Untitled record
Abstract
Controlled release multiparticulate oral solid formulation comprising 50 to 600 mg of levodopa and 10 to 80 mg of carbidopa, where the multiparticulates are in a capsule or powdered form and further comprise: a. a controlled release component comprising a1. beads or granules comprising a core of levodopa, carbidopa and a carboxylic acid, coated with one or more enteric polymers, or a2. beads or granules comprising a core of levodopa and carbidopa, coated with one or more enteric polymers, and beads or granules comprising a core of carboxylic acid coated with one or more enteric polymers, b. an immediate release component comprising a mixture of levodopa and carbidopa, where the carboxylic acid is a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid , fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid, boric acid and mixtures thereof, and where the molar ratio between carboxylic acid and levodopa is greater than 1: 4 and less than 3: 2.
Term
2.3 yearsto projected expiry
Projected expiry 26 December 2028, counted from filing; an application has no term until it is granted.
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- Filed
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8 claims: 4 independent, 4 dependent
- 1ES 2 804 348 T3 REIVINDICACIONES 1. Formulación sólida oral multiparticulada de liberación controlada que comprende 50 a 600 mg de levodopa y 10 a 80 mg de carbidopa, donde los multiparticulados están en una cápsula o en forma espolvoreada y además comprenden:a. un componente de liberación controlada que comprende a1. perlas o gránulos que comprenden un núcleo de levodopa, carbidopa y un ácido carboxílico, recubierto con uno o más polímeros entéricos, o a2. perlas o gránulos que comprenden un núcleo de levodopa y carbidopa, recubiertos con uno o más polímeros entéricos, y perlas o gránulos que comprenden un núcleo de ácido carboxílico recubierto con uno o más polímeros entéricos, b. un componente de liberación inmediata que comprende una mezcla de levodopa y carbidopa, donde el ácido carboxílico es un ácido carboxílico seleccionado del grupo consistente en ácido tartárico, ácido adípico, ácido succínico, ácido cítrico, ácido benzoico, ácido acético, ácido ascórbico, ácido edético, ácido fumárico, ácido láctico, ácido málico, ácido oleico, ácido sórbico, ácido esteárico, ácido palmítico, ácido bórico y mezclas de los mismos, y donde la relación molar entre el ácido carboxílico y la levodopa es superior a 1:4 e inferior a 3:2.
- 2Formulación sólida oral multiparticulada de liberación controlada según la reivindicación 1, donde la relación molar entre el ácido carboxílico y la levodopa es superior a 2:3 e inferior a 4:3.
- 3Formulación sólida oral multiparticulada de liberación controlada según la reivindicación 1 o 2, donde el ácido carboxílico es ácido tartárico.
- 4Formulación sólida oral multiparticulada de liberación controlada según cualquiera de las reivindicaciones 1-3, donde el núcleo de ácido carboxílico es una perla o gránulo distinta y separable de la levodopa.
- 5Formulación sólida oral multiparticulada de liberación controlada según cualquiera de las reivindicaciones 1-4,, donde el ácido carboxílico está físicamente separado de la levodopa y la carbidopa.
- 6Formulación sólida oral multiparticulada de liberación controlada según cualquiera de las reivindicaciones anteriores, para su uso para reducir las variaciones motoras de un paciente que padece la enfermedad de Parkinson o para reducir el tiempo inactivo de un paciente que padece la enfermedad de Parkinson o para aumentar el tiempo activo de un paciente que padece la enfermedad de Parkinson o para reducir el tiempo a activo de un paciente que padece la enfermedad de Parkinson o para aumentar o mantener los niveles de dopamina en un sujeto que padece una enfermedad asociada a niveles de dopamina reducidos o alterados.
- 7Formulación sólida oral multiparticulada de liberación controlada según cualquiera de las reivindicaciones 1 a 5 para su uso según la reivindicación 6, donde la enfermedad asociada a niveles de dopamina reducidos o alterados es cualquiera de síndrome de piernas inquietas, enfermedad de Alzheimer, distonía, esquizofrenia, enfermedad de Parkinson y parkinsonismo secundario, enfermedad de Huntington, trastorno de déficit de atención/hiperactividad (TDAH), síndrome de Shy-Drager y afecciones resultantes de una lesión cerebral, incluyendo intoxicación por monóxido de carbono o por manganeso.
- 8Formulación sólida oral multiparticulada de liberación controlada según cualquiera de las reivindicaciones 1 a 5 para su uso según la reivindicación 6, donde la enfermedad asociada a niveles de dopamina reducidos o alterados es la enfermedad de Parkinson.
Independent claims8
1,064 paragraphs in 41 sections, as filed
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DESCRIPTION
Controlled-release formulations of levodopa and uses thereof
FIELD OF THE INVENTION
The present invention relates to controlled release multiparticulate solid oral formulations as defined in the appended claims comprising levodopa, carbidopa and a carboxylic acid leading to improved pharmacokinetic properties. These formulations are useful for the treatment of conditions such as neurological diseases associated with reduced or altered levels of dopamine.
BACKGROUND OF THE INVENTION
Combinations of levodopa (LD) and a decarboxylase inhibitor (typically carbidopa (CD)) to treat Parkinson's disease (PD) are known in the pharmaceutical art and are considered by many to be the "gold standard" treatment for symptoms. of the EP. Currently, various formulations containing a combination of LD and CD are commercially available, for example SINEMET®, STALEVO®, PARCOPA® and ATAMET®. For example, US application 2007/0148238 describes multiparticulate compositions comprising levodopa and carbidopa. However, there remains a need for an oral formulation of LD that provides more stable plasma concentrations of LD, with minimal “peak-to-trough” fluctuations during daily dosing and that facilitates a longer duration of effect than currently available oral dosage forms. of CD / lD.
Patients with PD often have periods when their mobility becomes difficult, often resulting in an inability to move. Abnormally low levels of dopamine, a neurotransmitter that affects mobility and control of the musculoskeletal system, are commonly believed to be the cause of these motor symptoms in PD patients. However, the administration of dopamine is not effective in treating Parkinson's disease, since dopamine does not cross the blood-brain barrier. To solve this problem, PD patients are given levodopa, the metabolic precursor to dopamine, but levodopa is not without its problems either.
While levodopa crosses the blood-brain barrier and is rapidly converted to dopamine, LD is problematic due to its rapid decarboxylation by tissues other than the brain. Therefore, when LD is administered alone, large doses are required, since only a small part is transported to the brain unchanged. Furthermore, when levodopa is administered orally, it is rapidly decarboxylated to dopamine in extracerebral tissues, so that only a small part of a given dose is transported unchanged to the central nervous system. Carbidopa inhibits the decarboxylation of peripheral levodopa and does not cross the blood-brain barrier. Since its decarboxylase inhibitory activity is limited to extra-brain tissues, administration of carbidopa with levodopa has been popular to make levodopa more available for transport to the brain.
In addition to these difficulties associated with the absorption of LD, over time patients treated with LD also present symptoms of wasting. PD patients treated with LD can develop motor fluctuations characterized by dose-associated failure, peak-dose dyskinesia, and akinesia. The advanced form of motor fluctuations (also commonly known as the "on / off" phenomenon) is characterized by unpredictable changes ranging from mobility to immobility. Although the causes of these motor fluctuations are not fully understood, in some patients they may be attenuated by treatment regimens that produce constant plasma levels of LD. Therefore, a gap remains in the LD treatment of PD patients, as plasma concentration levels remain difficult to control.
Currently available controlled release formulations of CD / LD are intended to allow continuous release of the drug over an extended period of time in an attempt to maintain narrow plasma levels of LD. However, the use of these controlled release dosage forms is problematic as many PD patients wake up in the morning with little or no mobility due to depletion of the dose taken the previous day / evening. Once the previous dose has worn off, these patients are generally unwilling or even unable to wait for the extended period of time required for a controlled release dosage form to deliver the necessary plasma levels of LD. While the use of an immediate release LD formulation may reduce this waiting time, the use of an immediate release LD formulation requires more frequent dosing and is associated with more fluctuating plasma LD concentrations. DUODOPA<sup>®</sup>, an infusion therapy
ES 2 804 348 T3 intraduodenal approved outside the United States, demonstrates a significant reduction in motor complications and “off” time. Accumulated experiences with DUODOPA® and experimental infusion studies demonstrate that maintaining stable plasma concentrations of LD and avoiding low trough levels appear to be effective in reducing turn-off time ”, increasing turn-on time without deactivating dyskinesia, and reducing the severity of dyskinesia compared to standard oral formulations. However, such infusion therapies are extremely inconvenient for the patient.
The results of infusion therapies, such as DUODOPA<sup>®</sup>, strongly suggest a rationale for developing a LD treatment that provides constant or relatively constant plasma LD concentrations in order to optimize the relief of PD symptoms and minimize “off” times and dyskinesias. In fact, there is still a need for a more convenient dosage form, that is, oral, that improves the administration of LD to PD patients by reducing LD levels in the blood plasma, which in turn will result in times reduced shutdown times, long start-up times and shorter wait times until start-up. The present invention fills this gap by providing a novel controlled release LD oral solid dosage form that is formulated with a decarboxylase inhibitor and an acid, to provide the desired pharmacokinetic properties, i.e., more consistent plasma concentrations of LD over a period of time. extended period of time.
SUMMARY OF THE INVENTION
The present invention provides a controlled release multiparticulate solid oral formulation comprising 50 to 600 mg of levodopa and 10 to 80 mg of carbidopa, where the multiparticulates are in a capsule or in a powdered form and further comprising:
to. a controlled release component comprising a1. Beads or granules comprising a core of levodopa, carbidopa and a carboxylic acid, coated with one or more enteric polymers, or a2. Beads or granules comprising a core of levodopa and carbidopa coated with one or more enteric polymers and beads or granules comprising a carboxylic acid core coated with one or more enteric polymers
b. an immediate release component comprising a mixture of levodopa and carbidopa, where the carboxylic acid is a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid , fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid, boric acid and mixtures thereof, and where the mole ratio of carboxylic acid: levodopa is greater than 1: 4 and less than 3: 2.
Furthermore, the invention provides the controlled release multiparticulate oral solid formulation according to the appended claims for use in reducing motor fluctuations in a patient suffering from Parkinson's disease, reducing the "off" time in a patient suffering from Parkinson's disease, increasing the "on" time in a patient suffering from Parkinson's disease, reducing the waiting time in a patient suffering from Parkinson's disease and, on the other hand, increasing dopamine levels in a subject suffering from a disease associated with reduced or altered dopamine levels.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1: Graph showing that IPX066 formulations provide an infusion-like plasma profile for more than approximately six hours
Figure 2: Graph illustrating in vivo plasma concentration profiles for IPX066-B-05-07 formulations A, B and C compared to a reference (Sinemet®), as described in Example 1, infra.
Figure 3: Graph illustrating the in vivo plasma concentration profiles for formulations A, B, D and E of IPX066-B-06-02 compared to a reference (Sinemet®), as described in Example 2, infra .
Figure 4: graph illustrating in vivo plasma concentration profiles for IPX066-B-07-01 formulations A, B and C compared to a reference (Sinemet®), as described in Example 3, infra.
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Figure 5: graph illustrating in vivo plasma concentration profiles for IPX066 formulations.
Figure 6: table showing the robust and low intra-subject variability of the IPX066 formulations compared to Sinemet® CR.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to controlled release multiparticulate formulations as defined in the claims, the formulations comprising carbidopa and a carboxylic acid as defined in the claims, which are useful for the treatment of diseases or neurological conditions associated with reduced or altered dopamine. The pharmaceutical formulations of the invention provide more stable, or more constant, plasma LD concentrations in patients, resulting in decreased motor fluctuations, shorter off time, and longer on time in PD patients.
Definitions
All scientific and technical terms used in this application have the meanings commonly used in the art, unless otherwise specified. As used in this application, the following words or phrases have the specified meanings.
The term acid refers to a chemical compound that, when dissolved in water, gives a solution with a pH less than 7. The acid can be organic. You can have a pKa in the range of, for example, 2-5. Examples of acids suitable for the invention include, but are not limited to, tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, acid sorbic, stearic acid, palmitic acid and boric acid or mixtures thereof.
The term "effective amount" means an amount of the compound / composition according to the present invention effective to produce the desired therapeutic effect.
A lozenge or pill comprises a pharmaceutical formulation pressed into a shape. The shape can be any shape, for example round, oblong, triangular or other shapes.
A capsule comprises a pharmaceutical formulation in which the pharmaceutical formulation is enclosed in a hard or soft soluble container. The container can be in the form of gelatin or other material.
The term modified release (also known as MR) includes delayed release (also known as DR) and controlled release (also known as CR, sustained release (SR), prolonged release (PR), or extended release (ER)).
The term delayed release (also known as DR) refers to a pharmaceutical formulation or component that releases the active ingredients after a delay period.
The term controlled release (also known as CR) refers to a pharmaceutical formulation or a component thereof that releases, or delivers, one or more pharmaceutical agents over an extended period of time, in this case over a period of more than one time.
The term immediate release (also known as instant release or IR) refers to a pharmaceutical formulation or a component thereof that releases, or delivers, one or more pharmaceutical agents essentially immediately after administration and results in essentially complete dissolution. in about an hour (or less).
The terms release excipient or rate control excipient can be used interchangeably. Release excipients or rate-controlling excipients include all excipients and / or polymers that control the release of one or more pharmaceutical agents, for example LD, CD, and in this case an acid, after administration to a subject. Examples of release excipients or rate controlling excipients include, but are not limited to, hypromellose, hydroxypropyl cellulose, ethyl cellulose, and 2-propenoic acid. Delayed-release polymers, as a subset of release excipients or rate-controlling excipients, are used to delay the release of one or more pharmaceutical agents after administration to a subject. Examples of delayed release polymers include, but are not limited to, enteric polymers and / or neutral methacrylic polymers such as Eudragit® L100-55, Eudragit® S100 or Eudragit® FS30D (Rohm).
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The USP paddle method refers to the paddle and basket method as described in the United States Pharmacopeia, Edition XXII (1990).
The term peak-to-trough ratio refers to a comparison of the values for a maximum plasma level of active agent (for example, a high point on a line graph) and a minimum level (for example, a low point on a line graph). lines) for a set period of time. For example, in a line graph with plasma LD values varying from 400 ng / ml (peak) compared to 200 ng / ml (minimum) over a four hour period, a peak-to-minimum ratio of 2 is given for that time. More than one peak-to-valley relationship can be illustrated on a graph.
The term approximately when used in relation to percentages means ± 1%.
The mean plasma concentration of a substance (eg LD or CD) as used herein refers to the mean concentration of the substance found in multiple plasma samples. The mean plasma concentration is obtained by adding the concentrations of the substance found in the plasma samples and then dividing the sum by the number of plasma samples.
The upper small intestine refers to the portion closest to the stomach and includes the duodenum and jejunum.
The term "outer layer" refers to a coating or barrier applied to a pharmaceutical formulation or a component thereof and can be an enteric layer.
Diseases associated with reduced or altered dopamine levels include neurological or movement disorders such as restless leg syndrome, Alzheimer's disease, dystonia, schizophrenia, Parkinson's disease and secondary parkinsonism, Huntington's disease, attention deficit / hyperactivity disorder (ADHD), Shy-Drager syndrome, and conditions resulting from brain injury, including carbon monoxide or manganese poisoning.
The term treating a disease associated with reduced or altered dopamine levels means controlling a disease with the pharmaceutical formulation of the invention. Treatment can lessen the symptoms of a disease, reduce the severity of a disease, alter the course of disease progression, ameliorate and / or cure a disease associated with neurological or movement disorders associated with reduced or altered levels of dopamine.
