LEVODOPA FRACTIONATED DOSE COMPOSITION AND USE

Abstract

There is provided a convenient new treatment of Parkinson disease by a frequent administration of optimal levodopa doses mimicking a continuous intravenous or infusion treatment, thus mitigating motor complications; and a new carbidopa/levodopa pharmaceutical unit form providing said new treatment.

Claims

1.-29. (canceled)

30. A method for the treatment of Parkinson's disease or related levodopa (LD)-responsive disorders, comprising orally administering to a patient in need thereof, a composition comprising carbidopa/levodopa (CD/LD) at a dose which simulates continuous intravenous administration of LD when administered up to 9 times per day, wherein the dose comprises CD in an amount of 25 mg or less and LD in an amount of 100 mg or less, and wherein said composition does not comprise entacapone.

31. The method of claim 30, wherein the dose comprises CD in an amount of 25 mg and LD in an amount of 100 mg.

32. The method of claim 30, wherein the dose comprises CD in an amount of 18.75 mg or less and LD in an amount of 75 mg or less.

33. The method of claim 30, wherein the dose comprises CD in an amount of 12.5 mg or less and LD in an amount of 50 mg or less.

34. The method of claim 30, wherein the dose comprises CD in an amount of 6.25 mg or less and LD in an amount of 25 mg or less.

35. The method of claim 30, wherein said patient is a newly diagnosed patient at the initial stage of Parkinson's disease.

36. The method of claim 30, wherein said patient is a patient at the middle or late stage of Parkinson's disease.

37. The method of claim 30, wherein said patient is a parkinsonian patient previously administered a standard treatment with carbidopa/levodopa.

38. The method of claim 37, wherein said patient suffers from motor response complications.

39. The method of claim 30, wherein the CD/LD is present in a multiscore tablet comprising a fully scored top layer divided by two or three scores providing three or four sections, wherein each section comprises CD/LD, and a bottom inert layer partially penetrated by each of the scores.

40. The method of claim 39, wherein a total amount of CD/LD in the multiscore tablet is 25 mg or less of carbidopa and 100 mg or less of levodopa, wherein the top layer of the tablet is divided by three scores providing four sections, and wherein the total amount of CD/LD is evenly divided between each section of the tablet.

41. The method of claim 39, wherein one to four sections is administered as the dose 5 to 9 times per day.

42. The method of claim 39, wherein one to four sections is administered as the dose 5 to 6 times per day.

43. The method of claim 30, wherein the dose of LD provides a constant plasma concentration range of the LD for full efficacy with no motor response complications.

44. A method of treating or alleviating motor response complications related to Parkinson's disease or related levodopa (LD)-responsive disorder, comprising orally administering to a patient in need thereof, a composition comprising carbidopa/levodopa (CD/LD) at a dose which simulates continuous intravenous administration of LD when administered up to 9 times per day, wherein the dose comprises CD in an amount of 25 mg or less and LD in an amount of 100 mg or less, and wherein said composition does not comprise entacapone.

45. The method of claim 44, wherein the dose comprises CD in an amount of 25 mg and LD in an amount of 100 mg.

46. The method of claim 44, wherein the dose comprises CD in an amount of 18.75 mg or less and LD in an amount of 75 mg or less.

47. The method of claim 44, wherein the dose comprises CD in an amount of 12.5 mg or less and LD in an amount of 50 mg or less.

48. The method of claim 44, wherein the dose comprises CD in an amount of 6.25 mg or less and LD in an amount of 25 mg or less.

49. The method of claim 44, wherein said patient is a newly diagnosed patient at the initial stage of Parkinson's disease.

50. The method of claim 44, wherein said patient is a patient at the middle or late stage of Parkinson's disease.

51. The method of claim 44, wherein the CD/LD is present in a multiscore tablet comprising a fully scored top layer divided by two or three scores providing three or four sections, wherein each section comprises CD/LD, and a bottom inert layer partially penetrated by each of the scores.

