel controlled release formulation according to the invention are as follows:

Example 1

Contents For 1 tablet (t§) Leuodora υδΡ 200

SagMora Nudgoiz υδΡ 54 Cellulose acetate 50 Fine magnesium stearate 5.5 NP Powder ΙΠ & С В1е Но. 1 1.0

Example 2.

Contents For 1 tablet (t§) Leuodora υδΡ 200 SagЬShora Nudgoiz υдΡ 54 Vinyl acetate/croton acid 6.5 copolymer* Hydroxypropylcellulose NP® 17.0 Fine magnesium stearate 3.0 NP Powder Ked 347 Marco 0.4 Υεΐίολν ϋ & C Νο.10 Actipit 1.0 Bake NT

'Utas AδB-516 ^κ contains about 5% crotonic acid; molar viscosity 15-17 cph; molecular weight 95,000; available from Aϊγ Provis1$ ani Cbeppnca15, 1ps., Box 538, Ailieonne, PA 18105, i5A.

®Klise1 LPR ^K , molecular weight 75000, viscosity of 5% aqueous solution 75-150 cps, available from Hexyl, Insoglobulin, λνϋμινεβίον, Oela\uare, 19894, ΟδΑ.

NP Powder Ke 347 Maruo 0.4 ΥεΙΙοχν Ό & С Νο. 10 Ayuppit 1.0 Bake NT

^(|, See note ^<2) from example 2.

Example 6.

Example 3.

Contents For 1 tablet (ηΐβ) The European Union 200 Sagúora Nuigoiz úðΡ 54 Carboxyvinyl polymer 60 Microcrystalline cellulose 20 Fine magnesium stearate 5.5 NP Powder RP & S Kay No. 3 1.0

Contents For 1 tablet (ηΐβ) The European Union 400 Saguyora Nuigoiz υδΡ 108 Polymethyl methacrylate 120.0 Fine magnesium stearate 5.5 NP Powder P & S Kay No.3 0.4 Υεΐίον ϋ & C Νο.10 Akshppshp 1.0 Bake NT

Example 4.

Contents For 1 tablet (GP£) The Greek Orthodox Church 200 100 Sagúora Nuigoiz úðΡ 54 27 Vinyl acetate/croton acid 5.0 2.5 copolymer ¹ ” Hydroxypropylcellulose ΝΡ ^<2) 17.0 8.5 Fine magnesium stearate 3.0 1.5 NP Powder Ke 347 Maruo 0.3 0.15 ΥεΙΙονν ϋ & C Νο. 10 Ayuppit 1.1 0.55 Bake NT

Example 7.

Contents For 1 tablet (πΐβ) The European Union 100 Saguyora Nuigoiz υδΡ 54 Ethylcellulose 20.0 Methylcellulose 5.0 Fine magnesium stearate 5.5 NP Powder P & S Kay No.3 0.4 ΥεΙΙονν ϋ & C Νο.10 Ayuppit 1.0 Bake NT

^(1> See notes from example 2. ^<2> See notes from example 2.

Example 5.

Contents For 1 tablet (πΐβ) The European Union 200 Sagúora Nuigoiz úðΡ 54 Hydroxypropylcellulose NP’” 90 Fine magnesium stearate 8.0

The two controlled-release formulations No. 1 and No. 2 were compared with standard 8sheshe1 in 20 patients with uncomplicated Parkinson's disease. The observed mild weakness was similar for about two weeks in patients taking No. 1 or standard δίηειηεί and in patients taking No. 2 or standard δίηειεί. (The design of this study was that the two groups of 10 patients taking No. 1 and No. 2 respectively would be different, but would be treated with standard δίηειεί).

610201

For 1 tablet (££) Contents No.1 SK-2 No.2 sk-z Leuosura 100 200 SagIora 50 50 Polyvinyl acetate 3 20 Crotonic acid copolymer”’ Magnesium stearate 1.7 5.5 Hydroxypropylcellulose ΝΡ* ² ' 10 -

^(|) See notes from example 2.

^<2) See notes from example 2.

The pharmacological profiles of the sustained-release formulation were clearly differentiated from those of the standard ΞίηετηεΙ. In patients on No.1, the highest plasma concentrations of quosure were reached 2.8 ± 1.2 h after dosing, compared with 1.1 ± 0.33 h with the standard 5tete1. For formulation No.2, T was 3.1 ± 2.2 h, compared with 1.4 ± 0.5 h with the standard 5tete1. At 8 hours, the bioavailability of No.1 and No.2 relative to the standard 5tete1 was estimated to be 86% and 75%, respectively.