COMPOSITIONS OF THE INVENTION
A significant aspect of the invention relates to the unexpected discovery of the effect of carboxylic acid in controlling the absorption of LD, such that the resulting formulations produce more "adjusted", ie, more stable, plasma LD concentrations.
The present invention provides a controlled release multiparticulate solid oral formulation comprising 50 to 600 mg of levodopa and 10 to 80 mg of carbidopa, where the multiparticulates are in a capsule or in a powdered form and further comprising:
to. a controlled release component comprising a1. Beads or granules comprising a core of levodopa, carbidopa and a carboxylic acid, coated with one or more enteric polymers, or a2. Beads or granules comprising a core of levodopa and carbidopa coated with one or more enteric polymers and beads or granules comprising a core of carboxylic acid coated with one or more enteric polymers,
b. an immediate release component comprising a mixture of levodopa and carbidopa, where the carboxylic acid is a carboxylic acid selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid , fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid, boric acid and mixtures thereof, and where the mole ratio of carboxylic acid: levodopa is greater than 1: 4 and less than 3: 2. Pharmaceutical formulations can include a single acid or a mixture of acids.
The formulation is a multiparticulate formulation. In one embodiment of the invention, the multiparticulates are encapsulated. Alternatively, the multiparticulates can be in a dusted form that can be sprinkled directly on food or liquids for easy ingestion.
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In one embodiment of the invention, the formulation reduces intra-subject variability in levodopa absorption. Intra-subject variability can be calculated as the standard deviation of the levodopa concentration divided by the mean levodopa concentration determined in the range of about 0.5 hours after administration to about six hours after administration for a single dose of the formulation to an individual subject who, on average over at least 12 subjects, is less than or equal to about 0.40.
The multiparticulate oral solid controlled release formulation of the invention comprises 50 to 600 mg of levodopa and 10 to 80 mg of carbidopa.
In the multiparticulate oral solid controlled release formulation of the invention, the ratio of the moles of dicarboxylic acid to levodopa is greater than 1: 4 and less than 3: 2. In one embodiment, the ratio of the moles of dicarboxylic acid to levodopa is greater than 1: 2 and less than 4: 3. In yet another embodiment, the ratio of the moles of dicarboxylic acid to levodopa is greater than 2: 3 and less than 5: 4. In a further embodiment, the ratio of the moles of dicarboxylic acid to levodopa is greater than 1: 1 and less than 4: 3.
The multiparticulate oral solid controlled release formulation of the invention can reduce the within-subject variability of levodopa absorption. In accordance with the practice of the invention, the controlled release component may be a separate component (eg separate from the carboxylic acid and immediate release components). In one embodiment of the invention, the carboxylic acid component is a separate component (eg separate from the controlled release and immediate release components). In yet another embodiment, the immediate release component is a separate component (eg separate from the controlled release components and the carboxylic acid). In yet another embodiment of the invention, the controlled release component, the immediate release component, and the carboxylic acid component are each manufactured as separate and separate beads.
The controlled release multiparticulate oral solid formulation of the invention may further comprise one or more controlled release carboxylic acid components comprising a carboxylic acid and a rate control excipient, wherein the carboxylic acid is selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acetic acid, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof. In a particular embodiment, the carboxylic acid is tartaric acid. In addition, the controlled release carboxylic acid components may comprise a carboxylic acid core coated with one or more enteric polymers, where the carboxylic acid is selected from the group consisting of tartaric acid, adipic acid, succinic acid, citric acid, benzoic acid, acid acetic, ascorbic acid, edetic acid, fumaric acid, lactic acid, malic acid, oleic acid, sorbic acid, stearic acid, palmitic acid and boric acid or mixtures thereof. In a particular embodiment, the controlled release multiparticulate oral solid formulation has at least two controlled release carboxylic acid components that release the carboxylic acid at different rates.
In accordance with the practice of the invention, the excipient that controls the rate of the controlled release multiparticulate oral solid formulation may be an enteric polymer or a mixture of more than one type of enteric polymer. In one embodiment, the rate controlling excipient is a neutral methacrylic polymer.
In one embodiment of the controlled release multiparticulate oral solid formulation of the invention, the controlled release component comprises a core of levodopa and carbodopa coated with one or more polymers and and beads or granules comprising a carboxylic acid core coated with one or more enteric polymers.
The controlled release multiparticulate oral solid formulation provides an embodiment where carbidopa and levodopa are present in a ratio of from about 1: 1 to about 1:10. In one embodiment, the carbidopa: levodopa ratio is 1: 4.
The controlled release multiparticulate oral solid formulation of the invention is characterized by a carboxylic acid: levodopa mole ratio greater than 1: 4 and less than 3: 2. In another embodiment, the controlled release multiparticulate oral solid formulation has a carboxylic acid: levodopa mole ratio of greater than 1: 2 and less than 4: 3. In yet another embodiment, the controlled release multiparticulate oral solid formulation has a carboxylic acid: levodopa mole ratio of greater than 2: 3 and less than 4: 3. In a further embodiment, the controlled release multiparticulate oral solid formulation has a dicarboxylic acid: levodopa mole ratio of greater than 1: 1 and less than 4: 3.
The multiparticulate oral solid controlled release formulation of the invention comprises 50 to 600 mg of levodopa.
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The multiparticulate oral solid controlled release formulation of the invention comprises from 10 mg to 80 mg of carbidopa.
The pharmaceutical formulations of the invention may further comprise excipients, including, but not limited to, surfactants (ionic and nonionic), lipophilic carriers, and hydrophilic carriers.
In accordance with the practice of the invention, examples of excipients that control rate include, but are not limited to, hydroxypropyl cellulose, hypromellose, ethyl cellulose, and 2-propenoic acid. A suitable example of a 2-propenoic acid is Carbopol® (Noveon or Dow Chemical Co.). Examples of delayed release polymers include a neutral methacrylic polymer such as Eudragit® FS30D, Eudragit® S100, Eudragit® L10055 and / or any mixture or combination thereof (Rohm). Eudragit® L100-55 is an enteric polymer that can be used in coated dosage forms to direct drug release in the upper small intestine, where the pH is greater than 5.5. Eudragit® S100 can be used to achieve targeted drug delivery in the small intestine lower than the colon, where the pH is greater than 7. The modified release components of the formulations of this invention can be formulated with any and / or a mixture of the foregoing polymers to achieve the desired plasma LD concentration profiles. The choice of polymers that can be used in the invention includes, but is not limited to, Eudragit®, phthalate-cellulose acetate, phthalate-polyvinyl acetate, hydroxypropylmethylcellulose phthalate, succinate-hydroxypropylmethylcellulose acetate LF, succinate-acetate of hydroxypropylmethylcellulose HF and others.
The pharmaceutical formulations of the invention may further comprise other excipients commonly known and used by those skilled in the art, including a plasticizing agent (for example triethyl citrate), a lubricant (such as talc and magnesium stearate) and a disintegrant (such as such as croscarmellose sodium and crospovidone), or any combination thereof.
The invention provides a multiparticulate oral solid controlled release levodopa formulation as defined in the claims having or exhibiting a plasma or serum concentration profile of levodopa, said profile comprising an administration time, a first concentration and a second concentration.
In accordance with the practice of the invention, the first concentration can be equal to the maximum concentration in plasma or serum of levodopa of the profile, the second concentration can be the minimum concentration that occurs at a time after said first concentration and before or approximately six hours after the administration time. The second concentration can be greater than or equal to about fifty percent of said first concentration.
In one embodiment of the formulation, the levodopa plasma or serum concentration profile is a median levodopa plasma or serum concentration profile. In another embodiment, the levodopa concentration profile is the mean plasma or serum concentration profile of levodopa.
In a further embodiment, the levodopa plasma or serum concentration profile further comprises a third concentration. The levodopa profile at this third concentration can be greater than or equal to fifty percent of the first concentration. Furthermore, the third concentration can occur a time before said first concentration and within approximately ninety minutes of the administration time. In a specific embodiment, the levodopa in the third concentration can be greater than or equal to sixty percent of the first concentration and the second concentration can be greater than or equal to sixty percent of the first concentration.
In accordance with the practice of the invention, the second concentration may be the minimum concentration that occurs between one hour after said administration time and the second time. In one embodiment, the first concentration is between 825 and 1505 ng / ml for a 380 mg dose of levodopa.
The levodopa plasma or serum concentration profile can have a relationship between the mean AUC, which is measured in units of ng h / ml, and the mass of levodopa in the formulation, where this mass is measured in mg, between 11: 1 and 25: 1. In one embodiment, the ratio is between 14: 1 and 19: 1. Furthermore, the concentration profile in plasma or serum of levodopa may have a relationship between the mean AUC, which is measured in units of ng h / ml, and said first concentration, where said concentration is measured in units of ng / ml, from between 9: 2 and 6: 1.
The plasma or serum concentration profile of levodopa can have a mean AUC of between 4,330 and 8,000 ng h / ml for a 380 mg dose of levodopa. In one embodiment, the mean AUC is between 5,000 and 7,000 ng hr / ml for a 380 mg dose of levodopa.
The concentration profile in plasma or serum of levodopa can have a relationship between the first concentration, which is measured in units ng / ml, and the mass of levodopa in the formulation, where said mass is
ES 2 804 348 T3 measures in mg, between 3: 1 and 5: 1. In one embodiment, the ratio is between 5: 2 and 7: 2. In another embodiment, the ratio is greater than or equal to about 3: 1.
In one embodiment, the levodopa plasma or serum concentration profile comprises a time of administration, a first concentration at first occurring within one hour of the time of administration; a second concentration at a second moment, which occurs after said first moment; and a third concentration in a third moment, which occurs at least four hours after the second moment. The second concentration can be equal to the maximum concentration of levodopa in the profile; the first concentration can be equal to about fifty percent of the second concentration; said third concentration may be equal to approximately fifty percent of the second concentration.
In another embodiment, the controlled release multiparticulate oral solid formulation has a serum or plasma concentration profile of levodopa essentially the same as the IPX066 levodopa formulation of Figure 1 for a 380 mg dose of levodopa, or has a concentration profile in plasma or serum of levodopa essentially proportional to said formulation of Figure 1 for a dose other than 380 mg.
In yet another embodiment, the oral controlled release multiparticulate solid formulation has a plasma or serum concentration profile of levodopa such that the ratio of the maximum concentration of the profile to the concentration at any time between one hour and seven hours after administration of the formulation is less than or equal to 4: 1.
In a further embodiment, the oral multiparticulate solid controlled release levodopa formulation has a median plasma or serum concentration profile of levodopa comprising: a first concentration at a first time; a second concentration at a second time, which occurs within about one hour after said first time; a third concentration at a third time, which occurs at least four hours after said second time; and a maximum concentration. The second concentration can be equal to the maximum concentration of said profile; the first concentration is equal to fifty percent of said second concentration; the third concentration is equal to fifty percent of the second concentration.
Coating the pharmaceutical formulation
The controlled release oral multiparticulate solid formulation comprises beads or granules as defined in the claims comprising a carboxylic acid, which is coated with one or more enteric polymer. The acid causes a slow and variable drug release rate. The slow and prolonged release rate of the drug may be due to interference from the dissolution of the enteric coating, affected by the presence of the acid in the core. Interference can be significantly reduced by partially neutralizing the enteric polymers in the coating, for example by adding a base (eg NH3 or NH4OH) to the coating formulation to increase the pH of the coating. The neutralization technique can be equally effective for different enteric polymers, including, but not limited to, Eudragi® L100, S100, and FS100.
METHODS OF THE INVENTION
The invention provides the controlled release multiparticulate oral solid formulation as described herein for use in reducing motor fluctuations in a patient suffering from Parkinson's disease or to reduce the "off" time of a patient suffering from Parkinson's disease. or to increase the "on" time of a patient suffering from Parkinson's disease or to reduce the activation time of a patient suffering from Parkinson's disease or to improving or maintaining dopamine levels in a subject suffering from a disease associated with reduced or altered dopamine levels.
In particular, the invention also provides the controlled release multiparticulate oral solid formulation for use in improving or maintaining dopamine levels in a subject suffering from a condition associated with reduced or altered dopamine levels, comprising administering to the subject an effective amount of a pharmaceutical formulation of the invention thus maintaining dopamine levels in the subject suffering from a condition associated with reduced or altered dopamine levels.
Improving or maintaining dopamine levels in a subject can treat the subject suffering from a condition associated with reduced or altered dopamine levels. Examples of conditions associated with reduced or altered dopamine levels include, but are not limited to, Alzheimer's disease, dystonia, schizophrenia, and Parkinson's disease.
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The invention further provides the controlled release multiparticulate oral solid formulation for use in reducing motor fluctuations in a patient suffering from Parkinson's disease, comprising administering to the patient an effective amount of any of the formulations of the invention, thus providing a concentration Effective plasma levodopa to reduce motor fluctuations in the patient. In one embodiment of the invention, the formulation is administered at six hour intervals.
In addition, the controlled release multiparticulate oral solid formulation is provided for use in reducing the downtime of a patient suffering from Parkinson's disease, comprising administering to the patient an effective amount of any of the formulations of the invention, thus providing a plasma or serum concentration of levodopa effective in reducing patient downtime.
Furthermore, the invention provides the controlled release multiparticulate oral solid formulation for use in increasing the on-time of a patient suffering from Parkinson's disease, comprising administering to the patient an effective amount of any of the formulations of the invention, thus providing a plasma or serum concentration of levodopa effective to increase the active time of the patient.
The controlled release multiparticulate oral solid formulation is also provided for use in reducing the time to ignition (eg, accelerating the efficacy of levodopa) in a patient suffering from Parkinson's disease, comprising administering to the patient an effective amount of either of the formulations of the invention, thus providing a plasma or serum concentration of levodopa effective to reduce the activation time of the patient.
Determination of the on and off time can be based on the measurement of conventional parameters such as the Uniform Parkinson's Disease Rating Scale (UPDRS) motor test, the passing time and / or the number of finger taps. For each of these parameters, the definitions of on can be based on the change from the pre-dose measurement and the results analyzed in the standard way. For example, for the number of taps measuring a change of approximately 10% from the average of the pre-dose measurements you can define the on time. For ride time, a change of about 15% can be used.
In accordance with the practice of the invention, the plasma or serum concentration of levodopa comprises: a solid oral controlled release formulation of levodopa having a plasma or serum concentration profile of levodopa comprising: an administration time; a first concentration and a second concentration. In an embodiment of the method, said first concentration is equal to the maximum concentration of said profile; said second concentration is the minimum concentration that occurs at a time after said first concentration and before or equal to approximately six hours after the administration time; and where the second concentration is greater than or equal to approximately fifty percent of said first concentration. In another embodiment, the second concentration is the minimum concentration that occurs between one hour after said administration time and said second time.
The concentration profile can be the median plasma or serum concentration profile. In addition, the concentration profile can be the mean plasma or serum concentration profile.
In one embodiment, the concentration profile further comprises a third concentration, wherein said third concentration is greater than or equal to fifty percent of said first concentration and said third concentration occurs at a time prior to said first concentration and within approximately ninety minutes of said administration time In another embodiment, the third concentration is greater than or equal to sixty percent of said first concentration and said second concentration is greater than or equal to sixty percent of said first concentration.
In accordance with the practice of the invention, the disease includes, but is not limited to, Alzheimer's disease, dystonia, schizophrenia, and Parkinson's disease.
