DESC:TECHNICAL FIELD:
The present subject matter relates to a controlled release pharmaceutical composition comprising combination of levodopa (LD) and carbidopa (CD). The process to prepare such a pharmaceutical composition is also disclosed.

BACKGROUND:
Levodopa (LD) is the precursor to dopamine and is widely used in the management of Parkinson disease. It was first introduced into the market under the name Larodopa. Levodopa is also known by the chemical name: (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid and is reported to have the following chemical structure:

Carbidopa (CD) is a dopa decarboxylase inhibitor used in combination with levodopa to maximize levodopa concentration in brain. Carbidopa is also known by the chemical name: (2S)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid and is reported to have the following chemical structure:

Combinations of levodopa and a carbidopa are known in the pharmaceutical arts for treatment of Parkinson's disease (PD) and several formulations containing combination of levodopa and a carbidopa are commercially available, e.g., SINEMET®, SINEMET® CR, STALEVO®, PARCOPA®, and their corresponding generic products. Notwithstanding above, development of improved formulations of such combination is an ongoing research area.

United States Patent No 8,377,474 discloses a dosage form of carbidopa and levodopa that provides a constant or relatively steady levodopa plasma concentration over a prolonged period of time to optimize relief of symptoms with immediate onset of action. It discloses that the desired release profile can only be achieved when carboxylic acid is present in a distinct and separate component from the carbidopa and levodopa components. It further discloses an controlled-release dosage form of carbidopa and levodopa having three distinct components: a first controlled-release component comprising carbidopa, levodopa, and a rate-controlling excipient; a second controlled-release component comprising carboxylic acid and a rate-controlling excipient; and a third immediate-release component comprising carbidopa and levodopa.

United States Patent No 10,292,935 (US’935) discloses controlled release oral solid formulation comprising (a) a controlled release component comprising core of levodopa and/or an ester of levodopa or salts thereof, wherein the core is coated with a layer of a muco-adhesive polymer/coating and externally coated with a layer of an enteric coated polymer; and (b) a decarboxylase inhibitor component.

Further US’935 discloses the dosage form comprises two types of components, the first component is an immediate release levodopa and/or its ester or salts thereof, and the second component comprises a core containing levodopa and/or ester of levodopa or salts thereof coated or layered with a muco-adhesive polymer/coating and externally coated with an enteric coating polymer. US’935 further disclose the dosage form may comprise additionally a decarboxylase inhibitor, such as carbidopa.

Nonetheless, a need remains for an oral levodopa/carbidopa formulation as prior formulation may have disadvantages like use of muco-adhesive polymer/coating which has several limitations like dislodgement of the formulation or overhydration may compromise the formulation structure (Mucoadhesive Polymers and Their Applications in Drug Delivery Systems for the Treatment of Bladder Cancer, Gels, 2022).

Therefore, there remains a need in the art to develop alternative dosage forms of carbidopa and levodopa, which provide steady levodopa plasma concentration with immediate onset of action, which in turn reduces the "wearing off effect" and "on-off effect".

As part of developmental efforts, it was surprisingly found out that, use of neutralized enteric layer/coat between control release layer/coat and enteric layer/coat eliminates the need of muco-adhesive polymer/coating.

SUMMARY OF THE SUBJECT MATTER:

The present subject matter aims to provide a controlled-release pharmaceutical dosage form of carbidopa and levodopa, which provide a constant or steady levodopa plasma concentration over a prolonged period of time with decreased motor fluctuations, reduced "off time, and increased "on" time in patients. It has been surprisingly discovered that the desired release profile can still be achieved without muco-adhesive polymer/coating thereby reducing the potential issues with muco-adhesive coating.

An object of the present subject matter is to provide a simplified solid oral pharmaceutical composition comprising combination of levodopa and carbidopa or a pharmaceutically acceptable thereof as an active ingredient.

In an embodiment, the present subject matter relates to a solid oral pharmaceutical composition comprising combination of levodopa and carbidopa or pharmaceutically acceptable salts thereof as an active ingredient. The composition may further comprise other pharmaceutically acceptable excipients, wherein the composition is substantially devoid of muco-adhesive polymer/coating.