52. The method of claim 51, wherein a total amount of CD/LD in the multiscore tablet is 25 mg or less of carbidopa and 100 mg or less of levodopa, wherein the top layer of the tablet is divided by three scores providing four sections, and wherein the total amount of CD/LD is evenly divided between each section of the tablet.

53. The method of claim 51, wherein one to four sections is administered as the dose 5 to 9 times per day.

54. The method of claim 51, wherein one to four sections is administered as the dose 5 to 6 times per day.

55. The method of claim 44, wherein the dose of LD provides a constant plasma concentration range of the LD for full efficacy with no motor response complications.

56. A method for the treatment of Parkinson's disease or related levodopa (LD)-responsive disorders, comprising orally administering to a patient in need thereof, a composition comprising carbidopa/levodopa (CD/LD) at a dose which simulates continuous intravenous administration of LD, 4 times per day, wherein the dose comprises CD in an amount of 12.5 mg and LD in an amount of 50 mg.

57. The method of claim 56, wherein said composition does not comprise entacapone.

58. The method of claim 56, wherein the dose comprises CD in an amount of 6.25 mg or less and LD in an amount of 25 mg or less.

59. The method of claim 56, wherein said patient is a newly diagnosed patient at the initial stage of Parkinson's disease.

60. The method of claim 56, wherein said patient is a patient at the middle or late stage of Parkinson's disease.

61. The method of claim 56, wherein said patient is a parkinsonian patient previously administered a standard treatment with carbidopa/levodopa.

62. The method of claim 61, wherein said patient suffers from motor response complications.

63. The method of claim 56, wherein the CD/LD is present in a multiscore tablet having a fully scored top layer divided by two or three scores providing three or four sections, wherein each section comprises the dose of CD/LD, and a bottom inert layer partially penetrated by each of the scores.

64. The method of claim 63, wherein a total amount of CD/LD in the multiscore tablet is 25 mg or less of carbidopa and 100 mg or less of levodopa, wherein the total amount of CD/LD is evenly divided between each section of the tablet.

65. A method for the treatment of Parkinson's disease or related levodopa (LD)-responsive disorders, comprising orally administering to a patient in need thereof, a composition comprising carbidopa/levodopa (CD/LD) at a dose which simulates continuous intravenous administration of LD when administered up to 9 times per day, wherein the dose is selected from the group consisting of carbidopa-6.25 mg/levodopa-25 mg, carbidopa-8.3 mg/levodopa-33.3 mg, carbidopa-12.5 mg/levodopa-50 mg, carbidopa-16.6 mg/levodopa-66.6 mg, carbidopa-18.75 mg/levodopa-75 mg, carbidopa-25 mg/levodopa-100 mg, wherein the CD/LD are present in a multiscore tablet comprising a fully scored top layer divided by two or three scores providing three or four sections, wherein each section comprises the dose of CD/LD, and a bottom inert layer partially penetrated by each of the scores, and wherein a total amount of CD/LD in the multiscore tablet is 25 mg of carbidopa and 100 mg of levodopa, wherein the total amount of CD/LD is evenly divided between each section of the tablet, wherein the composition does not comprise entacapone.

66. The method of claim 65, wherein the dose is carbidopa-6.25 mg/levodopa-25 mg and wherein the total amount of CD/LD in the multiscore tablet is 25 mg of carbidopa and 100 mg of levodopa.

67. The method of claim 65, wherein said patient is a newly diagnosed patient at the initial stage of Parkinson's disease.

68. The method of claim 65, wherein said patient is a patient at the middle or late stage of Parkinson's disease.

69. The method of claim 65, wherein said patient is a parkinsonian patient previously administered a standard treatment with carbidopa/levodopa.

70. The method of claim 69, wherein said patient suffers from motor response complications.

71. The method of claim 65, wherein one or more sections is administered 5 to times per day.

72. The method of claim 65, wherein one or more sections is administered 5 to times per day.

73. The method of claim 65, wherein the dose of LD provides a constant plasma concentration range of the LD for full efficacy with no motor response complications.