In one embodiment, the blood plasma level does not fluctuate more than 40% between 0.5 hours after administration and six hours after administration.
ADVANTAGES OF THE INVENTION
Optimally, after administration to a patient suffering from a condition associated with reduced or altered dopamine levels, a pharmaceutical formulation of the invention releases LD into the patient's plasma at a constant or near constant level, that is, with a minimal peak-to-trough ratio of plasma LD concentration, without any significant decrease or fluctuation over a prolonged period of time, for example, emulating administration by infusion; thus reducing fluctuations
ES 2 804 348 T3 motor or the on-off effect associated with fluctuations in plasma LD levels caused by currently available oral dosage forms of CD / LD.
The pharmaceutical formulations of the invention provide a higher plasma LD profile to a patient than currently available oral pharmaceutical formulations. Formulations of the invention can provide a significantly lower plasma LD concentration peak-trough ratio (ie, reduce blood plasma LD ranges after the initial peak) with, for example, a Q6h dosage. Furthermore, some embodiments of the pharmaceutical formulations of the invention provide an improvement by increasing the plasma level of LD. The pharmaceutical formulations of the invention also provide narrow ranges of plasma LD levels, thus minimizing the "on-off effect" in some patients. The sustained and constant plasma LD profile of this invention is expected to provide superior and consistent disease control.
The following examples are presented to illustrate the present invention and to assist one of ordinary skill in the manufacture and use thereof. The examples are not intended to limit the scope of the invention in any way.
Example 1 (not according to the claimed invention): a tablet of carbidopa and levodopa with tartaric acid
The bioavailability / pharmacokinetic results of a tablet formulation of the present invention, with 50-200 mg of CD-LD with 215 mg of tartaric acid, were compared with the controlled release version of Sinemet®.
Preparation of a CD-LD tablet with tartaric acid (IPX066-B05-07)
CD, LD and hydroxypropyl were loaded into a mixer and mixed evenly. The powder mixture was then loaded into a high shear granulator and granulated with purified water. The granules were dried overnight in an oven at 60 ± 10 ° C. The dried granules were passed through a 25 mesh screen, then loaded and mixed with magnesium stearate in a mixer.
To prepare the final tartaric acid mixture, granulated tartaric acid was passed through a 20 mesh screen. Tartaric acid, microcrystalline cellulose and hypromellose were charged and mixed in a high shear mixer and granulated with ethyl alcohol. The resulting granules were dried in a fluid bed processor at 55 ± 10 ° C. The dried granules were passed through a 25 mesh screen, then loaded and mixed with magnesium stearate in a mixer.
The final mixtures of CD / LD and tartaric acid were compressed into a tablet.
Resulting effect of tartaric acid on the pharmacokinetics of carbidopalevodopa 50-200 mg formulations in human subjects
Table 1
<td>Product</td><td>Force (mg)</td><td>Dissolution in SGF</td>
<td>Pills IPX066 CD / LD with ac, tartaric</td><td> 50-200</td><td>Release for 4 hours</td>
<td>Pills IPX066 CD / LD without ac, tartaric</td><td> 50-200</td><td>Release for 6 hours</td>
<td>EPX066 CD / LD pickups with ac, tartaric</td><td> 50-200</td><td>Release for 6 hours</td>
<td>Sinemet® CR tablets<sup>to</sup></td><td> 50-200</td><td>Release for 3 hours</td>
<td colspan="3"><sup>to</sup>Merck & Co., Inc., expiration date Aug. 2007</td>
The in vitro dissolution profiles of the study drugs are listed below. Tables for IPX066-B05-07 formulations A, B and C are shown at the end of this example.
Table 2
<td>Test</td><td>Formulation</td><td colspan="6">Tartaric acid (mg)</td>
<td rowspan="3">ABC</td><td rowspan="3">Bilayer ER Bilayer</td><td colspan="6"> 215</td>
<td colspan="6"> 0</td>
<td colspan="6"> 215</td>
<td></td><td></td><td colspan="6" rowspan="2">Medication release (%); SGF, 50 rpm, USP II apparatus / lead basket</td>
<td>Test</td><td>Compound</td>
<td>TO B</td><td>CDP LDP CDP LDP</td><td> 30 16±1,8 16±1,8 13±0,6 13±0,7</td><td> 60 30±3,5 30±3,6 22±1,3 39±2,9</td><td> 120 55±6,2 54±6,3 38±2,5 13±0,7</td><td> 180 73±7,8 72±7,9 52±3,5 53±4,1</td><td> 240 86±7,5 84±7,5 64±4,3 66±5,0</td><td> 360 97±3,0 95±3,0 84±4,7 87±5,2</td>
ES 2 804 348 T3
<td>C</td><td>CDP LDP</td><td> 12±0,9 12±1,1</td><td> 39±24,6 39±5,0</td><td> 12±0,9 12±1,1</td><td> 55±6,3 55±6,7</td><td> 68±6,7 68±7,2</td><td> 86±5,3 87±5,9</td>
Results and discussion: Figure 2 shows a graph illustrating the in vivo plasma concentration profiles of three formulations of CD, LD with tartaric acid (here called IPX066-B05 -07 formulations A, B and C) compared to Sinemet® after of oral administration.
Pharmacokinetics of IPX066 Test B and Sinemet® CR
Following administration of an IPX066 tablet from Test B, multiple peaks appeared in the LD plasma profiles, with a maximum plasma concentration (Cmax) approximately 2.5 hours post-dose (Figure 2). In contrast, DC was absorbed slowly, with a median Cmax approximately 4 hours post-dose. Due to the extended dissolution rate, the IPX066 of Test B with a dissolution rate of 6 hours compared to the reference CR Sinemet® with a dissolution rate of 3 hours decreased by 46% in Cmax and 44% in AUC of LD and 38% of Cmax and 41% in AUC of CD.
Pharmacokinetics of IPX066 Test C and IPX066 Test B
Following administration of an IPX066 Test C tablet, multiple peaks also appeared in LD plasma profiles, with a Cmax approximately 3 hours post-dose (Figure 2). In contrast, DC was absorbed slowly, with a median Cmax occurring approximately 4.5 hours post-dose. Even with the extended dissolution rate, IPX066 Test C with the addition of 215 mg of tartaric acid, compared to IPX066 Test B without the addition of tartaric acid increased by 50% Cmax, 41% in AUC, 119% in C6h , and 65% in C8h of LD, and 32% of Cmax and 35% in AUC of CD
Pharmacokinetics of IPX066 Test C and IPX066 Test A
Following administration of one tablet of IPX066 Test A, multiple peaks also appeared in LD plasma profiles, with a Cmax at approximately 2 hours post-dose (Figure 2). In contrast, DC was absorbed slowly, with a median Cmax at approximately 4.5 hours post-dose. Compared to IPX066 Test A, IPX066 Test C contained the same amount of tartaric acid and yet a slower dissolution rate in 2 hours. As a result, LD Cmax, LD AUC, LD C6h, LD C8h, CD Cmax, and CD AUC were reduced by approximately 20%, 14%, 26%, 4%, 22%, and 18%, respectively.
Pharmacokinetics of IPX066 Test A and Sinemet® CR
Following administration of one tablet of IPX066 Test A, multiple peaks also appeared in plasma LD profiles, with Cmax at approximately 2 hours post-dose (Figure 2). In contrast, DC was absorbed slowly, with a median Cmax at approximately 4.5 hours post-dose. The BE evaluation showed that the IPX066 Test A with a dissolution rate of 4 hours and tartaric acid included in the formulation is bioequivalent to the reference CR of Sinemet®, with a dissolution rate of 3 hours with respect to the values of Cmax and AUC for LD and CD. Furthermore, the LD C6h and C8h of the IPX066 Test A were lower than those of the reference Sinemet® CR by approximately 25% and 4%, respectively.
These data demonstrated that decreasing the dissolution rate decreases the LD and CD exposure, and the addition of tartaric acid increases the Cmax and AUC of LD and CD.
IPX066-B05-07 Formulation A
<td>Ingredients</td><td colspan="2">Per pill</td>
<td></td><td>% (in weigh)</td><td>Mg</td>
<td>Carbidopa</td><td> 16,8</td><td> 54,0</td>
<td>Levodopa</td><td> 25,47</td><td> 200,0</td>
<td>Hydroxypropylcellulose (Klucel-LF)</td><td> 12,63</td><td> 99,2</td>
<td>Tartaric acid</td><td> 27,38</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 21,63</td><td> 169,8</td>
<td>Hypromellose (Methocel K100LV)</td><td> 5,48</td><td> 43,0</td>
<td>This magnesium ratio</td><td> 0,53</td><td> 4,2</td>
<td>Total</td><td> 100</td><td> 785,2</td>
<td colspan="3">Note. 53.09 mg CD, USP is equivalent to 50.0 mg CD anhydride</td>
ES 2 804 348 T3
IPX066-B05-07 Formulation B
<td>Ingredients</td><td colspan="2">Per pill</td>
<td></td><td>% (in weigh)</td><td>mg</td>
<td>Carbidopa</td><td> 16,8</td><td> 54,08</td>
<td>Levodopa</td><td> 62,20</td><td> 200,0</td>
<td>Hydroxypropyl cellulose</td><td> 20,0</td><td> 64,3</td>
<td>Hypromellose (Methocel K100LV)</td><td> 5,48</td><td> 43,0</td>
<td>Magnesium stearate</td><td> 1,0</td><td> 3,2</td>
<td>Purified water</td><td> -</td><td> -</td>
<td>Total</td><td> 100</td><td> 321,5</td>
IPX066-B05-07 Formulation C
<td>Ingredients</td><td colspan="2">Per pill</td>
<td></td><td>% (in weigh)</td><td>ng</td>
<td>Carbidopa</td><td> 6,30</td><td> 54,0</td>
<td>Levodopa</td><td> 23,34</td><td> 200,0</td>
<td>Hydroxypropylcellulose (Klucel-LF)</td><td> 19,94</td><td> 170,9</td>
<td>Tartaric acid</td><td> 25,09</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 17,82</td><td> 152,7</td>
<td>Hypromellose (Methocel K100LV)</td><td> 7,03</td><td> 60,2</td>
<td>Magnesium stearate</td><td> 0,48</td><td> 4,1</td>
<td>Total</td><td> 100</td><td> 856,9</td>
<td colspan="3">Note. 53.09 mg CD, USP is equivalent to 50.0 mg CD anhydride</td>
Example 2 (not according to the claimed invention):
Preparation of formulations A and B of IPX066-B06-02
The following steps were performed to prepare enteric coated granules containing CD and LD.
CD, LD, and microcrystalline cellulose (Avicel PH-101) were loaded and mixed evenly. The powder mixture was loaded into a high shear granulator and granulated with purified water. The granulated wet mass was extruded in an extruder with a nozzle size of 1.0 mm. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm crossover disc. The CD / LD granules were dried at 60 ± 10 ° C in a fluid bed processor. The CD / LD tablets were passed through sieves of different sizes. The collected pellets were retained on 18 and 25 mesh meshes.
The following steps were performed to prepare the enteric coating solution for the CDLD granules.
For formulation IPX066-B06-02 A, Eudragit® S100 and Eudragit® L100 (in a 2: 1 weight ratio) and triethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. Talc was dispersed into the polymer solution and mixed continuously throughout the coating process.
For formulation IPX066-B06-02 B, Eudragit® S100 and triethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. Talc was dispersed into the polymer solution and mixed continuously throughout the coating process.
For both formulations, the CD / LD granules were spray coated using the coating dispersion prepared on a Glatt GPCG-I. The coated pellets were dried. The dried and coated CD / LD granules were sieved through a 16 mesh mesh. The selected CD / LD granules were loaded and mixed with talc in a mixer.
The following steps were performed to prepare enteric coated granules containing tartaric acid (TA).
The TA was screened from a 20 mesh mesh. The selected TA and microcrystalline cellulose (Avicel PH101) were loaded into a high shear mixer and granulated with purified water. The granules were extruded in an extruder with a nozzle size of 1.0 mm. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm disk. The seeds were dried overnight in an oven at 60 ± 10
ES 2 804 348 T3 ° C. The dried granules were passed through 16, 18 and 25 mesh meshes. The retained granules were collected 18 and 25 mesh mesh. A sealant coating solution was prepared by charging hypromellose (Pharmacoat 606) and ethylcellulose in an alcoholic solution. The mixture was mixed until dissolved. The dried TA granules were loaded into a coater and spray coated with the prepared sealer coating solution. The coated CD / LD granules were dried and passed through a 14 mesh mesh.
The following steps were performed to prepare the enteric coating solution for the TA granules.
For formulation IPX066-B06-02 A, Eudragit® S100 and Eudragit® L100 (in a 2: 1 weight ratio) and ethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. The talc was dispersed in the polymer solution and mixed continuously throughout the coating process.
For formulation IPX066-B06-02 B, Eudragit® S100 and triethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. The talc was dispersed in the polymer solution and mixed continuously throughout the coating process.
For both formulations, the sealed coated TA granules were loaded into a Glatt GPCGI coater and spray coated with the prepared enteric coating solution. The coated TA granules were dried. The dried, coated TA granules were passed through a 12 mesh screen. The coated TA granules were charged and mixed with talc in a mixer. The following steps were performed to encapsulate the enteric coated drug granules and the enteric coated TA granules.
The coated CD / LD granules prepared as described above and the coated TA granules prepared as described above were encapsulated in hard gelatin capsules. The filled capsules contained 50 mg of carbidopa anhydride, 200 mg of LD and 215 mg of TA.
Preparation of IPX066-B06-02 Formulations D and E
The following steps were performed to prepare the final mixture of carbidopa (CD) and levodopa (LD).
CD, LD, microcrystalline cellulose and croscarmellose sodium were loaded into a mixer and mixed evenly into a powder. Cornstarch was dispersed in purified water and stirred for 15 minutes, transferred to boiling water and continuously stirred until it became a starch paste. The spray rate of the peristaltic pump was verified using the starch paste. The powder mixture prepared above was loaded into a high shear granulator and granulated with starch paste at a flow rate of 50 ~ 1000g / min. The granules were dried in an oven at 60 ± 10 ° C until the LOD was less than 3.0%. The dried granules were passed through a 25 mesh screen. The selected CD / LD granules, crospovidone and magnesium stearate were loaded and mixed in a mixer.
To prepare the final TA mix, granulated TA was passed through a 20 mesh screen. The TA and microcrystalline cellulose were charged and mixed in a high shear mixer and granulated with purified water. The resulting granules were dried in an oven at 60 ± 10 ° C until the LOD measured with a moisture analyzer was less than 2.0%. The dried granules were passed through a Fitzmill equipped with a 24 mesh screen. The dry TA granules and magnesium stearate were charged and mixed in a mixer.
The final blends were compressed into core tablets as follows. The final CD / LD mixture and the final TA mixture were weighed, mixed and compressed into a tablet. The tablet contained 50 mg of carbidopa anhydride, 200 mg of LD and 215 mg of TA.
A sealing layer was applied to the core tablet by spray coating it with hypromellose dissolved in the mixture of isopropyl alcohol and a purified water solution in a Pan Coater. The tablets were dried on a coating tray at 60 ± 10 ° C until the LOD was less than 3.0%.
The enteric coating solution was prepared as follows.
For IPX066-B06-02 Formulation D, Eudragit® S100 and Eudragit® L100 (in a 0.25: 1 weight ratio) and triethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. Talc was dispersed into the polymer solution and mixed continuously throughout the coating process.