In an embodiment, a solid oral pharmaceutical composition described herein preferably comprises two types of components, the first type of component comprises immediate release component (IR component) and the second type of component comprises controlled release component (CR component).

In an embodiment, a solid oral pharmaceutical composition described herein preferably comprises two types of components, the first type of component comprises immediate release component (IR component) and the second type of component comprises controlled release component (CR component), wherein the composition is substantially devoid of muco-adhesive polymer/coating.

An aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) levodopa and carbidopa as an active ingredients,
(b) an immediate release component (IR component),
(c) a controlled release component (CR component).

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer/coat and/or enteric release layer/coat.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer and an enteric release layer wherein the composition is substantially devoid of muco-adhesive polymer/coating.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer and a composite enteric release layer comprising at least two separate coatings of enteric coating, wherein the composition is substantially devoid of muco-adhesive polymer/coating.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer and a composite enteric release layer comprising first at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and at least one layer comprising enteric coating, wherein the composition is substantially devoid of muco-adhesive polymer/coating.

According to another embodiment, the present subject matter relates to a process for the preparation of a pharmaceutical composition, comprising the steps of:
1. preparation of an immediate release component
2. preparation of a controlled release component
3. preparation of desired pharmaceutical composition using immediate release component and controlled release components.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:

As used herein, "a" or "an" means one or more unless otherwise specified.
The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

In this specification, the word “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

As used herein, the terms “levodopa” is intended to encompass levodopa and salts thereof as well as an ester of levodopa and salts thereof. Similarly, the term “carbidopa” is intended to encompass carbidopa and salts thereof as well as an ester of carbidopa and salts thereof.

Accordingly, the present subject matter relates to a solid oral pharmaceutical composition comprising combination of levodopa and carbidopa as an active ingredient. The composition may further comprise other pharmaceutically acceptable excipients.

An aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) levodopa and carbidopa as an active ingredients,
(b) an immediate release component (IR component),
(c) a controlled release component (CR component).

Another aspect of the present subject matter provides a controlled release component comprising levodopa and/or carbidopa in its core, coated with a layer of controlled release coat and further coated with an outer layer of an enteric coating (enteric layer).

Another aspect of the present subject matter provides a controlled release component comprising levodopa and/or carbidopa in its core, coated with a layer of controlled release coat and further coated with an outer layer of one or more enteric coatings. If more than one enteric coating is employed, the coating may be same or different.
Another aspect of the present subject matter provides a controlled release component comprising levodopa and/or carbidopa in its core, coated with a layer of controlled release coat and further coated with a composite enteric outer layer comprising layers of two different enteric coatings, wherein one such coating is a neutralized enteric coating.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer/coat and/or enteric release layer/coat.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer/coat and/or enteric release layer/coat wherein the composition is substantially devoid of muco-adhesive polymer/coating.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings which includes controlled release coat and enteric release coat including neutralized enteric coat, wherein the composition is substantially devoid of muco-adhesive polymer/coating.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa coated with a layer of controlled release coat and further coated with an outer layer of first enteric layer coat which is neutralized enteric layer and then an outer coat of another enteric layer, wherein the composition is substantially devoid of muco-adhesive polymer/coating.

It was surprisingly found out that, use of neutralized enteric layer in between control release coat and final enteric coat could achieve a desirable pharmacokinetic profile (PK profile) compared with reference composition having muco-adhesive polymer/coating.

In another embodiment, an immediate release component may be formulated as a powder, coating, mini-tablet, bead, pellet, granule or combination thereof that is separate from controlled release component.

In another embodiment, a controlled release component may be formulated as a powder, coating, mini-tablet, bead, pellet, granule or combination thereof that is separate from immediate release component.

In another embodiment, the controlled release component may comprise the drug containing core comprises both of levodopa and carbidopa. Similarly the immediate release component also comprises both levodopa and carbidopa.

In another embodiment, the controlled release component may comprise the drug containing core comprising levodopa and is free of carbidopa and the immediate release component comprises both levodopa and carbidopa.

In further embodiments of the subject matter, the pharmaceutical composition as defined herein may have 20-500 mg of the levodopa. Further, the composition may have 10-150 mg of carbidopa. In specific embodiment, the composition may contain carbidopa /levodopa 35/140 mg, 52.5/210 mg, 70/280 mg, 87.5/350 mg.