Description

DETAILED DESCRIPTION

[0057] The present invention provides

[0058] a method for the treatment of PD and related LD-requiring disorders, with concurrent prevention or treatment of MRCs, in a patient in need of said treatment, which comprises administering to said patient a CD/LD single dose selected from the group consisting of 6.25 mg/25 mg, 8.(3) mg/33.(3) mg, 12.5 mg/50 mg, 16.(6) mg/66.(6) mg, 18.75 mg/75 mg, 25 mg/100 mg, 31.25 mg/125 mg, and 33.(3) mg/133.(3) mg from 5 times to 9 times per day;

[0059] a pharmaceutical unit form consisting of a multiscore tablet comprising a pharmaceutical composition comprising CD/LD 25 mg/100 mg in admixture with a pharmaceutical carrier, and divided, by two or three scores, in three or four sections, each section comprising, respectively, CD/LD 8.(3) mg/33.(3) mg, and CD/LD 6.25 mg/25 mg;

[0060] the use of CD and LD for the preparation of a medicament for the treatment of PD, with concurrent prevention or treatment of MRCs, said medicament consisting of a multiscore tablet comprising a pharmaceutical composition comprising CD/LD 25 mg/100 mg in admixture with a pharmaceutical carrier, and divided, by two or three scores, in three or four sections, each section comprising, respectively, CD/LD 8.(3) mg/33.(3) mg, and CD/LD 6.25 mg/25 mg.

[0061] According to a first aspect, the present invention provides a tool for an easy realization of a new protocol for treating patients suffering from PD by concurrently preventing or treating MRCs.

[0062] Said new protocol provides a method for the treatment of Parkinson's disease in a patient in need of said treatment, while concurrently preventing or treating MCCs, which comprises treating said patient with a CD/LD single dose selected from the group consisting of 6.25 mg/25 mg, 8.(3) mg/33.(3) mg, 12.5 mg/50 mg, 16.(6) mg/66.(6) mg, 18.75 mg/75 mg, 25 mg/100 mg, 31.25 mg/125 mg, and 33.(3) mg/133.(3) mg, from 5 times to 9 times per day.

[0063] The new protocol is assured by using a pharmaceutical unit form consisting of a multiscore tablet comprising a pharmaceutical composition comprising CD/LD 25 mg/100 mg in admixture with a pharmaceutical carrier, and divided, by two or three scores, in three or four sections, each section comprising, respectively, CD/LD 8.(3) mg/33.(3) mg, and CD/LD 6.25 mg/25 mg, thus allowing the administration of one or more unit doses of CD/LD 6.25 mg/25 mg or. 8.(3) mg/33.(3) mg,

[0064] Said single dose is being selected from the group consisting of from one section, two sections, three sections, the whole tablet and the whole tablet plus one section or more sections of a second bilayered tablet as described above. In the case of a three-score tablet, three sections correspond to the whole tablet.

[0065] The treatment of early stage PD is typically initiated with CD/LD (DopaSnap) at an unit dose of 6.25/25 mg or 8.(3) mg/33.(3) mg, according to the age and the weight of the patient, given orally every 3-4 hours while awake, over a period of 16-18 hours. For these early stage patients, the above CD/LD 6.25 mg/25 mg or 8.(3) mg/33.(3) mg unit dose is typically given at 5 to 6 times per day (from 31.25 mg/125 mg to 37.5 mg/150 mg per day or from 41.(6) mg/166.(6) mg to 50 mg/200 mg). This daily dose is subsequently titrated up over subsequent days and weeks to the lowest amount that optimally relieves motor symptoms or to a maximum single dose, usually in the range of from 16.(6) mg/66.(6) mg to 33.(3) mg/133.(3) mg, corresponding to a daily dose of from 83.(3) mg/666.(6) mg to 166.(6)/800 mg, normally in the range of from 18.75 mg/75 mg to 31.25 mg/125 mg, corresponding to a daily dose of from 93.75 mg/375 mg to 187.5 mg/750 mg. or from per single dose.