ES 2 804 348 T3
For formulation IPX066-B06-02 E, Eudragit® S100 and triethyl citrate were dissolved in isopropyl alcohol and acetone solution. The mixture was mixed until dissolved. The talc was dispersed in the polymer solution and mixed continuously throughout the coating process.
The sealed coated tablet was loaded into a Pan Coater and spray coated with the prepared enteric coating solution. The coated tablet was dried on the coating pan at 40 ± 10 ° C for at least 30 minutes.
Resulting Effect of Tartaric Acid and Enteric Coating pH on the Pharmacokinetics of Formulations of 50-200 mg Carbidopa-Levodopa in Human Subjects
This study shows the effect of the addition of acid and various pH's of the enteric coating in the 50-200 mg carbidopa (CD) / levodopa (LD) formulation on the PK of CD and LD.
Table 3
<td>Product</td><td>Force (mg)</td><td>enteric coating pH</td>
<td>Capsules IPX066 CD / LD with ac, tartaric</td><td> 50-200</td><td> 6,5</td>
<td>Capsules IPX066 CD / LD with ac, tartaric</td><td> 50-200</td><td> 7,0</td>
<td>Sinemet® CR tablets<sup>to</sup></td><td> 50-200</td><td>N / A</td>
<td>EPX066 CD / LD pickups with ac, tartaric</td><td> 50-200</td><td> 6,5</td>
<td>EPX066 CD / LD pickups with ac, tartaric</td><td> 50-200</td><td> 6,0</td>
<td colspan="3"><sup>to</sup>Merck & Co., Inc., expiration date Aug. 2007</td>
The formulation information for the study drugs is listed below. The formulation tables for IPX066-B06-02 A, B, D and E are shown at the end of this example.
Table 4
<td>Test</td><td>Formulation</td><td>Particle size (pm)</td><td>Tartaric acid (mg)</td>
<td>TO</td><td>Capsule</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
<td>B</td><td>Capsule</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
<td>D</td><td>Tablet</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td></td>
<td>AND</td><td>Tablet</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
Results and discussion: Figure 3 shows a graph illustrating the in vivo plasma concentration profiles of four formulations of CD, LD and TA (here referred to as IPX066-B06-02 formulations A, B, D and E) compared to Sinemet® after oral administration.
Pharmacokinetics of IPX066 Test A and Sinemet® CR
After administration of one capsule of IPX066 Test A, a peak appeared in the median plasma LD profiles, with a maximum plasma concentration (Cmax) at approximately 5.0 hours post-dose (Figure 3). In contrast, CD was absorbed slowly, with a median Cmax at approximately 6.0 hours post-dose. Due to the delayed dissolution rate (enteric-coated pH = 6.5), no LD concentration was observed before 1 hour for IPX066 Test A and the LD concentration with IPX066 Test A between 5 and 8 hours was higher than that of the Sinemet® reference CR based on the median profile, suggesting that the addition of TA (215 mg) increases the absorption of LD in the posterior part of the intestine. The AUC of LD for IPX066 Test A was only 58% of the reference Sinemet® CR.
Pharmacokinetics of IPX066 Test B and Sinemet® CR
After administration of one capsule of IPX066 Test B, a peak also appeared in the mean plasma LD profiles, with a delayed and lower Cmax at approximately 4.0 hours post-dose (Figure 3). In contrast, DC was absorbed slowly, with a median Cmax at approximately 4.75 hours post-dose. No LD concentration was observed before 2 h for IPX066 Test B. Even with the addition of TA (215 mg), IPX066 Test B did not have a higher lD concentration between 5 and 8 hours compared to Sinemet® CR. This could be because the dissolution rate of TA is slower than that of LD. The AUC of LD for IPX066 Test B was only 23% of that of the Sinemet® CR reference.
ES 2 804 348 T3
Pharmacokinetics of IPX066 Test D and Sinemet® CR
After administration of an IPX066 Test D tablet, a peak also appeared in the median plasma LD profiles, with a slower and lower Cmax at approximately 4.25 hours post-dose (Figure 3). In contrast, CD was absorbed slowly, with a median Cmax at approximately 6.0 hours post-dose. No LD concentration was observed before 2 h for IPX066 Test D. Even with the addition of TA (215 mg), the AUC of LD of IPX066 Test D was only 24% of the concentration of the reference Sinemet® CR and the concentration of LD between 5 and 8 h was lower than that of Sinemet® CR. This is due to the highly variable in vitro dissolution profile and faster release rate of TA compared to LD.
Pharmacokinetics of IPX066 Test E and Sinemet® CR
After administration of one tablet of IPX066 Test E, a peak also appeared in the median plasma LD profiles, with a slower and lower Cmax at approximately 4.0 hours after the dose (Figure 3). In contrast, DC was absorbed slowly, with a median Cmax at approximately 5.0 hours post-dose. No LD concentration was observed before 2 hours for IPX066 Test E. Even with the addition of tartaric acid (215 mg), the AUC LD of IPX066 Test E was only 20% of that of the Sinemet® reference CR and the LD concentration between 5 and 8 h was lower than that of Sinemet® CR. This is also due to the highly variable in vitro dissolution profile and faster release rate of TA compared to LD.
These data demonstrated that the delayed dissolution rate decreases the exposure of LD and CD, and the addition of TA, which has a dissolution rate similar to LD and CD, has a higher concentration of LD between 5 and 8 hours compared to Sinemet. ® CR.
IPX066-B06-02 Formulation A
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 14,06</td><td> 53,98</td>
<td>Levodopa</td><td> 52,10</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 28,36</td><td> 108,85</td>
<td>Eudragit® L100</td><td> 1,14</td><td> 4,39</td>
<td>Eudragit® S100</td><td> 2,34</td><td> 8,98</td>
<td>Triethyl acetate</td><td> 1,00</td><td> 3,82</td>
<td>talcum powder</td><td> 1,00</td><td> 3,83</td>
<td>Total</td><td> 100,0</td><td> 383,85</td>
<td></td><td></td><td></td>
<td>Tartaric acid</td><td> 57,6</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 14,4</td><td> 53,8</td>
<td>Ethylcellulose</td><td> 6,6</td><td> 24,8</td>
<td>Hypromellose, type 2910</td><td> 1,4</td><td> 5,1</td>
<td>Eudragit® L100</td><td> 4,6</td><td> 17,2</td>
<td>Eudragit® S100</td><td> 9,4</td><td> 35,1</td>
<td>Triethyl acetate</td><td> 4,0</td><td> 14,9</td>
<td>talcum powder</td><td> 2,0</td><td> 7,5</td>
<td>Total</td><td> 100,0</td><td> 373,4</td>
IPX066-B06-02 Formulation B
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 12,92</td><td> 53,98</td>
<td>Levodopa</td><td> 47,88</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 26,06</td><td> 108,85</td>
<td>Eudragit® S100</td><td> 8,85</td><td> 36,95</td>
<td>Triethyl acetate</td><td> 2,53</td><td> 10,55</td>
<td>talcum powder</td><td> 1,76</td><td> 7,37</td>
<td>Total</td><td> 100,0</td><td> 417,70</td>
<td></td><td></td><td></td>
<td>Tartaric acid</td><td> 57,6</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 14,4</td><td> 53,8</td>
<td>Ethylcellulose</td><td> 6,6</td><td> 24,8</td>
<td>Hypromellose</td><td> 1,4</td><td> 5,1</td>
ES 2 804 348 T3
<td>Eudragit® S100</td><td> 14,0</td><td> 52,3</td>
<td>Triethyl acetate</td><td> 4,0</td><td> 14,9</td>
<td>talcum powder</td><td> 2,0</td><td> 7,5</td>
<td>Total</td><td> 100,0</td><td> 373,4</td>
IPX066-B06-02 Formulation D
<td>Ingredients</td><td>% (in weigh)</td><td>(mg)</td>
<td>Carbidopa</td><td> 8,57</td><td> 53,98</td>
<td>Levodopa</td><td> 31,77</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 15,17</td><td> 95,5</td>
<td>Cornstarch</td><td> 1,43</td><td> 8,98</td>
<td>Croscarmellose sodium</td><td> 1,43</td><td> 8,98</td>
<td>Crospovidone</td><td> 0,93</td><td> 5,88</td>
<td>Magnesium stearate</td><td> 1,13</td><td> 7,11</td>
<td>Tartaric acid</td><td> 34,15</td><td> 215,0</td>
<td>Hypromellose, type 2910</td><td> 2,93</td><td> 18,42</td>
<td>Eudragit® L100</td><td> 1,40</td><td> 8,82</td>
<td>Eudragit® S100</td><td> 0,35</td><td> 2,20</td>
<td>Triethyl acetate</td><td> 0,50</td><td> 3,15</td>
<td>talcum powder</td><td> 0,25</td><td> 1,57</td>
<td>Total</td><td> 100,0</td><td> 629,59</td>
IPX066-B06-02 Formulation E
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 8,57</td><td> 53,98</td>
<td>Levodopa</td><td> 31,77</td><td> 200,0</td>
<td>Avicel PH101</td><td> 15,17</td><td> 95,5</td>
<td>Cornstarch</td><td> 1,43</td><td> 8,98</td>
<td>Croscarmellose sodium</td><td> 1,43</td><td> 8,98</td>
<td>Crospovidone</td><td> 0,93</td><td> 5,88</td>
<td>Magnesium stearate</td><td> 1,13</td><td> 7,11</td>
<td>Tartaric acid</td><td> 34,15</td><td> 215,0</td>
<td>Hypromellose, type 2910</td><td> 2,93</td><td> 18,42</td>
<td>Eudragit® L100</td><td> 1,75</td><td> 11,02</td>
<td>Triethyl acetate</td><td> 0,5</td><td> 3,15</td>
<td>talcum powder</td><td> 0,25</td><td> 1,57</td>
<td>Total</td><td> 100,0</td><td> 629,59</td>
Example 3 (not according to the claimed invention):
Preparation of formulations LPX666-B07-01 A, B and C
The following steps were performed to prepare enteric coated granules containing carbidopalevodopa (CD-Ld).
CD, LD and microcrystalline cellulose (Avicel PH-101) were mixed together. The mixture was loaded into a high shear granulator and granulated with purified water. The granulated wet mass was extruded in an extruder with a 1.0 mm die. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm cross disc. The spheres obtained from the spheronizer were dried at 60 ± 10 ° C in a Glatt GCPG-1 coater. Drying the granules on the Glatt GPCG-I eliminated discoloration of the granules and also reduced the amount of DHP degradation product. The drug loaded granules were screened with 16, 18 and 25 mesh screens and the collected granules were retained on 18 and 25 mesh screens. The core granules were then coated with aqueous hypromellose solution (Pharmacoat 606) in a Glatt GCPG-I coater. The coated granules were sieved with an 18 mesh mesh after drying on the GPCG-I.
The enteric coating solution was prepared as follows. For formulation IPX066-B07-01 A, Eudragit® S100 and Eudragit® L100 were separately dispersed in a 5: 1 weight ratio in purified water and mixed until uniform dispersion. A 1N NH4OH solution was then added dropwise to both solutions until the pH reached 5.5. The two solutions were combined and mixed thoroughly. I know
ES 2 804 348 T3 prepared a talc suspension by dispersing talc in a solution of triethyl citrate in purified water and then stirring for 1 hour. The above mixture of L100 and S100 was then combined with the talc dispersion and mixed thoroughly. The dispersion was sieved through a 140 mesh screen before starting the coating process. For Formulation B of IPX066-B07-01, the same procedure was followed as for Formulation A, except that only the Eudragit® S100 polymer was used. For formulation IPX066-B07-01 C, the same procedure was followed as for formulation A, except that only the Eudragit® FS30D polymer was used.
The hypromellose coated seeds were spray coated with the enteric coating dispersion preparation. The coated CD / LD pellets were dried in an oven. The dried cD / LD granules were passed through a 14 mesh screen. The final mix was prepared by mixing the selected CD / LD granules with talc.
The following steps were performed to prepare enteric coated granules containing TA.
TA was passed through a 20 mesh screen. The selected TA and microcrystalline cellulose (Avicel PH101) were loaded into a high shear mixer and granulated with purified water. The wet mass was extruded in an extruder with a 1.0 mm die. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm cross disc. The granules obtained were dried overnight in an oven at 60 ± 10 ° C. The dried granules were passed through 16, 18 and 25 mesh meshes and the collected granules were retained in 18 and 25 mesh meshes. The sealer coat solution was prepared by dissolving hypromellose (Pharmacoat 606) and ethylcellulose in alcoholic solution. The lock coat solution was applied to the TA granules in a Glatt GPCG-I coater. The granules were dried on a GPCGI and passed through a 14 mesh mesh.
The enteric coating solution was prepared as follows. For Formulation A of IPX066-B07-01, Eudragit® S100 and Eudragit® L100 were separately dispersed in a 5: 1 weight ratio in purified water and mixed until uniform dispersion. A 1N NH4OH solution was then added dropwise to both solutions until the pH reached 5.5. The two solutions were combined and mixed thoroughly. A talc suspension was prepared by dispersing talc in a solution of triethyl citrate in purified water and then stirred for 1 hour. The above mixture of L100 and S100 was then combined with the talc dispersion and mixed thoroughly. The dispersion was sieved through a 140 mesh screen before starting the coating process. For Formulation B of IPX066-B07-01, the same procedure was followed as for Formulation A, except that only the Eudragit® S100 polymer was used. For formulation IPX066-B07-01 C, the same procedure was followed as for formulation A, except that only the Eudragit® FS30D polymer was used. The selected tartaric acid granules were loaded onto a Glatt GPCG-I coater and spray coated with the enteric coating dispersion.
The coated seeds were oven dried. The dried coated tablets were sieved through a 14 mesh screen. The final mixture was prepared by mixing the selected granules and the talc.
The coated CD / LD granules and the coated TA granules were encapsulated in hard gelatin capsules. The filled capsules contained 50 mg of carbidopa anhydride, 200 mg of LD and 215 mg of TA.
Resulting effect of tartaric acid and enteric coating pH on the pharmacokinetics of carbidopa-levodopa 50-200 mg formulations in human subjects
Goals:
This study tested the effect of adding acid and various pH's of the enteric coating (Eudragit® S100 / L100 = 5, Eudragit® S100 and Eudragit® FS 30D) to the carbidopa (CD) / levodopa (LD) formulation of 50 -200 mg in the PK of CD and LD.
Table 5
<td>Product</td><td>Force (mg)</td><td>Enteric coating polymer</td>
<td>LPX066 CD / LD Capsules with Ac, Tartaric</td><td> 50-200</td><td>Eudragit® S100 / L100 = 5</td>
<td>Capsules IPX066 CD / LD with ac, tartaric</td><td> 50-200</td><td>Eudragit® S100</td>
<td>EPX066 CD / LD capsules with ac, tartaric</td><td> 50-200</td><td>Eudragit® FS 30D</td>
<td>Sinemet® CR tablets<sup>to</sup></td><td> 50-200</td><td>N / A</td>
<td colspan="3"><sup>to</sup>Merck & Co., Inc., expiration date 02/2009</td>
Formulation information and in vitro dissolution profiles for study drugs are listed below. The formulation tables for IPX066-B07-01 A, B and C are shown at the end of this example.