In one embodiment of the subject matter, the pharmaceutical composition as defined herein may contain carbidopa and levodopa ranging from 20-60% w/w of the immediate release component on an individual basis. In specific embodiments, it may contain carbidopa and levodopa ranging from 30-50% or 40-50% w/w of the immediate release component on an individual basis.

In one embodiment of the subject matter, the pharmaceutical composition as defined herein may contain levodopa ranging from 40-80% w/w of the controlled release component. In specific embodiments, it may contain levodopa ranging from 50-70% or 60-70% w/w of the controlled release component.

In one embodiment, the controlled release component comprises a core comprising levodopa and/or carbidopa, coated with a control release layer, which is further coated with one or more enteric coatings. The control release layer may constitute about 2-15% w/w (e.g. 3-10%, 3-8% w/w, 4-7% w/w, 5-6% w/w) of the controlled release component. The enteric release coat may constitute about 1-20% w/w (e.g. 2-15%, 3-10%, 5-10% w/w, 5-9% w/w) of the controlled release component.

In another embodiment, the control release coat/layer comprises a control release polymer and/or enteric polymer. The control release coat/layer may further contain conventional pharmaceutically acceptable excipients such as pore former, anti-tacking agent.

Suitable control release polymers useful in the present subject matter include, but are not limited to, ethylcellulose, cellulose acetate, Eudragit® E, Eudragit® RS, Eudragit® RL, and Eudragit® NE, or mixtures thereof. Control release polymer(s) may constitute about 1-7 % w/w of the controlled release component.

In one embodiment, the controlled release component comprises one or more enteric coatings to make up a composite enteric layer. If more than one enteric coating is employed, they may be same or different. In one aspect, the enteric layer comprises a coating comprising neutralized enteric coating having pH adjusting agents in addition to other enteric coating. In one aspect, the enteric layer comprises a coating comprising neutralized enteric coating having pH adjusting agents in addition to other non-neutralized enteric coating. The composite enteric release layer may constitute about 1-20% w/w of the controlled release component. The neutralized enteric release coat may constitute about 1-15% w/w of the controlled release component.

In one embodiment, the neutralized enteric coating is adjusted to a pH from 4 to 8, specifically between pH 5 to 7 or pH 5.5 to 6.5. In another embodiment, the neutralized enteric coating may be adjusted to any pH of 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8.

In one embodiment, the enteric coating comprises enteric polymers. Enteric coating polymers are known in the art. In general, enteric coating polymers are designed to prevent drug release from an oral solid dosage form in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine.

Suitable enteric coating polymers useful in the present subject matter include, but are not limited to, poly(methacrylic acid-co-methyl methacrylate), poly(methacrylic acid-co-ethyl methacrylate), shellac, zein, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinates. The preferred enteric polymers release at a pH of greater than or equal to pH 5.5. Examples include Eudragit® L100, Eudragit® L30D55 or Eudragit® L100-55. The enteric coating polymers may constitute about 1-20% w/w of the mass of the controlled release component.

In one aspect, the controlled release component comprises a composite enteric layer as its sub part. Such composite enteric layer comprises at least two separate coatings of enteric coating. At least one layer of composite enteric layer comprises a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent. At least one layer composite enteric layer comprises an enteric coating comprising an enteric polymer. The enteric coating and neutralized enteric coating of composite enteric layer may further contain conventional pharmaceutically acceptable excipients such as buffering agent, plasticizer, anti-tacking agent.

It was surprisingly found out that use of neutralized enteric layer in between control release coat and enteric coat could achieve a desirable pharmacokinetic profile compared with reference composition having muco-adhesive polymer/coating.
In one aspect, the controlled release component comprises levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer and a composite enteric release layer comprising at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and at least one layer comprising enteric coating, wherein the composition is substantially devoid of muco-adhesive polymer/coating. Preferably, neutralized enteric layer of composite enteric layer is structured to be present in between controlled release layer and outer enteric layer.