[0066] However, large inter-patient differences are not unexpected. Motor symptom relief involves the amelioration of parkinsonian tremor, rigidity, hypokinesia as well as difficulty with gait and balance. In some patients, the optimal dose of LD (in DopaSnap) may be as low as 25 mg or 50 mg, depending on such factors as body size and drug tolerance. Once patients have reached their optimal dose, they ordinarily continue treatment at that dose until symptoms change in ways that require dose adjustment. In some individuals dose adjustments are required throughout the day depending on such factors as food ingestion and activity status.

[0067] Within a year or two of treatment initiation, patients will be benefitted by shifting to a more frequent dosing schedule in order to maintain more constant brain dopamine levels and avoid both high peaks just after dosing and low troughs between dosing. Replacing brain dopamine in this more physiologic manner has been shown to delay the onset and reduce the severity of motor response complications. This is a syndrome, which occurs in some 40% of all PD patients after 5 years of dopaminergic treatment and in nearly 80% within 10 years is manifested by response fluctuations and abnormal involuntary movements which can become as disabling as the parkinsonian symptoms themselves.

[0068] The rise in the LD dose/motor response relation with disease progression intensifies the need for precise dosing afforded by DopaSnap in late stage patients.

[0069] The treatment of middle and late stage parkinsonian patients thus generally focuses on attempts to ameliorate the severely dysfunctional effects of motor complications. It has been shown that the constant administration of optimal-dose LD can rapidly reduced or even abolish these complications. With DopSnap treatment it becomes easy to take relatively low, frequent doses, for example LD single doses of from 25 mg to 125 mg every 90 min to 125 mg every 2 hours, that simulate constant infusion therapy. Generally, LD doses in the 75 mg to 125 mg range given every 2 hours (8-9 times over 16 hours) provide the best results, although wide inter- and intra-patient variability occurs. For example, in the late stage of PD, over 16 hours, a DopaSnap single dose of from 18.75 mg/75 mg to 31.25 mg/125 mg) every two hours provides a CD/LD daily dose of from 168 mg/675 mg to 281.25 mg/1125 mg allowing the prevention or treatment of MRCs.

[0070] According to an embodiment, the present invention provides a three-score/four section, bilayered tablet formed by a top, scored layer comprising a pharmaceutical composition comprising, as active ingredients, CD, in a total amount of 25 mg, and LD, in a total amount of 100 mg, in admixture with a pharmaceutical carrier for immediate release, adjoined to an inert bottom layer comprising a pharmaceutical carrier without active ingredient, each of the four sections of said top layer of said tablet comprising a CD/LD amount of 6.25 mg/25 mg.

[0071] Each DopaSnap tablet is triple-scored for ease of fractionated dosing and may be used whole (25/100 of CD/LD) or divided into 6.25/25 mg, 12.5/50 mg or 18.75 mg/75 mg CD/LD doses. The deep scoring permits tablet segments to be easily snapped apart manually without cutting instruments. Ease of fractionation is essential for elderly, motor-impaired patients.

[0072] DopaSnap tablets employ bilayered, deeply scored design. The top layer contains CD/LD and is pre-divided by 3 deep scores during the manufacturing process to provide exact doses. The bottom layer does not contain active drug; it provides mechanical stability and serves as the break region when splitting the tablet.

[0073] Accordingly, in the top layer, CD and LD are formulated with the calculated amount of CD and the calculated amount of LD active ingredients in admixture with a conventional pharmaceutical acceptable carrier in an immediate release formulation. Said calculated amount of the active ingredients in said top layer assures

(a) a total CD amount per tablet of 25 mg; and
(b) a total LD mount per tablet of 100 mg.

[0074] The bottom, inert layer that only serves for a precise splitting of single sections, without any loss of active ingredients is a formulation of a conventional pharmaceutical carrier, preferably the same as that of the top layer, without active ingredient

[0075] Two or three scores divide the top layer in three or four sections, each containing 8.(3) mg CD and 33.(8) LD and, respectively, 6.25 mg CD and 25 mg LD and penetrate the bottom layer without cutting it, thus allowing the perfect splitting of the desired number of sections.