ES 2 804 348 T3
Table 6
<td>Test</td><td>Formulation</td><td>Particle size (pm)</td><td>Tartaric acid (mg)</td>
<td>TO</td><td>Capsule</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
<td>B</td><td>Capsule</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
<td>C</td><td>Capsule</td><td>D (v, 0.9) = 36.22 D (v, 0.9) = 139.48</td><td> 215</td>
Results and discussion: Figure 4 shows a graph illustrating the in vivo plasma concentration profiles of three formulations of CD, LD and TA (called Formulations IPX066-B07-01 A, B and C) compared to Sinemet® after the oral administration.
Pharmacokinetics of IPX066 Test A Sinemet® CR
After the administration of a capsule of IPX066 Test A, a peak appeared in the median plasma LD profiles, with a maximum plasma concentration (Cmax) at approximately 2.75 hours post-dose (Figure 4), and the concentration LD remained at the same level from 2.0 to 3.5 h. In contrast, DC was absorbed slowly, with a median Cmax at approximately 4.0 hours post-dose. Due to the delayed dissolution rate (enteric coating with Eudragit<sup>® </sup>S100 / L100 = 5), the LD absorption (the ascending phase of the plasma profile) of IPX066 Test A was slow compared to Sinemet® CR and the LD concentration of IPX066 Test A between 5 and 10 hours was higher than that of the of the Sinemet® Reference Cr based on the median profile, suggesting that the addition of TA (215 mg) increases LD absorption in the lower intestine. The AUC of LD for IPX066 Test A was only 87.72% of the reference Sinemet® CR.
Pharmacokinetics of IPX066 Test B and Sinemet® CR
After administration of one capsule of IPX066 Test B, a peak also appeared in the median plasma LD profiles, with a slower and lower Cmax at approximately 5.0 hours post-dose (Figure 4). In contrast, CD was absorbed slowly, with a median Cmax at approximately 4.5 hours post-dose. No LD concentration was observed before 0.75 h for IPX066 Test B. Due to the tartaric acid (215 mg) in the formulation, the IPX066 Test B also has a higher LD concentration between 5 and 8 hours compared to Sinemet® CR. However, the AUC of LD for IPX066 Test B was only 56.5% of the reference Sinemet® CR.
Pharmacokinetics of IPX066 Test C and Sinemet® CR
After administration of an IPX066 Test C tablet, only 4 subjects had a detectable LD concentration (Figure 4). This is due to the slow in vitro release profile of the central CD / LD core.
These data demonstrated that the delayed dissolution rate decreases LD and CD exposure, and the addition of TA to the LD and CD formulation has a higher LD concentration between 5 and 8 hours compared to Sinemet.<sup>®</sup> CR.
IPX066-B07-01 Formulation A
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 11,24</td><td> 53,98</td>
<td>Levodopa</td><td> 41,65</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 22,67</td><td> 108,85</td>
<td>HPMC</td><td> 3,98</td><td> 19,10</td>
<td>Eudragit® L100</td><td> 1,70</td><td> 8,17</td>
<td>Eudragit® S100</td><td> 8,51</td><td> 40,85</td>
<td>Triethyl acetate</td><td> 7,13</td><td> 34,26</td>
<td>talcum powder</td><td> 3,04</td><td> 14,58</td>
<td>Ammonia solution</td><td> 0,08</td><td> 0,38</td>
<td>Total</td><td> 100,0</td><td> 480,17</td>
<td></td><td></td><td></td>
<td>Tartaric acid</td><td> 42,27</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 10,58</td><td> 53,8</td>
<td>Ethylcellulose</td><td> 4,88</td><td> 24,8</td>
<td>HPMC</td><td> 1,00</td><td> 5,1</td>
ES 2 804 348 T3
<td>Eudragit® L100</td><td> 3,48</td><td> 17,7</td>
<td>Eudragit® S100</td><td> 17,36</td><td> 88,3</td>
<td>Triethyl acetate</td><td> 14,57</td><td> 74,1</td>
<td>talcum powder</td><td> 5,70</td><td> 29,0</td>
<td>Ammonia solution</td><td> 0,16</td><td> 0,8</td>
<td>Total</td><td> 100,0</td><td> 508,6</td>
IPX066-B07-01 Formulation B
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 12,65</td><td> 53,98</td>
<td>Levodopa</td><td> 46,87</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 25,51</td><td> 108,85</td>
<td>Hypromellose, type 2910</td><td> 4,48</td><td> 19,10</td>
<td>Eudragit® S100</td><td> 6,42</td><td> 27,38</td>
<td>Triethyl acetate</td><td> 3,21</td><td> 13,71</td>
<td>talcum powder</td><td> 0,80</td><td> 3,40</td>
<td>Ammonia solution</td><td> 0,06</td><td> 0,27</td>
<td>Total</td><td> 100,0</td><td> 426,69</td>
<td></td><td></td><td></td>
<td>Tartaric acid</td><td> 42,38</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 10,61</td><td> 53,8</td>
<td>Ethylcellulose</td><td> 4,89</td><td> 24,8</td>
<td>Hypromellose, type 2910</td><td> 1,01</td><td> 5,1</td>
<td>Eudragit® S100</td><td> 26,01</td><td> 131,95</td>
<td>Triethyl acetate</td><td> 13,01</td><td> 65,98</td>
<td>talcum powder</td><td> 1,81</td><td> 9,16</td>
<td>Ammonia solution</td><td> 0,29</td><td> 1,46</td>
<td>Total</td><td> 100,0</td><td> 507,25</td>
IPX066-B07-01 Formulation C
<td>Ingredients</td><td>% (in weigh)</td><td>Amount (mg)</td>
<td>Carbidopa</td><td> 8,57</td><td> 53,98</td>
<td>Levodopa</td><td> 31,74</td><td> 200,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 17,28</td><td> 108,85</td>
<td>Hypromellose, type 2910</td><td> 3,03</td><td> 19,10</td>
<td>Eudragit® FS 30D</td><td> 30,31</td><td> 190,97</td>
<td>Triethyl acetate</td><td> 0,91</td><td> 5,71</td>
<td>talcum powder</td><td> 8,07</td><td> 50,86</td>
<td>Ammonia solution</td><td> 0,10</td><td> 0,63</td>
<td>Total</td><td> 100,0</td><td> 630,10</td>
<td></td><td></td><td></td>
<td>Tartaric acid</td><td> 38,60</td><td> 215,0</td>
<td>Microcrystalline cellulose (Avicel PH101)</td><td> 9,66</td><td> 53,8</td>
<td>Ethylcellulose</td><td> 4,45</td><td> 24,8</td>
<td>Hypromellose, type 2910</td><td> 0,92</td><td> 5,1</td>
<td>Eudragit® FS 30D</td><td> 35,75</td><td> 199,1</td>
<td>Triethyl acetate</td><td> 1,08</td><td> 6,0</td>
<td>talcum powder</td><td> 9,44</td><td> 52,6</td>
<td>Ammonia solution</td><td> 0,11</td><td> 0,6</td>
<td>Total</td><td> 100,0</td><td> 557,0</td>
Example 4 (not according to the claimed invention):
The data in this document shows the bioavailability / pharmacokinetic results of an enteric coated CD / LD tablet formulation, using 50-200 mg of CD-LD with 0-430 mg of tartaric acid, compared to the release version. Sinemet® controlled.
Four formulations of IPX-066-AH1 were evaluated for PK parameters. Information on the study medications is shown below in Table 7.
ES 2 804 348 T3
Formulation A is a capsule containing IR beads with a fast dissolving profile.
Formulation B is a capsule containing ER CD / LD beads and ER TA beads. The ER CD / LD beads were formulated by coating the IR beads with Eudragit® polymers (S100: L100 2: 1 ratio). The ER TA beads were coated with a sealing layer and a coating of Eudragit® (ratio S100: L100 2: 1) with a dissolution profile similar to CD / LD beads.
Formulation C is a capsule containing ER CD / LD beads and ER TA beads. The ER CD / LD beads were formulated by coating the IR beads with Eudragit® polymers (S100: L100 ratio 5: 1). The ER TA beads were coated with a sealing layer and a coating of Eudragit® (S100: L100 ratio 5: 1) with a dissolution profile similar to CD / LD beads.
Formulation D is similar to Formulation B, except that the amount of TA beads is twice the amount in Formulation B.
Formulation E is the reference product, Sinemet® CR 200 mg tablets.
Table 7 IPX066-AH1 (AD)
<td colspan="2">Product</td><td>Force (mg)</td><td>enteric coating pH</td>
<td>Formulation A</td><td>EPX066 CD / LD IR Capsules</td><td> 50-200</td><td></td>
<td>Formulation B</td><td>Capsules IPX066 CD / LD with 215 mg of ac. tartaric</td><td> 50-200</td><td>6.5 (SL2)<sup>b</sup></td>
<td>Formulation C</td><td>Capsules IPX066 CD / LD with 215 mg of ac. tartaric</td><td> 50-200</td><td>6.5 (SL5)<sup>b</sup></td>
<td>Formulation D</td><td>Capsules IPX066 CD / LD with 430 mg of acid. tartaric</td><td> 50-200</td><td>6.5 (SL2)<sup>b</sup></td>
<td>Formulation E (reference)</td><td>Sinemet® CR tablets<sup>to</sup></td><td> 50-200</td><td> -</td>
<td colspan="4">“Merck & Co., Inc., expiration date Aug. 2007 <sup>b</sup>SL2: Eudragit® S100: L100 2: 1; SL5: Eudragit® S100: L100 5: 1</td>
The qualitative and quantitative compositions for these formulations are summarized below in Table 8.
Table 8 Qualitative and quantitative composition of the formulation
<td rowspan="2"></td><td colspan="4">Formulation</td>
<td>TO</td><td>B</td><td>C</td><td>D</td>
<td>Ingredients</td><td colspan="4">mg / capsule</td>
<td></td><td>Component I</td><td>Component II</td><td>Component IV</td><td>Component II</td>
<td>Carbidopa, USP</td><td> 27</td><td> 27</td><td> 27</td><td> 27</td>
<td>Levodopa, USP</td><td> 100</td><td> 100</td><td> 100</td><td> 100</td>
<td>Microcrystalline cellulose, NF (Avicel PH101)</td><td> 18,4</td><td> 18,4</td><td> 18,4</td><td> 18,4</td>
<td>Lactose, monohydrate, NF</td><td> 18,4</td><td> 18,4</td><td> 18,4</td><td> 18,4</td>
<td>Sodium starch, glycolate, NF</td><td> 9,2</td><td> 9,2</td><td> 9,2</td><td> 9,2</td>
<td>Sodium lauryl sulfate, NF</td><td> 9,2</td><td> 9,2</td><td> 9,2</td><td> 9,2</td>
<td>Povidone, USP</td><td> 1,84</td><td> 1,85</td><td> 1,85</td><td> 1,85</td>
<td>Talc, USP</td><td> 1,95</td><td> 1,95</td><td> 4,2</td><td> 1,95</td>
<td>Copolymer ac. methacrylic, type A, NF (Eudragit® L100)</td><td></td><td> 2,25</td><td> 2,15</td><td> 2,25</td>
<td>Copolymer ac. methacrylic, type B, NF (Eudragit® S100)</td><td></td><td> 4,55</td><td> 10,75</td><td> 4,55</td>
<td>Triethyl citrate, NF</td><td> -</td><td> 1,95</td><td> 9,00</td><td> 1,95</td>
<td>1N NH4OH solution</td><td> -</td><td> -</td><td> 0,1</td><td> -</td>
<td>Purified water, USP</td><td> -</td><td> -</td><td>N / A *</td><td> -</td>
<td>Acetone, NF</td><td>N / A *</td><td>N / A *</td><td> -</td><td>N / A *</td>
<td>Isopropyl Alcohol, USP</td><td>N / A *</td><td>N / A *</td><td> -</td><td>N / A *</td>
<td></td><td></td><td>Component III</td><td>Component V</td><td>Component III</td>
<td>Tartaric acid, NF</td><td> -</td><td> 107,5</td><td> 107,5</td><td> 215</td>
<td>Microcrystalline cellulose, NF (Avicel PH101)</td><td></td><td> 26,95</td><td> 26,9</td><td> 53,9</td>
ES 2 804 348 T3
<td>Ethylcellulose, NF (Ethocel Standard10FP Premium)</td><td></td><td> 11,2</td><td> 11,3</td><td> 22,4</td>
<td>Hypromellose, USP, type 2910 (Pharmacoat 606, 6 cps)</td><td></td><td> 20,35</td><td> 20,25</td><td> 40,7</td>
<td>Copolymer ac. methacrylic, type A, NF (Eudragit® L100)</td><td></td><td> 9,75</td><td> 6,1</td><td> 19,5</td>
<td>Copolymer ac. methacrylic, type B, NF (Eudragit® S100)</td><td></td><td> 19,3</td><td> 30,35</td><td> 38,6</td>
<td>Triethyl citrate, NF</td><td> -</td><td> 8,3</td><td> 25,55</td><td> 16,6</td>
<td>Talc, USP</td><td> -</td><td> 5,2</td><td> 10,3</td><td> 10,4</td>
<td>NH4OH 1N</td><td> -</td><td> -</td><td> 0,3</td><td> -</td>
<td>Purified water, USP</td><td> -</td><td> -</td><td>N / A *</td><td> -</td>
<td>Acetone, NF</td><td>N / A *</td><td>N / A *</td><td> -</td><td>N / A *</td>
<td>Isopropyl Alcohol, USP</td><td>N / A *</td><td>N / A *</td><td> -</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td><td>1 unit</td><td>1 unit</td><td>1 unit</td>
<td>Total loaded capsule weight</td><td> 184,97</td><td> 403,3</td><td> 448,4</td><td> 611,85</td>
<td colspan="5">* Evaporated in the drying process</td>
Manufacture of formulations IPX066- AH1
Four formulations of IPX066- AH1
Component 1 Fabrication - CD-LD Quick Release Beads
Carbidopa, levodopa and microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, sodium lauryl sulfate and povidone were mixed and loaded into a high shear granulator and granulated with purified water. The granulated wet mass was extruded in an extruder with a 1.0 mm size die. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm cross disc. The spheres obtained from the spheronizer were dried and the drug loaded granules were sieved at 16, 18 and 25 mesh. The retained granules were collected on 18 and 25 mesh meshes. The final mix was prepared by mixing the screened CD / LD granules with talc.
Component II Fabrication - Eudragit® S100: L100 Coated CD-LD Quick Release Beads (2: 1)
The CD / LD core seeds (also called granules) were prepared as Component I seeds, except there was no final talc mix. The enteric coating solution was prepared by dissolving Eudragit® S100 and Eudragit® L100 in the 2: 1 weight ratio and triethyl citrate in isopropyl alcohol and acetone solution. The talc was then dispersed into the polymer solution and mixed continuously throughout the coating process. The CD / LD granules were spray coated using the coating dispersion in a coater. The coated granules were dried and then sieved through a 16 mesh mesh. The final mix was prepared by mixing the selected CD / LD granules with talc.
Component III Fabrication - Eudragit® S100: L100 Coated Tartaric Acid Rapid Release Beads (2: 1)
The tartaric acid was passed through a 20 mesh screen. Filtered tartaric acid and microcrystalline cellulose were charged into a high shear mixer and granulated with purified water. The wet mass was extruded in an extruder with a 1.0 mm die. The extrudate was loaded and spheronized into a spheronizer equipped with a 3mm cross disc and the resulting granules were dried overnight in an oven at 60 ± 10 ° C. The dried granules were passed through the 16, 18 and 25 mesh meshes and the granules retained on the 18 and 25 mesh meshes were collected.
A sealant coating solution was prepared by dissolving hypromellose (Pharmacoat 606) and ethylcellulose in alcoholic solution. The sealer coating solution was applied to the tartaric acid granules in a coater. The granules were dried and the dried granules were passed through a 14 mesh screen.