Another aspect of the present subject matter the controlled release components and/or the immediate release components may further contain conventional pharmaceutically acceptable excipients such as a diluents, pore formers, disintegrants, lubricants, binders, glidants, wetting agents, pH adjusting agents, anti-tacking agents, plasticizer, neutralizing agent, buffering agents or mixtures thereof.

The terms “diluent” and “diluents” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluent according to the present subject matter can be selected form the group of, but not limited to sugar and sugar alcohol such as calcium carbonate; dicalcium phosphate; pregelatinized starch; calcium sulfate, mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, cellulose acetate; ethylcellulose; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride and microcrystalline cellulose (MCC). Diluents may constitute about 1-10% w/w of the immediate release component and may constitute about 10-20% w/w of the controlled release component.

The terms “disintegrant” and “disintegrants” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable disintegrants according to the present subject matter can be selected form but not limited to croscarmellose sodium (CCS), alginic acid, sodium alginate, carboxymethylcellulose calcium, chitosan, crospovidone, glycine, pregelatinized starch, guar gum, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate and starch. Disintegrant may constitute about 2-7% w/w of the immediate release component and may constitute about 0-10% w/w of the controlled release component.

The term “binder” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable binders that may be employed in the compositions of the present subject matter include acacia, povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Binder may constitute about 0-3% w/w of the immediate release component and may constitute about 0-3% w/w of the controlled release component.

Examples of glidants that may be suitable in the compositions of the present subject matter include colloidal silicon dioxide, corn starch, talc or mixtures thereof. Glidant may constitute about 0.1-5% w/w of the immediate release component and may constitute about 0.1-5% w/w of the controlled release component.

Suitable examples of pH adjusting agents that may be used in the compositions of the present subject matter include pharmaceutically acceptable acids or bases. Suitable examples of pharmaceutically acceptable acids that may be used include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, and mixtures thereof. Suitable examples of pharmaceutically acceptable bases that may be used include but are not limited to ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, trolamine, and mixtures thereof. In specific embodiments, the pH adjusting agent is a base e.g. sodium hydroxide.

The terms “lubricant” and “lubricants” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricant according to the present subject matter can be selected form but not limited to magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine, magnesium stearate, myristic acid, palmitic acid, stearic acid, talc, tribehenin. Lubricant may constitute about 0.1-2% w/w of the immediate release component and may constitute about 0.1-2% w/w of the controlled release component.

The terms “plasticizer” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical plasticizer according to the present subject matter can be selected form selected from TEC (Triethyl Citrate), Polyethylene Glycol, Tween80, Span 80, Sodium dioctyl sulfate, Sodium deoxycholate, Lecithin or their mixture thereof. Plasticizer may constitute 0.1-3% of the controlled release component.
The terms “pore former” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical pore former according to the present subject matter can be selected form but not limited to include lactose, sucrose, mannitol, povidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcelluose or combinations thereof. Pore former may constitute 1-5% of the controlled release component.
The terms “anti-tacking agent” and “anti-tacking agents” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable anti-tacking agent according to the present subject matter can be selected form the group of, but not limited to glyceryl monostearate (GMS), Colloidal Silicon Dioxide (Aerosil 200), talc, talc micronized or combinations thereof.
The terms “buffering agent” and “buffering agents” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable buffering agent according to the present subject matter can be selected form the group of, but not limited to lactic acid, acetic acid, histidine, aspartate, citric acid, phosphoric acid or combinations thereof.

The terms “wetting agent” and “wetting agents” is intended to be interpreted in the context of pharmaceutical formulation science. Suitable wetting agents
according to the present subject matter can be selected form but not limited to Sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, Kolliphor SLS fine, sodium lauryl ether sulfate, Sodium Lauryl sulphate or combinations thereof.

In certain embodiments, the solid oral composition may comprise an immediate release component and a controlled release component, wherein upon administration of such composition to a patient, the immediate release component provides a therapeutic dose of levodopa within one hour or less after administration, preferably within 45 minutes or less after administration and most preferably about 30 minutes or less after administration. Once the required therapeutic plasma level of levodopa is achieved by the immediate release component, the controlled release component(s) provides and/or maintains required therapeutic plasma level of levodopa over a period of for at least 4-12 hours, specifically 6-12 hours and even more specifically 4, 5, 6, 7, 8, 9, 10, 11 or 12 hours after administration.