[0076] The pharmaceutical carriers include starches, cellulose and derivatives thereof; silica gel, microsilica gel; lubricants such as talc, stearic acid or magnesium stearate; diluents such as talc, powdered cellulose, lactose, starches such as maize or corn starch, pregelatinized starch, mannitol, sorbitol; disaggregating agents such as microcrystalline cellulose, low substituted hydroxypropylcellulose, or crospovidone; lubricants such as polyethylene glycol or magnesium stearate; ligands such as methylcellulose, sodium carboxymethylcellulose, alginic acid, alginates; sweeteners, such as sucrose, dextrose, mannitol, saccharin; or flavoring agents such as natural or synthetic oils.

[0077] Normally, layer (a), containing the calculated amount of the active ingredients in admixture with a binder, such as starch, starch past, pregelatinized starch or povidone, giving cohesiveness to the powder; a disintegrating agent such as crospovidone, cellulose, microcrystalline cellulose (MCC, for example PH-200, PH-102 or PH103 or PH-301) low substituted hydroxhpropylcellulose, or carboxymethyl cellulose, facilitating the breakup of the tablet, or section(s), after oral administration; and a lubricant, such as talc, stearic acid or magnesium stearate, preventing the formation of strong compacts, thus favoring the final compression phase of the tablet manufacturing process.

[0078] Layer (b) is formed by a pharmaceutical carrier, preferably the same as that of layer (a), but without the active ingredients.

[0079] DopaSnap may also be manufactured as an orally disintegrable tablet by using excipients such as MCC PH-102 or PH-301, microsilica gel, low-substituted hydroxypropylcellulose in both the active layer (a) and the inert layer (b), for example as described in CN100384411(C).

[0080] The tablets are preferably manufactured using a first granulation (preferably wet granulation) comprising CD/LD and a second (preferably wet) granulation compounding the pharmaceutical carrier, preferably the same as that of the active layer.

[0081] In particular, for the manufacture of the three score, four sections tablet of the present invention, the active layer is separately prepared by mixing the calculated amount of CD and LD with a binder such as povidone or pregelatinized starch. Water is added to the mixture and said mixture is submitted to wet granulation. After a possible dying of the granulate in a fluidized bed dyer, the mass is submitted to a screening through an 18.mesh screen and milled. The mixture thus obtained is blended with a disintegrating agent such as cellulose or microcrystalline cellulose, and with a lubricant, such as stearic acid or with al earth-metal salt stearate, preferably magnesium stearate, preferably in a V-blender.

[0082] Separately, the calculated amount of a binder, a disintegrating agent and a lubricant, preferably the same used in the preparation of the blended mixture for the active layer, is submitted to blending, preferably in a V-blender.

[0083] The tablets are only manufactured on a Bi-Layer Tablet Compression machine. The manufacture method utilizes a protuberance known as an embossing that rises from the lower punch of a tablet die in said tablet compression machine. The active, above granulation containing the calculated amount of CD/LD enters the die, forms a layer above the highest point of said embossing, and is tamped by the upper punch. The inert, second granulation enters said die on top of said first granulation, is tamped by the upper punch, and then the tablet is compressed by the upper punch so that said compression pushes said first granulation below the highest points of said embossing. Said embossing occupies a position on the lower punch trisecting or quadrisecting said lower punch, so that said compression causes the active layer to be divided into three or four sections.

[0084] As set forth above, the present invention provides a tool for an easy realization of a new protocol for treating patients suffering from PD by concurrently preventing or treating MRCs.

[0085] Said new protocol provides a method for the treatment of Parkinson's disease in a patient in need of said treatment, while concurrently preventing or treating MCCs, which comprises treating said patient with a CD/LD single dose selected from the group consisting of 6.25 mg/25 mg, 12.5 mg/50 mg, 18.75 mg/75 mg, 25 mg/100 mg and 31.25 mg/125 mg, from 5 times to 9 times per day, said single dose being selected from the group consisting of from one section, two section, three sections, the whole tablet and the whole tablet plus one section of a second of the three-score/four section, bilayered tablets as described above.