An additional seal coat was produced by dissolving hypromellose (Pharmacoat 606) in alcoholic solution. The sealer coating solution was applied in the coater to the tartaric acid granules and then the granules were dried in GPCG-I. The dried granules were passed through a 14 mesh screen.
ES 2 804 348 T3
An enteric coating solution was prepared by dissolving Eudragit® S100 and Eudragit® L100 in a 2: 1 weight ratio and triethyl citrate in isopropyl alcohol and acetone solution. It was mixed until dissolved. The talc was dispersed in the polymer solution and mixed continuously throughout the coating process. The selected tartaric acid granules were loaded into a coater and spray coated with the enteric coating dispersion. The coated seeds were dried and the dried coated granules were sieved through a 14 mesh mesh. The final mixture was prepared by mixing the selected granules and the talc.
Component IV Fabrication - CD-LD Quick Release Beads Coated with Eudragit® S100 and Eudragit® L100 (5: 1)
The manufacturing method for this component is the same as for the component II beads, except that the preparation of the enteric coating dispersion was changed.
Specifically, the enteric coating dispersion is prepared by loading the required amount of a first portion of purified water into a stainless steel container and into which, while stirring, the methacrylic acid copolymer, type A, NF is loaded and dispersed , thus forming a dispersion. The required amount of 1N NH4OH solution was added dropwise to the dispersion.
A required amount of a second portion of purified water was charged into a separate stainless steel container. While stirring, the methacrylic acid copolymer, type B, NF was charged and dispersed. The required amount of 1N NH4OH solution was then added dropwise to the dispersion.
A required amount of a third portion of purified water was charged into a separate stainless steel container. Triethyl citrate was charged and dissolved and talc was added to the solution.
The first dispersion above was added and mixed with the second dispersion, to which was then added the third dispersion above. The mixed solutions were sieved through a 140 mesh mesh.
Fabrication of Component V - TA quick release beads coated with Eudragit® S100 and Eudragit® L100 (5: 1)
The manufacturing method for component V beads is the same as for component III beads, except that the preparation of the enteric coating dispersion was changed. Specifically, the enteric coating dispersion was prepared by loading the required amount of a first portion of purified water into a stainless steel container and, while stirring, the methacrylic acid copolymer, Type A and NF were charged and dispersed to produce a dispersion. ; The required amount of 1N NH4OH solution was then added dropwise to the above dispersion.
In a separate stainless steel container, the required amount of the second portion of purified water was charged and, while stirring, the methacrylic acid copolymer, Type B and NF, were charged and dispersed to produce a dispersion; the required amount of 1N NH4OH solution was then added to the above dispersion.
In a separate stainless steel container, the required amount of the third portion of purified water was charged and to which was added and charged triethyl citrate; then talc was added to the above solution.
The first dispersion above was added and mixed with the second dispersion and then the third dispersion above was added. The mixed solutions were sieved through a 140 mesh mesh.
Manufacture of IPX066 capsules
The required amounts of the bead components were filled into hard gelatin capsules according to the fill weights specified in Table 9 below. In-process fill weight is controlled to a target ± 10% of target weights according to Table 9.
Table 9 Target Fill Weights of IPX066 Capsule Test Formulations
<td></td><td colspan="4">Formulation</td>
<td>Components (edit)</td><td>IPX066-AH1 (A) mg / capsule</td><td>IPX066-AH1 (B) mg / capsule</td><td>IPX066-AH1 (C) mg / capsule</td><td>IPX066-AH1 (D) mg / capsule</td>
<td>Component I Pearls</td><td> 184,97</td><td> -</td><td> -</td><td> -</td>
<td>Component II Pearls</td><td> -</td><td> 194,75</td><td> -</td><td> 194,75</td>
ES 2 804 348 T3
<td>Component III Pearls</td><td> -</td><td> 208,55</td><td> -</td><td> 417,1</td>
<td>Component IV Pearls</td><td> -</td><td> -</td><td> 210,25</td><td> -</td>
<td>Component V Pearls</td><td> -</td><td> -</td><td> 238,55</td><td> -</td>
<td colspan="2">Total loaded capsule weight</td><td> 403,3</td><td> 448,8</td><td> 611,85</td>
Pharmacokinetic result of the IPX066- AH1 bioassay
The pharmacokinetic parameters of CD and LD for the four formulations tested compared to Sinemet® CR after oral administration are summarized in Table 10.
Table, 10 Median ratio of Cmax transformed with Ln, AUC of Levodopa and Carbidopa
<td></td><td>Parameter</td><td>Test / ref.</td><td>Proportion (%)</td>
<td>LD</td><td>Ln (Cmax)</td><td>A / E</td><td> 192,54</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 127,05</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 123,22</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 111,99</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 126,53</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 115,03</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 127,15</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 108,74</td>
<td>CD</td><td>Ln (Cmax)</td><td>A / E</td><td> 144,73</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 88,97</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 124,35</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 81,06</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 161,73</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 91,24</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 139,79</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 88,03</td>
Results and discussion: These data demonstrated that formulation A, with the inclusion of a water soluble filler such as lactose and a surfactant such as sodium lauryl sulfate, exhibits rapid absorption of LD with a maximum of 30 minutes. The PK profiles of the B and D formulation are desirable. Both formulations exhibit a significantly higher plasma LD concentration at 6 hours post-dose relative to the Sinemet® CR tablet. The LD uptake of formulation B and D is also similar to that indicated by a relative AUC of 115% and 109%, respectively. Since the PK profiles of formulations B and D are similar, formulation D with twice the amount of Ta beads does not offer any additional benefit over formulation B. Formulation C, with a coating consisting of a 5: 1 Eudragit® S100: L100 ratio, exhibits a PK profile suggesting faster in vivo release relative to Formulation C and D. This is further supported by a 127% AUC relative to Sinemet® CR tablet indicating LD was rapidly released and absorbed from the upper gastrointestinal tract.
Example 5
These data in this document show the bioavailability / pharmacokinetic results of an enteric coated CD / LD tablet formulation using 50-300 mg of CD-LD with 0-270 mg of tartaric acid compared to the Sinemet controlled release version. ®. Information on the study medications is shown below in Table 11.
Formulation A IPX066-AH2 (IPX066-AH2 (A)) is a capsule containing 5 beads of different components. Component I is a type of CD / LD immediate release bead. Component II is a CD / LD ER bead type with a rapid ER release profile. Component III is a CD / Ld ER bead type with a slow ER release profile. Component IV is a TA bead type with a release profile similar to Component II. Component V is a TA bead type with a release profile similar to Component III.
Formulation B IPX066-AH2 (IPX066-AH2 (B)) (not according to the claimed invention) is a capsule containing CD / LD ER microspheres formulated with Cremophor RH40 and Poloxamer 188. TA is not included in the formulation.
ES 2 804 348 T3
Formulation C IPX066-AH2 (IPX066-AH2 (C)) (not according to the claimed invention) is a capsule containing CD / LD ER beads formulated with Cremophor RH40 and Poloxamer 188 and TA.
Formulation D IPX066-AH2 (IPX066-AH2 (D)) (not according to the claimed invention) is a capsule containing CD / LD ER beads formulated with TA. The capsule does not contain Cremophor RH40 or Poloxamer 188.
The reference product is Sinemet® CR Tablets 200 mg.
Table 11. IPX066-AH2
<td colspan="2">Product</td><td>CD-LD strength <sup>(</sup>mg)</td><td>enteric coating pH</td>
<td>TO</td><td>Combo capsules IPX066 CD / LD with 270 mg of tartaric acid (IR + fast release core + slow release core)</td><td> 75-300</td><td>6.5 (SL2) for quick and slow release core</td>
<td>B</td><td>IPX066 CD / LD capsules with surfactants</td><td> 50-200</td><td>6.5 (SL2)</td>
<td>C</td><td>Capsules IPX066 CD / LD / ac. tartaric acid with 215 mg of ac. Tartaric and durfactants</td><td> 50-200</td><td>6.5 (SL5)</td>
<td>D</td><td>Capsules IPX066 CD / LD / ac. tartatic with 215 mg of ac. tartaric</td><td> 50-200</td><td>6.5 (SL2)</td>
<td>AND</td><td>Sinemet® CR tablets<sup>to</sup></td><td> 50-200</td><td> -</td>
<td colspan="4">"Merck & Co., Inc.</td>
The qualitative and quantitative compositions for these formulations are summarized below in Table 12 and Table 13.
_______________ Table 12. Formulation A (IPX066-AH2 (A)) _______________
<td></td><td>Formulation A</td>
<td>Ingredients</td><td>mg / capsule</td>
<td>Component I</td><td></td>
<td>Carbidopa USP</td><td> 6,75</td>
<td>Levodopa USP</td><td> 25</td>
<td>Microcrystalline cellulose NF</td><td> 4,6</td>
<td>Lactose, monohydrate NF</td><td> 4,5</td>
<td>Sodium starch glycolate NF</td><td> 2,3</td>
<td>Sodium Lauryl Sulfate NF</td><td> 2,3</td>
<td>Povidone USP</td><td> 0,46</td>
<td>Talc USP</td><td> 0,23</td>
<td>USP purified water</td><td>N / A *</td>
<td>Component II</td><td></td>
<td>Carbidopa USP</td><td> 6,75</td>
<td>Levodopa USP</td><td> 25</td>
<td>Microcrystalline cellulose NF</td><td> 4,6</td>
<td>Lactose, monohydrate NF</td><td> 4,6</td>
<td>Sodium starch glycolate NF</td><td> 2,3</td>
<td>Sodium Lauryl Sulfate NF</td><td> 2,3</td>
<td>Povidone USP</td><td> 0,46</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 0,55</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 1,15</td>
<td>Triethyl citrate NF</td><td> 0,48</td>
<td>Talc USP</td><td> 0,49</td>
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td>Component III</td><td></td>
<td>Carbidopa USP</td><td> 26,99</td>
<td>Levodopa USP</td><td> 100</td>
<td>Microcrystalline cellulose NF</td><td> 54,42</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 2,18</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 4,5</td>
<td>Triethyl citrate NF</td><td> 1,91</td>
<td>Talc USP</td><td> 1,91</td>
ES 2 804 348 T3
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td>Component IV</td><td></td>
<td>Tartaric acid NF</td><td> 27</td>
<td>Microcrystalline cellulose NF</td><td> 6,79</td>
<td>Ethylcellulose NF</td><td> 2,81</td>
<td>Hypromellose, type 2910 USP</td><td> 5,01</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 2,44</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 4,84</td>
<td>Triethyl citrate NF</td><td> 2,08</td>
<td>Talc USP</td><td> 1,31</td>
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td>Component V</td><td></td>
<td>Tartaric acid NF</td><td> 107,5</td>
<td>Microcrystalline cellulose NF</td><td> 26,85</td>
<td>Ethylcellulose NF</td><td> 12,38</td>
<td>Hypromellose, type 2910 USP</td><td> 2,63</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 8,62</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 17,5</td>
<td>Triethyl citrate NF</td><td> 7,45</td>
<td>Talc USP</td><td> 4,69</td>
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td>
<td>Total weight of loaded capsule</td><td> 526,63</td>
<td colspan="2">* evaporated in the drying process</td>
Table 13. Formulations B, C and D (IPX066-AH2 (B), IPX066-AH2 (C), IPX066-AH2 (D))
<td rowspan="2"></td><td colspan="3">Formulation</td>
<td>B</td><td>C</td><td>D</td>
<td>Ingredients</td><td colspan="3">mg / capsule</td>
<td>Carbidopa USP</td><td> 26,99</td><td> 26,99</td><td> 26,99</td>
<td>Levodopa USP</td><td> 100</td><td> 100</td><td> 100</td>
<td>Microcrystalline cellulose, NF</td><td> 118,75</td><td> 65,00</td><td> 30,00</td>
<td>Lactose, monohydrate NF</td><td> 53,75</td><td> -</td><td> -</td>
<td>Mannitol USP</td><td> -</td><td> -</td><td> 50,00</td>
<td>Povidone USP</td><td> 17,35</td><td> -</td><td> -</td>
<td>Talc, USP</td><td> 23,99</td><td> 11,11</td><td> 9,97</td>
<td>Copolymer ac. methacrylic, type A, NF (Eudragit® L100)</td><td> 48,98</td><td> 20,13</td><td> 18,09</td>
<td>Copolymer ac. methacrylic, type B, NF (Eudragit® S100)</td><td> 98,19</td><td> 40,35</td><td> 36,17</td>
<td>Triethyl citrate, NF</td><td> 42,18</td><td> 17,32</td><td> 15,55</td>
<td>Poloxamer 188, NF</td><td> 33,5</td><td> 33,5</td><td> -</td>
<td>Polyoxil 40 Hydrogenated Castor Oil (Cremophor RH 40)</td><td> 17,5</td><td> 17,5</td><td></td>
<td>Tartaric acid NF</td><td> -</td><td> 107,5</td><td> 107,5</td>
<td>Hypromellose, USP, type 2910</td><td> -</td><td> 52,58</td><td> 47,18</td>
<td>Acetone, NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td><td>1 unit</td><td>1 unit</td>
<td>Total loaded capsule weight</td><td> 581,18</td><td> 491,98</td><td> 441,45</td>
* Evaporated in the drying process
Manufacture of Formulation A beads (IPX066-AH2 (A))
Quick Release I-CD / LD Bead Component Manufacturing
ES 2 804 348 T3
The manufacturing method for this component beads is the same as for component I beads in IPX066-AH1, as discussed in Example 4 above.
Eudragit® S100: L100 (2: 1) Coated Quick Release Bead Component II-CD-LD Fabrication
The manufacturing method for this component beads is the same as for component II beads in IPX066-AH1, as discussed in Example 4 above.
Eudragit® S100: L100 (2: 1) Coated Slow Release Bead Component III-CD-LD Fabrication
The manufacturing method for this component beads is the same as for the enteric coated CD-LD beads in Formulation A tested in IPX066-B06-02, as discussed in Example 2 above.
Eudragit® S100: L100 (2: 1) Coated Rapid Release IV-TA Bead Component Fabrication
The manufacturing method for this component beads is the same as that for component III beads in the IPX066-AH1 biostudy, as discussed in Example 4 above.
Eudragit® S100: L100 (2: 1) Coated Slow Release V-TA Bead Component Fabrication
The manufacturing method for this component beads is the same as for the enteric coated tartaric acid beads in Formulation A tested in IPX066-B06-02 as discussed in Example 2 above.
Manufacture of IPX066 capsules for formulation A
The required amounts of the bead components were filled into hard gelatin capsules according to the specified target fill weights ± 10%.
Table 14. Target Fill Weights of IPX066 Capsule Test Formulations
<td>Components (edit)</td><td>IPX066-AH2 (A) mg / capsule</td>
<td>Component I beads</td><td> 46,2</td>
<td>Component II pearls</td><td> 48,7</td>
<td>Component III pearls</td><td> 191,9</td>
<td>Component IV beads</td><td> 52,1</td>
<td>Component V beads</td><td> 187,7</td>
<td>Total loaded capsule weight</td><td> 526,6</td>
Manufacture of Test B formulation (IPX066-AH2 (B) (not according to claimed invention)
To prepare formulation B, a suitable amount of ethanol and purified water was mixed and Cremophor RH40 was dissolved therein and loaded into a first solution; then povidone was loaded and mixed into the solution. A separate granulation fluid was prepared by dissolving the required amount of povidone in the required amount of purified water.