Although the peak plasma concentrations of quosure for No.1 and No.2 were only about half of those obtained from the standard δίνεινεί after 8 days, the levels of No.1 or No.2 exceeded those of δίνεινεί, demonstrating the sustained release properties of both SC formulas.

Based on these results and the preferred 1:4 ratio for the No. 2 tablets, four formal clinical and pharmacological studies were conducted in patients with motor tremor. Of the thirty patients (22 with "\ueapp£-o(1" and 8 with unpredictable "on-oη"), only a few showed marked improvement with a reduced "oη" period and a mild effect during the day. Many others had nocturnal improvements consisting of better sleep and mobility, combined with restored morning function. High sustained plasma iodine levels were found, but associated with unpredictable variability.

Formulation No. 2 has proven extremely difficult to use because of the marked delay in response at the beginning after each dosing, the requirement for very high daily doses (150-400% of the standard 8|pete(), and the very poor correlation between the time of drug administration (dosing) and the rise in plasma quosur levels. In fact, plasma quosur levels are slightly higher at night and early morning than during the day, even though the drug is administered during the day, not at night. Severe, persistent, and unpredictable periods of dyskinesia and similar persistent “οίί” periods are observed. Dosed B.I.ί. treatment is unsuccessful in 9 of 9 patients with mild to moderate tremor. Formulation No. 2 is given almost as often as standard 8|pete1 in most patients.

The results of these studies clearly show that the release rate and bioavailability of tablet No. 2 are quite low in vivo and probably too sensitive to the effects of food and gastric pH. It is found that in many patients the daily dose is retained in the stomach and is not released overnight. A fragmentable tablet with faster dissolution characteristics such as No. 1 has the potential to eliminate some of these problems.

These considerations led 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 carboplatin and 200 mg of fluorouracil. Fifty patients were enrolled in studies No. 3 and preliminary clinical and/or pharmacokinetic data relate to approximately 40 of them.

All four investigators found formulation No. 3 to be much easier to administer than No. 2, due to the following: 1) the predictability of the onset of response; 2) the doses required are comparable to or slightly higher than standard δΐηεπιεί; and 3) the longer duration of therapeutic action during the day. Most patients who complete the initial phase of the No. 3 study request long-term treatment due to clinical improvement. In general, the frequency of dosing can be reduced by 25-50% with No. 3 compared with standard δΐηεπιεί. Clinical tremor is reduced during the day and sometimes completely eliminated. Patients with mild to moderate tremor (particularly at the end of the “\ueapp£-o!G” period) benefit the most, although half of the severely ill also improve. Pharmacokinetic data indicate that plasma levels of levodopa are sustained for 3 to 6 h after a dose of No.3, compared to 1 to 2 h of standard 8-h.

The onset of response after a single dose of formulation No. 3 is somewhat delayed compared with standard 8te1 and can begin after 45 min. In patients with advanced disease, the nocturnal and early morning responses with No. 3 are better than those with standard sinemet, but significantly weaker than with No. 2. Plasma L-DOPA levels correlate well with the results of the observations, as early morning L-DOPA levels are generally higher with No. 3 than with standard sinemet, but much lower than with No. 2.

Dyskinesia, mental distress, and psychosis are seen at higher doses in patients who have similar side effects to standard 5-six. Prolonged dyskinesia or “on” periods have not been a significant problem to date.

Another formulation (Example 2) with solvent properties intermediate to those of No. 2 and No. 3 is also being developed. It will provide greater overnight improvements in severely ill patients than formulation No. 3.

Patent claims

Claims (3)

1. A controlled release orally dosage formulation comprising a uniform dispersion of from 25 to 100 [mu] g of Ngdora, from 100 to 400 [mu] o <1ora, from 1 to 10 substance, which improves the sliding properties of the tablet and a pharmaceutically acceptable dye mixed therein in a polymeric carrier containing from 5 to 25 water-soluble copolymer of polyvinyl acetate and crotonic acid, according to the administration of the SAGUSHORA and the Euodor, being released slowly and together with the formulation. 2. A formulation according to claim 1 comprising 200 mg of 1UMS (1 ore and 50 cUagers, or 100 m 2 1uodors and 25mg cUagIor. The formulation according to claim 1, comprising 200 πΐβ 1 euodors, 50 µg sagg1dora, 5-6.5 m т vinyl acetate and crotonic acid copolymer, and about 17 µg hydroxypropyl cellulose. Attachment: 3 figures