[0086] The treatment of early stage PD is typically initiated with CD/LD (DopaSnap) at a dose of 6.25/25 mg given orally every 3-4 hours while awake, over a period of 16-18 hours. For these early stage patients, the above CD/LD 6.25 mg/25 mg unit dose is typically given at 5 to 6 times per day (from 31.25 mg/125 mg to 37.5/150 mg per day). This dose is subsequently titrated up over subsequent days and weeks to the lowest amount that optimally relieves motor symptoms or to a maximum, usually in the range of about 18.75 mg/75 mg to 31.25 mg/125 mg per dose. However, large inter-patient differences are not unexpected. Motor symptom relief involves the amelioration of parkinsonian tremor, rigidity, hypokinesia as well as difficulty with gait and balance. In some patients, the optimal dose of LD (in DopaSanp) may be as low as 25 mg or 50 mg, depending on such factors as body size and drug tolerance. Once patients have reached their optimal dose, they ordinarily continue treatment at that dose until symptoms change in ways that require dose adjustment. In some individuals dose adjustments are required throughout the day depending on such factors as food ingestion and activity status.

[0087] Within a year or two of treatment initiation, patients will be benefitted by shifting to a more frequent dosing schedule in order to maintain more constant brain dopamine levels and avoid both high peaks just after dosing and low troughs between dosing. Replacing brain dopamine in this more physiologic manner has been shown to delay the onset and reduce the severity of motor response complications. This is a syndrome, which occurs in some 40% of all PD patients after 5 years of dopaminergic treatment and in nearly 80% within 10 years is manifested by response fluctuations and abnormal involuntary movements which can become as disabling as the parkinsonian symptoms themselves.

[0088] The rise in the LD dose/motor response relation with disease progression intensifies the need for precise dosing afforded by DopaSnap in late stage patients.

[0089] The treatment of middle and late stage parkinsonian patients thus generally focuses on attempts to ameliorate the severely dysfunctional effects of motor complications. It has been shown that the constant administration of optimal-dose LD can be rapidly reduced or even abolish these complications. With DopSnap treatment it becomes easy to take relatively low, frequent doses, for example from 25 to 125 mg every 90 min to 125 mg every 2 hours, that simulated constant infusion therapy. Generally, LD doses in the 75 to 125 mg range given every 2 hours (8-9 times over 16 hours) provide the best results, although wide inter- and intra-patient variability occurs.

Example 1

Preparation of a Carbidopa/Levodopa 25/100 Tablet

[0090] A tablet comprising an inert layer with a superimposed, adjoined active layer, formed by four unitary segments each containing equal amounts of carbidopa/levodopa 6.25 mg/25 mg has the following characteristics:

Tablet Size: 0.675″×0.332″ (corresponding to 17.145 mm×8.433 mm)

Thickness: 4 mm

Tablet Weight: 600 mg

Active Layer: 250 mg

[0091] Inert layer: 350 mg.

[0092] The active layer (also referred to as top layer) has the formulation given in Table 1 below.

TABLE-US-00001 TABLE 1 Material mg/Dose % Internal Carbidopa.sup.1 25 10.0 Phase Levodopa 100 40.0 Pre-Gelatinized Starch 1500 25 10.0 Purified Water — — External Microcrystalline Cellulose PH-200 72.5 29.0 Phase Pre-Gelatinized Starch 1500 25 10.0 Magnesium stearate 2.5 1.0 Total: 250 100.0 .sup.1Weight adjusted based on Certificate of Analysis (COA) Loss on Drying.