Appropriate amounts of carbidopa, levodopa, microcrystalline cellulose, lactose monohydrate, and poloxamer were charged into a suitable granulator and mixed until a uniform powder was formed. The mixed powder was granulated by adding the first solution from above, followed by continuous granulation by adding the separated granulation fluid from above, resulting in a wet mass. The wet mass was extruded through a suitable extruder equipped with a 1.0 mm die. The extrudate was spheronized in a spheronizer at an appropriate speed and the wet extruded beads were dried in a fluidized bed drier. The dried beads were then passed through a US # 16 mesh, a US # 18 mesh, a US # 25 mesh and a tray. Only the beads that pass through the 18 mesh but are retained on the 25 mesh are collected.
The enteric coating dispersion was prepared by dispensing and mixing a suitable amount of acetone and isopropyl alcohol, and while the solution was mixed, triethyl citrate was charged and dissolved in the solution. Mixing continued until the material was completely dissolved. While mixing, methacrylic acid copolymer, type A, NF was loaded into the solution. The solution was mixed until the material was completely dissolved and then, again while mixing, was charged into the methacrylic acid copolymer, type B, NF solution. Mixing continued until the material was completely dissolved. While i know
ES 2 804 348 T3 mixed, talc was charged and dispersed in the solution. Mixing continued throughout the coating process.
The beads collected above were loaded into a suitable fluidized bed coater equipped with a Wurster insert and spray coated using the enteric coating dispersion above. The coated beads were dried and the dried beads were passed through a US # 14 mesh. The resulting screened material was charged and a suitable amount of talc was added to a suitable mixer and mixed until uniform.
Manufacture of Test C formulation (IPX066-AH2 (C)) (not according to the claimed invention)
A suitable amount of ethanol and purified water was dispensed and mixed into a stainless steel container into which a suitable amount of Cremophor RH40 was charged and dissolved, resulting in a granulating solution.
A suitable amount of carbidopa, levodopa, tartaric acid, microcrystalline cellulose, and poloxamer was charged into a suitable granulator and mixed until uniform. The mixed powder was granulated with the granulation solution above, thus creating a wet mass. The wet mass was extruded through a suitable extruder equipped with a 1.0 mm die and the extrudate was spheronized in a suitable spheronizer at an appropriate speed.
The wet extruded beads were dried in the fluid bed drier. The LOD was measured using a moisture analyzer and the drying process was stopped when the LOD value was not higher than a target value of 3%. The dried beads were then passed through a US # 16 mesh, a US # 18 mesh, a US # 25 mesh and a tray. Only the peels retained on the 18 mesh and 25 mesh were collected and mixed.
The seal coat solution was prepared as follows. An ethanol solution was prepared by mixing the required amount of alcohol, USP, and purified water in a stainless steel container. A suitable amount of hypromellose was loaded and dissolved in the ethanol solution.
The collected beads retained on the 18 mesh and 25 mesh were loaded into a fluidized bed coater equipped with a Wurster insert and spray coated using the lock coat solution prepared above. The coated beads were dried in the fluidized bed and the dried beads were passed through a US # 14 mesh. Those that pass through the mesh were collected.
The enteric coating dispersion was prepared as follows. A suitable amount of methacrylic acid copolymer, type A, NF, methacrylic acid copolymer, type B, NF, triethyl citrate and talc was dispensed. A suitable amount of acetone and isopropyl alcohol was mixed well and during mixing, triethyl citrate was charged and mixed into the solution. The methacrylic acid copolymer, type A, NF was further charged into the solution. Mixing continued until the material was completely dissolved. The methacrylic acid copolymer, type B, NF was further charged into the solution. Mixing continued until the material was completely dissolved. The talc was then charged and dispersed in the solution. Mixing was done throughout the process.
The collected beads were coated with the enteric coating dispersion as follows. The collected beads were loaded into a suitable fluidized bed coating device equipped with a Wurster insert and spray coated with the above enteric coating dispersion. The coated beads were dried and the dried beads passed through a US # 14 mesh. The sieved material was mixed and charged with a suitable amount of talc in a mixer.
Manufacture of Test D formulation (IPX066-AH2 (D)) (not according to claimed invention)
A granulation solution was prepared by dissolving polyoxyl in a solution of ethanol and purified water.
A suitable amount of carbidopa, levodopa, screened tartaric acid, microcrystalline cellulose, lactose monohydrate, and poloxamer were charged and mixed in a granulator. The mixed material was granulated with the granulation solution thus creating a wet mass. The wet mass was extruded through a suitable extruder equipped with a 1.0 mm die. The resulting extrudates were spheronized in a suitable spheronizer. The wet extruded beads were dried in a fluid bed drier and the LOD was measured using a moisture analyzer. The drying process was stopped when the LOD value was not higher than a target value of 3%.
ES 2 804 348 T3
The dried beads were passed through a US # 16 mesh, a US # 18 mesh, a US # 25 mesh and a tray. Only the beads retained between the 18 mesh and 25 mesh were collected.
The dried beads were covered with a sealing layer. The sealing layer can be prepared as follows. An ethanol solution was prepared by mixing the required amount of alcohol, USP, and purified water in a stainless steel container into which a suitable amount of hypromellose was charged. The dried beads were loaded into a fluidized bed coater equipped with a Wurster insert and spray coated using the lock coat solution. The coated beads were then dried in a fluidized bed and the dried coated beads passed through a US # 14 mesh. The beads that passed through the mesh were collected.
The collected beads were coated with an enteric coating dispersion. The enteric coating dispersion was prepared as follows. A suitable amount of methacrylic acid copolymer, type A, NF, methacrylic acid copolymer, type B, NF, triethyl citrate and talc was dispersed. A suitable amount of acetone and isopropyl alcohol was mixed well. During mixing, triethyl citrate was charged and dissolved in the acetone and isopropyl alcohol solution. Then, while mixing, methacrylic acid copolymer, type A and NF were loaded into the solution. Mixing continued until the material was completely dissolved. During mixing, the methacrylic acid copolymer, type B and NF were loaded into the solution. Mixing continued until the material was completely dissolved. The talc was then charged and dissolved in the solution. Mixing continued throughout the coating process.
The sealed coated beads were loaded into a suitable fluidized bed coater equipped with a Wurster insert and spray coated using the enteric coating dispersion. The resulting coated beads were dried and the dried beads were passed through a US # 14 mesh. The sieved material was charged and mixed with a suitable amount of talc in a mixer until uniform.
Pharmacokinetic result of the IPX066-AH2 bioassay
The pharmacokinetic parameters of CD and LD for the four formulations tested compared to Sinemet® CR after oral administration are summarized in Table 15.
Table 15. Median ratio of Cmax transformed with Ln, AUC of Levodopa and CarNdopa
<td></td><td>Parameter</td><td>Test / ref.</td><td>Proportion (%)</td>
<td>LD</td><td>Ln (Cmax)</td><td>A / E</td><td> 80,83</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 16,19</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 18,15</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 16,55</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 108,65</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 10,54</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 15,08</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 15,79</td>
<td>CD</td><td>Ln (Cmax)</td><td>A / E</td><td> 80,12</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 7,03</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 13,85</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 14,41</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 94,93</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 2,69</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 12,54</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 11,06</td>
Results and Discussion
These data demonstrate that Formulation A provides a desirable in vivo plasma concentration profile. By combining two components of tartaric acid beads (enteric coated in the fast or slow release core) with three components of CD / LD drug beads (instant release portion and enteric coated portion with coating in the rapid release core) or slow), formulation A showed a significantly flatter plasma concentration profile, with a lower Cmax (80.7%) and a comparable AUC (109%) relative to the reference drug Sinemet® CR.
A PK simulation study was performed to calculate the peak-to-trough plasma concentration (PT) ratio assuming a dosing regimen three times daily (every 6 hours). The PT ratio is defined at steady state 18 hours after the plasma concentration dose. The simulation results
ES 2 804 348 T3 are summarized in Table 16, which shows that formulation A has a PT ratio significantly less than 1.7 relative to Sinemet® CR of 3.4.
The addition of surfactants in the formulation significantly decreased the bioavailability of LD. Furthermore, it is more advantageous to have separate drug and tartaric acid seeds in the formulation, and incorporation of tartaric acid into the same drug seeds significantly decreased the bioavailability of LD.
Table 16. Simulation of steady-state plasma concentration, AUC, and concentration ratio ____________________________________________ peak to valley __________________________________________
<td>Formulation</td><td>CD-LD dose (mg)</td><td>Css, max</td><td>Css, 18h</td><td>Peak to valley ratio in plasma</td>
<td>A (IPX066-AH2 (A))</td><td> 75-300</td><td> 1030</td><td> 591</td><td> 1,7</td>
<td>E (reference)</td><td> 50-200</td><td> 1212</td><td> 349</td><td> 3,4</td>
Example 6 (not according to the claimed invention)
The formulation with surfactant seeds containing separate CD / LD and tartaric acid seeds for IPX-066 was evaluated for PK parameters.
IPX066-AH3
Information on the study drugs is detailed in Table 17 below. Formulation A (IPX066AH3 (A)) is a capsule containing CD / LD ER beads formulated with Cremophor RH40 and Poloxamer 188 15 and ER TA beads with a similar dissolution profile.
Table 17. IPX066-AH3
<td colspan="2">Product</td><td>CD-LD Force (mg)</td><td>enteric coating pH</td>
<td>A (IPX066-AH3 (TO))</td><td>IPX066 CD / LD capsules containing surfactant with 215 mg of tartaric acid</td><td> 50-200</td><td>6.5 (SL2)</td>
<td>B</td><td>Sinemet® CR tablets</td><td> 50-200</td><td> -</td>
The qualitative and quantitative compositions for these formulations are summarized below in Table 18.
______________ Table 18. Qualitative and quantitative composition of the test formulation______________
<td></td><td>Formulation A (IPX066- AH3 (A))</td>
<td>Ingredients</td><td>mg / capsule</td>
<td></td><td>Pearl I</td>
<td>Carbidopa USP</td><td> 17,99</td>
<td>Levodopa USP</td><td> 66,67</td>
<td>Microcrystalline cellulose NF (Avicel PH-101)</td><td> 79,17</td>
<td>Lactose, monohydrate NF</td><td> 35,83</td>
<td>Poloxamer 188, NF (Lutrol F-68, NF)</td><td> 22,33</td>
<td>Hydrogenated Castor Oil Polyoxyl 40, NF (Cremophor RH 40)</td><td> 11,67</td>
<td>Povidone USP</td><td> 11,57</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 32,65</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 65,46</td>
<td>Triethyl citrate NF</td><td> 28,12</td>
<td>Talc USP</td><td> 15,99</td>
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td></td><td>Pearl II</td>
<td>Tartaric acid</td><td> 71,67</td>
<td>Microcrystalline cellulose NF (Avicel PH-101)</td><td> 17,93</td>
<td>Ethylcellulose NF (Ethocel Standard-10FP Premium)</td><td> 7,53</td>
<td>Hypromellose, Type 2910 USP (Pharmacoat 606, 6 cps)</td><td> 13,50</td>
<td>Copolymer ac. methacrylic, Type A NF (Eudragit® L100)</td><td> 14,77</td>
<td>Copolymer ac. methacrylic, Type B NF (Eudragit® S100)</td><td> 29,50</td>
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<td>Triethyl citrate NF</td><td> 12,63</td>
<td>Talc USP</td><td> 7,20</td>
<td>Acetone, NF</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td>
<td>Total weight</td><td> 562,18</td>
Manufacture of Test Formulation
Component I Bead Making - CD / LD Beads
The manufacturing method for beads of this component is the same as for Formulation B IPX066AH2, as discussed above in Example 5.
Component II Bead Making - TA Beads
The manufacturing method for this component beads is the same as that for component III beads in IPX066-AH1, except that the content for the enteric coating is higher in the formulation, as discussed in Example 4 above.
Pharmacokinetic result of IPX066-AH3:
The pharmacokinetic parameters of CD and LD for the formulations tested compared to Sinemet® CR after oral administration are summarized in Table 19.
Table 19. Mean ratio of Cmax transformed with Ln AUC of Levodopa and Carbidopa
<td></td><td>Parameter</td><td>Test / ref.</td><td>Proportion (%)</td>
<td>LD</td><td>Ln (Cmax) Ln (AUC)</td><td>A / B A / B</td><td> 14,89 9,88</td>
<td>CD</td><td>Ln (Cmax) Ln (AUC)</td><td>A / B A / B</td><td> 4,87 7,11</td>
Results and Discussion
The addition of surfactants in the formulation significantly decreased the bioavailability of LD even when the formulation contains separate seeds of drugs and tartaric acid.
Example 7: Formulations for IPX066-AH4
Four formulations of IPX-066 were evaluated for PK parameters. Information for the study medications is shown below in Table 20.
Table 20. IPX066-AH4
<td>Formulation</td><td>CD-LD dose (mg)</td><td>Molar ratio TA: LD</td><td>Capsule quantity / dose</td>
<td>A (IPX066-AH4 (A))</td><td> 75-300</td><td> 1,4:1</td><td> 2</td>
<td>B (IPX066-AH4 (B))</td><td> 90-360</td><td> 1,4:1</td><td> 3</td>
<td>C (IPX066-AH4 (C))</td><td> 90-360</td><td> 0,5:1</td><td> 2</td>
<td>D (IPX066-AH4 (D))</td><td> 90-360</td><td> 0,75:1</td><td> 2</td>
<td>Sinemet® CR ° tablets</td><td> 50-200</td><td> -</td><td> -</td>
<td colspan="4">"Merck & Co., Inc.</td>
These formulations contain CD / LD beads and LD beads with different release characteristics. Similar to Formulation A IPX066-AH2, these beads are coated with Eudragit® L100 and S100 polymers in a 1: 2 ratio. The amounts of CD / lD and TA in each of the bead types are shown in Table 20.
Component I is a CD / LD bead type exhibiting an immediate release dissolution profile.
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Component II is a CD / LD bead type that exhibits a faster sustained release dissolution profile.
Component III is a CD / LD bead type that exhibits a slower sustained release dissolution profile.
Component IV is a TA bead type that exhibits a dissolution profile that mimics those of Component II.
Component V is a type of TA bead that exhibits a dissolution profile that mimics those of Component III.
Component VI is a type of TA bead that exhibits a dissolution profile intermediate between components II and III.
The qualitative and quantitative compositions for these formulations are summarized below in Table 10-21.