The oral pharmaceutical composition may be in the form or a tablet or capsule or may be sprinkled.

In one embodiment, the pharmaceutical composition is a pharmaceutical capsule composition (for oral administration) filled with the immediate release component and controlled release component.

In one embodiment, the pharmaceutical composition of the present subject matter is a pharmaceutical capsule composition suitable for oral administration to a human.

Another aspect of the present subject matter provides a capsule composition comprising
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising a core comprising levodopa and/or carbidopa coated with a layer of controlled release coat and further coated with an outer layer of first enteric layer coat which is a neutralized enteric layer and then an outer coat of another enteric layer, wherein the composition is substantially devoid of mucoadehsive polymer.

Another aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising,
(a) an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
(b) a controlled release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients and one or more coatings comprising controlled release layer and a composite enteric release layer comprising first at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and at least one layer comprising enteric coating, wherein the composition is substantially devoid of muco-adhesive polymer/coating.
Another preferred aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising the controlled release component comprising levodopa and/or carbidopa and one or more coating comprising
a) controlled release layer and
b) a composite enteric release layer comprising
i. first at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and
ii. at least one layer comprising enteric coating.

Another more preferred aspect of the present subject matter relates to a solid oral pharmaceutical composition comprising comprising,
A. an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
B. a controlled release component comprising levodopa and/or carbidopa, and one or more coatings comprising
a) controlled release layer and
b) a composite enteric release layer comprising
i. first at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and
ii. at least one layer comprising enteric coating,
wherein the composition is substantially devoid of muco-adhesive polymer/coating.

A further aspect of the subject matter there provides the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.

An embodiment of the present subject matter provides the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of Parkinson’s disease (PD). In an aspect, the medicament is in the form of capsule.

In one aspect of the subject matter, there is provided a method of treating Parkinson’s disease (PD) in a patient in need thereof, which method comprises the oral administration of an effective amount of the pharmaceutical composition, as defined herein, to the patient.
In another embodiment, the patient is an adult human patient.

In one embodiment there is provided a method of treating Parkinson’s disease (PD) in a patient in need thereof, which method comprises the oral administration of an effective number of the pharmaceutical capsule(s), as defined herein, to the patient.

According to one embodiment, there is provided the process for preparation of the levodopa/carbidopa composition comprising granulation and/or coating processes, including, but not limited to, wet-granulation, fluid bed granulation/coating, dry granulation, or extrusion/spheronization.

According to another embodiment, the present subject matter relates to a process for the preparation of a pharmaceutical composition, comprising the steps of:
1. preparation of an immediate release component
2. preparation of a controlled release component
3. preparation of desired pharmaceutical composition using Immediate Release component and Controlled Release Component.

According to another embodiment, the present subject matter relates to a process for the preparation of a capsule, comprising the steps of:
1. preparation of an immediate release component
2. preparation of a controlled release component
3. filling the immediate release component and controlled release component in a capsule shell.

According to detailed embodiment, the present subject matter relates to a process for the preparation of a capsule, comprising the steps of:
1. Preparation of immediate release component comprising:
a) mixing active ingredient(s), diluent, disintegrant, lubricant and glidant (except extra granular material comprising lubricant and glidant),
b) roller compacting above blend and passing the material through convenient sieve and mixing with extra granular component.
2. Preparation of controlled release component comprising:
a) mixing active agent/agents, diluent, binder and anti-tacking agent and granulating this mass with a binder solution, extruding wet mass so obtained through an extruder and spheronizing it to form drug loaded core pellets,
b) coating drug loaded core pellets with a control release coating solution comprising a control release polymer, pore former, anti-tacking agent and solvent; drying the pellets after completion of coating to prepare core coated with control release coat,
c) enteric coating the core coated with controlled release coat with one or more enteric coating layers. If more than one enteric layers are applied, then first enteric layer is applied comprising neutralized enteric coating using enteric coating solution comprising enteric coating polymer, buffering agent, plasticizer, anti-tacking agent, a pH adjusting agent and solvent. After neutralized enteric layer is completed, further coating with another enteric coating comprising enteric coating polymer, placticizer and anti-tacking agent and solvent and drying such pellets to form dry controlled release pellets.
d) mixing the dry controlled release pellets with lubricant to prepare final controlled release component
3. filling the immediate release component and controlled release component in the capsule shell.