[0093] Said active layer is manufactured by the following 6-step process. [0094] 1. Wet granulation process with high shear or top spray fluidized granulation. Mixing Carbidopa, Levodopa and the Pre-Gelatinized Starch 1500, adding purified water. [0095] 2. Drying wet granules from 1 by fluidized bed dryer. [0096] 3. Milling dried granules from 2 by Co-mil with 1000 micron screen. [0097] 4. Calculation and weigh-off the external excipients based on the weight of milled dried granules from 3. [0098] 5. Mixing external phase, Microcrystalline Cellulose PH-200, Pre-Gelatinized Starch 1500 and magnesium stearate, preferably in a V-blender. [0099] 6. Discharge final blend. Ready for compression.
The inert layer (also referred to as bottom segment) has the formulation given in Table 2 below.

TABLE-US-00002 TABLE 2 Material mg/Dose % Microcrystalline Cellulose PH-200 140 40.0   Pre-Gelatinized Starch 1500 206.5 59.0   Magnesium Stearate 3.5  1.0   Total: 350 100%

[0100] Said inert layer is manufactured by a direct blending process: (a) weigh-off excipients; (b) blending Microcrystalline Cellulose PH-200, Pre-Gelatinized Starch 1500 and magnesium stearate, preferably in a V-blender, (c) discharge final blend. Ready for compression. The compression is made by using a bi-layer press machine fitted with the appropriate tooling and compress into tablets.

Example 2

Preparation of a Carbidopa/Levodopa 25/100 Tablet

[0101] A tablet comprising an inert layer with a superimposed, adjoined active layer, formed by four unitary segments each containing equal amounts of carbidopa/levodopa 6.25 mg/25 mg has the following characteristics:

Tablet Size: 0.7480″×0.2920″ (corresponding to 19 mm×7.417 mm)

Thickness: 4.0 mm

Tablet Weight: 640 mg

Active Layer: 310 mg

[0102] Inert layer: 330 mg
1. Active Layer: The active layer (also referred to as top layer) has the following formulation qualitative and quantitative composition given in Table 1 below.

TABLE-US-00003 TABLE 1 Material mg/Dose % Internal Carbidopa 26.99* 8.71 Phase Levodopa 100.0 32.26 Microcrystaliine Cellulose, PH 102 8.01 2.58 Pre-Gelatinized Starch 1500 15.00 4.84 Purified Water 0.0 0.0 External Microcrystalline Cellulose PH-200 156.90 50.61 Phase Magnesium stearate 3.10 1.000 Total weight of Active Layer: 310.00 100.0 *Equivalent to 25 mg label claim for Carbidopa (a monohydrate).
Active layer is manufactured by Wet granulation process with high shear granulation and followed by Dry mixing process with the following 6-step process. [0103] 1. Mix Carbidopa, Levodopa, Microcrystalline Cellulose PH 102 and the Pre-Gelatinized Starch 1500 together and granulate by adding a suspension of Starch 1500 in purified water. [0104] 2. Dry the wet granules in a fluidized bed dryer. [0105] 3. Mill dried granules from step 2 by Co-mill with 1000 micron screen. [0106] 4. Calculate and weigh-off the external phase excipients based on the weight of milled dried granules obtained from step 3. [0107] 5. Mixing external phase (MCC PH 102) and Combo drug granules to a specified time preferably in a V-blender and finally lubricate the blend with magnesium stearate. [0108] 6. Discharge final blend. Ready for compression, along with Placebo or Inactive or Inert Layer.
2. Placebo or Inactive or Inert Layer: The inert layer (also referred to as bottom segment) has the following formulation qualitative and quantitative composition given in Table 2 below.

TABLE-US-00004 TABLE 2 Material mg/Dose % Microcrystalline Cellulose PH-102 326.70 99.0 Magnesium Stearate 3.30 1.0 Total weight of Inert Layer 330.00 100.0

[0109] Said inert layer is manufactured by a direct blending process: [0110] (a) Weigh-off excipients; [0111] (b) Blend Microcrystalline Cellulose PH-102 along with magnesium stearate, preferably in a V-blender, for a specified time. [0112] (c) Discharge final blend. Ready for compression.
3. Tablet compression: The compression is made by using a bi-layer press machine fitted with the appropriate tooling and compress into tablets.

REFERENCES

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