According to another embodiment, the suitable solvent used for the process of preparation for the pharmaceutical composition can be selected form but not limited to water, isopropyl alcohol, acetone, ethyl alcohol, methyl alcohol, dimethyl sulfoxide, ether, dichloromethane, ethyl acetate or combinations thereof.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting

Examples
Table 1-Carbidopa and levodopa composition
Ingredients Reference Example
Example 1 Example 2 Example 3 Example 4 Example
5 Example
6 Example
7
%w/w %w/w %w/w %w/w %w/w %w/w %w/w %w/w
Immediate Release component
Intragranular
Carbidopa 46.2 46.08 46.20 46.20 46.08 46.08 46.08 46.08
Levodopa 42.80 42.68 42.80 42.80 42.68 42.68 42.68 42.68
MCC 5.29 5.29 5.29 5.29 5.29 5.29 5.29 5.29
CCS 4.00 4.00 4.00 4.00 4.00 4.00 4.00 4.00
Magnesium Stearate 0.49 0.49 0.49 0.49 0.49 0.49 0.49 0.49
Lubrication
Colloidal Silicon Dioxide 0.98 0.98 0.98 0.98 0.98 0.98 0.98 0.98
Magnesium Stearate 0.49 0.49 0.49 0.49 0.49 0.49 0.49 0.49
Total wt. of granules 100.000 100.000 100.000 100.000 100.000 100.000 100.00 100.00
Controlled Release component
Intragranular %w/w %w/w %w/w %w/w %w/w %w/w %w/w %w/w
Levodopa 61.83 67.04 67.04 67.04 65.11 65.11 75.00 75.00
MCC 8.36 15.74 15.74 15.74 15.29 15.29 17.61 17.61
Mannitol 8.36 - - - - - - -
Hypromellose - 3.58 3.57 3.57 3.47 3.47 4.00 4.00
Colloidal Silicon Dioxide - 0.73 0.73 0.73 0.71 0.71 0.82 0.82
Binder solution
Kolliphor SLS fine 4.18 1.40 1.40 1.40 1.36 1.36 1.36 1.36
Povidone K-30 0.84 - - - - - - -
Hypromellose - 0.89 0.89 0.89 0.87 0.87 0.87 0.87
IPA q.s. - q.s. q.s. q.s. q.s. q.s. q.s.
Purified Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Controlled Release Coating
Levodopa core pellets 83.58 89.39 89.39 85.98 86.82 86.82 81.82 81.60
Cellulose acetate 1.88 3.75 2.33 2.24 2.26 2.26 2.13 2.65
Copovidone 2.30 3.43 2.13 2.05 2.07 2.07 1.95 1.43
Talc micronized - 1.44 0.89 0.86 0.87 0.87 1.06 1.29
Acetone (80%) : IPA (20%) q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Muco-Adhesive Coating
Levodopa pellets 87.76 - - - - - - -
Eudragit E 100 6.38 - - - - - - -
Talc 0.64 - - - - - - -
Acetone (80%) : IPA (20%) q.s. - - - - - - -
Neutralized Enteric Coating
Eudragit L 30 D 55 - - - 1.78 1.80 1.80 2.84 2.84
Citric acid - - - 0.18 0.18 0.18 0.28 0.28
TEC (Triethyl citrate) - - - 0.36 0.37 0.37 0.58 0.58
Talc - - - 0.41 0.41 0.41 0.65 0.65
Water - - - q.s. q.s. q.s. q.s. q.s.
pH adjusted by 1N NaOH - - - pH 6.0 pH 5.6 - 6.0 pH 6.0 pH 6.0 pH 6.0
Enteric Coating
Eudragit L100 3.31 3.32 3.32 4.57 3.30 3.30 6.66 6.66
TEC (Triethyl citrate) 0.95 0.95 0.95 0.51 0.95 0.95 0.74 0.74
Talc micronized 0.47 0.47 0.47 0.56 0.47 0.47 0.81 0.81
Acetone (40%) : IPA (60%) q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s
Lubrication
Talc micronized 0.48 0.49 0.51 0.49 0.50 0.50 0.47 0.47
Total weight of Controlled release component 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
Empty Hard Gelatin Capsules Fill immediate release component and controlled release component into capsule

Example 2: In-vivo pharmacokinetic study (PK study)
Reference example and formulations of example 2 and 3 were administered to human subjects. Plasma samples were collected for concentration analysis of carbidopa and levodopa at several time points. Concentrations of carbidopa and levodopa were determined using suitable technique. Pharmacokinetic parameters were calculated. The results for carbidopa and levodopa are shown in Table 2 below:

Table 2: Bioequivalence (BE) results of example 2

PK Parameters PK study data of Carbidopa PK study data of Levodopa
Fasting Fed Fasting
N (number of human subjects) 24 24 24
Cmax (%Ratio (T/R) 97.57 92.4 96.18
AUC 0-t (%Ratio (T/R) 96.86 94.09 97.37
AUC 0-inf (%Ratio (T/R) 96.9 94.06 97.41

Table 3: Bioequivalence (BE) results of example 3 in Fed condition

PK Parameters PK study data of Carbidopa PK study data of Levodopa
N (number of human subjects) 20 20
Cmax (%Ratio (T/R) 98.60 98.26
AUC 0-t (%Ratio (T/R) 100.21 102.78
AUC 0-inf (%Ratio (T/R) 100.18 102.77

The results as per table 2 and 3 indicates that both formulations 2 and 3, which do not contain muco-adhesive coating are bioequivalent to reference example containing muco-adhesive coating. It was surprisingly found that formulation 2 provides a bioequivalent profile with respect to carbidopa in both fasting and fed condition.
Also, it was surprisingly found that example 3, which contains a neutralized enteric coating layer in between the controlled release layer and final enteric coating layer exhibits bio equivalency in fed condition for both levodopa and carbidopa against the reference composition containing muco-adhesive coating.

CLAIMS:We claim:

1. A solid oral pharmaceutical composition comprising a combination of levodopa and/or carbidopa or pharmaceutically acceptable salts and pharmaceutically acceptable excipients, wherein the composition is devoid of muco-adhesive polymer.

2. The solid oral pharmaceutical composition according to claim 1, comprising two types of components, the first type of component comprises immediate release component and the second type of component comprises controlled release component.

3. The solid oral pharmaceutical composition according to claim 2, wherein the immediate release component and the controlled release component comprises levodopa and/or carbidopa.

4. The solid oral pharmaceutical composition according to claim 2, wherein the immediate release component comprises levodopa and/or carbidopa and the controlled release component (CR component) comprises levodopa.

5. The controlled release component according to claim 2 comprising levodopa and/or carbidopa and further comprises one or more coating comprising
a. controlled release layer and
b. a composite enteric release layer comprising
i. at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and
ii. at least one layer comprising enteric coating.

6. A solid oral pharmaceutical composition according to claim 1 comprising,
A. an immediate release component comprising levodopa and/or carbidopa, and pharmaceutically acceptable excipients,
B. a controlled release component comprising levodopa and/or carbidopa, and one or more coatings comprising
a. controlled release layer and
b. a composite enteric release layer comprising
i. at least one layer comprising a neutralized enteric coating comprising an enteric coating polymer and a pH-adjusting agent and
ii. at least one layer comprising enteric coating,
wherein the composition is devoid of muco-adhesive polymer/coating.

7. The solid oral pharmaceutical composition according to claim 6 comprising
i. controlled release layer comprising control release polymer and other excipients.
ii. enteric release layer comprising enteric coating polymer and other excipients.

8. The solid oral pharmaceutical composition according to claim 6 wherein
i. controlled release layer constitute about 2-15% w/w of the controlled release component.
ii. enteric release layer constitute about 1-20% w/w of the controlled release component.

9. The solid oral pharmaceutical composition according to claim 1 wherein the process for the preparation of a composition comprises the steps of:
i. preparation of an immediate release component
ii. preparation of a controlled release component
iii. Optionally filling the immediate release component and controlled release component in a capsule shell.

10. The solid oral pharmaceutical composition according to claim 1, wherein the composition is used for the treatment of Parkinson’s disease (PD).