Table 21. Qualitative and quantitative composition of formulation
<td rowspan="2"></td><td colspan="4">Formulation</td>
<td>Formulation A (IPX066- AH4 (A))</td><td>Formulation B (IPX066- AH4 (B))</td><td>Formulation C (IPX066-AH4 (C))</td><td>Formulation D (IPX066- AH4 (D))</td>
<td>Ingredients</td><td colspan="4">mg / capsule</td>
<td colspan="5">Component I</td>
<td>Carbidopa, USP</td><td> 6,75</td><td> 6,48</td><td> 9,72</td><td> 9,72</td>
<td>Levodopa, USP</td><td> 25</td><td> 24</td><td> 36</td><td> 36</td>
<td>Microcrystalline cellulose, NF</td><td> 4,6</td><td> 4,42</td><td> 6,62</td><td> 6,62</td>
<td>Lactose, monohydrate, NF</td><td> 4,6</td><td> 4,42</td><td> 6,62</td><td> 6,62</td>
<td>Sodium starch, glycolate, NF</td><td> 2,3</td><td> 2,21</td><td> 3,31</td><td> 3,31</td>
<td>Sodium lauryl sulfate, NF</td><td> 2,3</td><td> 2,21</td><td> 3,31</td><td> 3,31</td>
<td>Povidone, USP</td><td> 0,46</td><td> 0,44</td><td> 0,66</td><td> 0,66</td>
<td>Talc, USP</td><td> 0,23</td><td> 0,22</td><td> 0,33</td><td> 0,33</td>
<td>USP purified water</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td colspan="5">Component II</td>
<td>Carbidopa USP</td><td> 6,75</td><td> 5,4</td><td> 8,10</td><td> 8,10</td>
<td>Levodopa USP</td><td> 25</td><td> 20</td><td> 30</td><td> 30</td>
<td>Microcrystalline cellulose, NF</td><td> 4,6</td><td> 3,68</td><td> 5,52</td><td> 5,52</td>
<td>Lactose, monohydrate, NF</td><td> 4,6</td><td> 3,68</td><td> 5,52</td><td> 5,52</td>
<td>Sodium starch, glycolate, NF</td><td> 2,3</td><td> 1,84</td><td> 2,76</td><td> 2,76</td>
<td>Sodium lauryl sulfate, NF</td><td> 2,3</td><td> 1,84</td><td> 2,76</td><td> 2,76</td>
<td>Povidone, USP</td><td> 0,46</td><td> 0,37</td><td> 0,55</td><td> 0,55</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 0,56</td><td> 0,45</td><td> 0,67</td><td> 0,67</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 1,14</td><td> 0,91</td><td> 1,36</td><td> 1,36</td>
<td>Triethyl citrate, NF</td><td> 0,49</td><td> 0,39</td><td> 0,58</td><td> 0,58</td>
<td>Talc, USP</td><td> 0,49</td><td> 0,39</td><td> 0,58</td><td> 0,58</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td colspan="5">Component III</td>
<td>Carbidopa, USP</td><td> 26,99</td><td> 20,51</td><td> 30,77</td><td> 30,77</td>
<td>Levodopa, USP</td><td> 100,00</td><td> 76,00</td><td> 114,00</td><td> 114,00</td>
<td>Microcrystalline cellulose, NF</td><td> 54,53</td><td> 41,36</td><td> 62,04</td><td> 62,04</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 2,19</td><td> 1,67</td><td> 2,50</td><td> 2,50</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 4,49</td><td> 3,41</td><td> 5,12</td><td> 5,12</td>
<td>Triethyl citrate, NF</td><td> 1,91</td><td> 1,45</td><td> 2,18</td><td> 2,18</td>
<td>Talc, USP</td><td> 1,92</td><td> 1,46</td><td> 2,18</td><td> 2,18</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
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<td colspan="5">Component IV</td>
<td>Tartaric acid NF</td><td> 27,00</td><td> 21,50</td><td> 11,40</td><td> -</td>
<td>Microcrystalline cellulose, NF</td><td> 6,74</td><td> 5,37</td><td> 2,85</td><td> -</td>
<td>Ethylcellulose NF</td><td> 2,81</td><td> 2,24</td><td> 1,19</td><td> -</td>
<td>Hypromellose, Type 2910 USP</td><td> 0,94</td><td> 0,75</td><td> 0,40</td><td> -</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 2,16</td><td> 1,72</td><td> 0,91</td><td> -</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 4,41</td><td> 3,51</td><td> 1,86</td><td> -</td>
<td>Triethyl citrate, NF</td><td> 1,87</td><td> 1,49</td><td> 0,79</td><td> -</td>
<td>Talc, USP</td><td> 1,18</td><td> 0,94</td><td> 0,50</td><td> -</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td> -</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td></td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td></td>
<td colspan="5">Component V</td>
<td>Tartaric acid NF</td><td> 107,50</td><td> 81,70</td><td> 43,4</td><td> -</td>
<td>Microcrystalline cellulose, NF</td><td> 26,90</td><td> 20,44</td><td> 10,86</td><td> -</td>
<td>Ethylcellulose NF</td><td> 12,40</td><td> 9,42</td><td> 5,00</td><td> -</td>
<td>Hypromellose, Type 2910 USP</td><td> 2,55</td><td> 1,94</td><td> 1,03</td><td> -</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 8,60</td><td> 6,54</td><td> 3,47</td><td> -</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 17,55</td><td> 13,34</td><td> 7,09</td><td> -</td>
<td>Triethyl citrate, NF</td><td> 7,45</td><td> 5,66</td><td> 3,01</td><td> -</td>
<td>Talc, USP</td><td> 4,70</td><td> 3,57</td><td> 1,90</td><td> -</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td> -</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td> -</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td> -</td>
<td colspan="5">Component VI</td>
<td>Tartaric acid NF</td><td> -</td><td> -</td><td> -</td><td> 82,20</td>
<td>Microcrystalline cellulose, NF</td><td> -</td><td> -</td><td> -</td><td> 20,57</td>
<td>Ethylcellulose NF</td><td> -</td><td> -</td><td> -</td><td> 9,14</td>
<td>Hypromellose, Type 2910 USP</td><td> -</td><td> -</td><td> -</td><td> 2,29</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> -</td><td> -</td><td> -</td><td> 6,58</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> -</td><td> -</td><td> -</td><td> 13,42</td>
<td>Triethyl citrate, NF</td><td> -</td><td> -</td><td> -</td><td> 5,70</td>
<td>Talc, USP</td><td> -</td><td> -</td><td> -</td><td> 3,59</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td><td>N / A *</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td><td>1 unit</td><td>1 unit</td><td>1 unit</td>
<td>Total loaded capsule weight</td><td> 521,62</td><td> 409,34</td><td> 439,41</td><td> 487,25</td>
<td colspan="5">* evaporated in the drying process</td>
Manufacture of test formulations
Quick Release Component I-CD-LD Bead Making
The manufacturing method for this component beads is the same as for component 5 I beads for Formulation A in IPX066-AH2, as discussed in Example 5 above.
Eudragit® S100: L100 (2: 1) Coated Quick Release Component II-CD-LD Beads Fabrication
The manufacturing method for this component beads is the same as for component II beads for Formulation A in IPX066-AH2, as discussed in Example 5 above.
Eudragit® S100: L100 (2: 1) Coated Slow Release Component III-CD-LD Beads Fabrication
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The manufacturing method for this component beads is the same as for component III beads for Formulation A in IPX066-AH2, as discussed in Example 5 above.
Eudragit® S100: L100 (2: 1) Coated Component IV-TA Quick Release Beads Fabrication
The manufacturing method for the beads of this component is the same as for the beads of component IV for Formulation A in IPX066-AH2, as discussed in Example 5 above, except that no additional sealing coating was introduced between the sealing coating layer and enteric coating layer.
Manufacture of slow release component V-TA beads coated with Eudragit® S100: L100 (2: 1)
The manufacturing method for this component beads is the same as for component V beads for Formulation A in IPX066-AH2, as discussed in Example 5 above.
Eudragit® S100: L100 (2: 1) Coated Medium Release Component VI-TA Beads Fabrication
The manufacturing method for this component beads is the same as for component V beads, except that the ratio of ethylcellulose / hypromellose content in the seal coat is 4/1 instead of 5/1.
Manufacture of IPX066 capsules
The required quantities of the component beads were filled into hard gelatin capsules according to the fill weights specified in Table 22 below. In-process fill weight is controlled at target ± 10% of target weights according to Table 22.
Table 22. Target Fill Weights of IPX066 Capsule Test Formulations
<td>Components (edit)</td><td>IPX066-AH2 (A) mg / capsule</td><td>IPX066-AH4 (B) mg / capsule</td><td>IPX066-AH4 (C) mg / capsule</td><td>IPX066-AH4 (D) mg / capsule</td>
<td>Component I beads</td><td> 46,24</td><td> 44,4</td><td> 66,57</td><td> 66,57</td>
<td>Component II pearls</td><td> 48,69</td><td> 38,95</td><td> 58,40</td><td> 58,40</td>
<td>Component III pearls</td><td> 191,93</td><td> 145,86</td><td> 218,79</td><td> 218,79</td>
<td>Component IV beads</td><td> 47,11</td><td> 37,52</td><td> 19,89</td><td></td>
<td>Component V beads</td><td> 187,65</td><td> 142,61</td><td> 75,76</td><td></td>
<td>Component VI beads</td><td></td><td> -</td><td> -</td><td> 143,49</td>
<td>Total loaded capsule weight</td><td> 521,62</td><td> 409,34</td><td> 439,41</td><td> 487,25</td>
Pharmacokinetic result for IPX066-AH4
The pharmacokinetic parameters of CD and LD for four formulations tested compared to Sinemet® CR after oral administration are summarized in Table 23.
Table 23. Mean ratio of Cmax transformed with Ln AUC of Levodopa and Carbidopa
<td></td><td>Parameter</td><td>Test / ref.</td><td>Proportion (%)</td>
<td>LD</td><td>Ln (Cmax)</td><td>A / E</td><td> 92,29</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 119,02</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 132,54</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 133,78</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 105,14</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 136,15</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 143,73</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 154,34</td>
<td>CD</td><td>Ln (Cmax)</td><td>A / E</td><td> 92,76</td>
<td></td><td>Ln (Cmax)</td><td>B / E</td><td> 116,37</td>
<td></td><td>Ln (Cmax)</td><td>EC</td><td> 126,66</td>
<td></td><td>Ln (Cmax)</td><td>OF</td><td> 135,66</td>
<td></td><td>Ln (AUC)</td><td>A / E</td><td> 111,12</td>
<td></td><td>Ln (AUC)</td><td>B / E</td><td> 149,98</td>
<td></td><td>Ln (AUC)</td><td>EC</td><td> 145,70</td>
<td></td><td>Ln (AUC)</td><td>OF</td><td> 164,13</td>
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Results and Discussion
Test formulation A (IPX066-AH4 (A)) showed a consistent in vivo plasma concentration profile as did formulation A (IPX066-AH2 (A)) in IPX066-AH2. The formulation IPX066-AH2 (A) and IPX066-AH4 (A) differ only in the filler used, that is, lactose in IPX066-AH2 (A) and mannitol in IPX066-AH4 (A). The relative AUC (relative to Sinemet® CR tablet) is 109% and 105% for the IPX066-AH2 (A) and IPX066-AH4 (A) formulations, respectively. Relative Cmax (relative to Sinemet® CR tablet) is 80.7% and 92.3% for formulations IPX066-AH2 (A) and IPX066-AH4 (A), respectively. Therefore, the in vivo performance and bioavailability of the formulation is reproducible and consistent.
Based on a simulation study, the steady-state maximum plasma concentration (PT) ratio was calculated assuming dosing three times a day, every 6 hours. The simulated TP ratios, defined as the Cmax and Css ratio, 18 hours, are summarized in Table 24. The results showed that the PT ratio of formulation A (IPX066-AH4 (A)), B (IPX066-AH4 (B)), C (IPX066-AH4 (C)), and D (IPX066AH4 (D)) are 1.8, 2.3, 2.8, and 2.0, respectively. The PT ratio of the Sinemet® CR tablet is 3.9. Therefore, all IPX066 test formulations have a lower PT ratio relative to the reference Sinemet® CR tablet.
These data also demonstrated that the optimal molar ratio TA: LD is 0.75, when comparing the PT ratio of formulations B, C and D.
The PK results also indicated that replacing TA beads from the fast and slow release profiles with TA beads with an intermediate release profile in the formulation did not significantly change the overall plasma LD profile in vivo, as evidenced by the relationship PT.
Table 24. Simulation of steady-state plasma concentration, AUC, and peak-to-valley concentration ratio
<td>Test formulation</td><td>CDLD dose (mg)</td><td>Molar ratio TA: LD</td><td>Css, max</td><td>Css, 18h</td><td>AUCss, 24</td><td>Peak to valley ratio in plasma</td>
<td>TO</td><td> 75-300</td><td> 1,4</td><td> 920</td><td> 511</td><td> 13215</td><td> 1,8</td>
<td>B</td><td> 90-360</td><td> 1,4</td><td> 1238</td><td> 549</td><td> 17048</td><td> 2,3</td>
<td>C</td><td> 90-360</td><td> 0,5</td><td> 1337</td><td> 477</td><td> 18204</td><td> 2,8</td>
<td>D</td><td> 90-360</td><td> 0,75</td><td> 1384</td><td> 679</td><td> 19848</td><td> 2,0</td>
<td>E (reference)</td><td> 50-200</td><td> 0</td><td> 984</td><td> 254</td><td> 12348</td><td> 3,9</td>
Example 8
IPX066-AH5 (A) (47.5 mg CD / 190 mg LD) was evaluated for PK parameters in a three-way PK crossover study using Sinemet® CR (200 mg) as a reference. The qualitative and quantitative compositions for this formulation are summarized below.
Table 25. Quantitative composition of the formulation IPX066-AH5 (A)
<td>Dose strength</td><td rowspan="2"> %</td><td>190 mg</td>
<td>Ingredients</td><td>mg / capsule</td>
<td>Carbidopa</td><td> 10,21</td><td> 51,29<sup>α</sup></td>
<td>Levodopa</td><td> 37,84</td><td> 190,00</td>
<td>Tartaric acid</td><td> 17,63</td><td> 88,52</td>
<td>Microcrystalline cellulose</td><td> 19,23</td><td> 96,55</td>
<td>Mannitol</td><td> 1,01</td><td> 5,07</td>
<td>Ethylcellulose</td><td> 2,03</td><td> 10,2</td>
<td>Hypromellose type 2910</td><td> 0,43</td><td> 2,16</td>
<td>Sodium starch glycolate</td><td> 0,50</td><td> 2,53</td>
<td>Sodium lauryl sulfate</td><td> 0,50</td><td> 2,53</td>
<td>Povidone</td><td> 0,34</td><td> 1,73</td>
<td>talcum powder</td><td> 1,36</td><td> 6,84</td>
<td>Ac copolymer, methacrylic, Type A (Eudragit® L100)</td><td> 2,09</td><td> 10,51</td>
<td>Ac copolymer, methacrylic, Type B (Eudragit® S100)</td><td> 4,25</td><td> 21,33</td>
<td>Triethyl citrate NF</td><td> 1,82</td><td> 9,16</td>
<td>Croscarmellose sodium</td><td> 0,69</td><td> 3,46</td>
<td>Magnesium stearate</td><td> 0,05</td><td> 0,25</td>
<td>Purified water</td><td>N / A **</td><td>N / A **</td>
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<td>Isopropyl alcohol</td><td>N / A **</td><td>N / A **</td>
<td>Acetone</td><td>N / A **</td><td>N / A **</td>
<td>Ethyl alcohol</td><td>N / A **</td><td>N / A **</td>
<td>total</td><td> 100%</td><td> 502,13</td>
<td>Hard gelatin capsules</td><td></td><td>1 unit (size 00)</td>
<td colspan="3">* Carbidopa is supplied as a monohydrate; thus, the amount is equivalent to 47.50 mg of carbidopa * * Evaporated during the drying process,</td>
Formulation Manufacturing
Four different component beads were made for formulation IPX066-AH5 (A). The qualitative and quantitative compositions for each component seed are summarized in Table 26.
Table 26. Qualitative and quantitative composition for 4-component beads in the test formulation ____________________________________ of IPX066 capsules____________________________________
<td rowspan="2"></td><td>Formulation</td>
<td>Formulation Code A (IPX066-AH5 (A))</td>
<td>Ingredients</td><td>mg / capsule</td>
<td colspan="2">Component I</td>
<td>Carbidopa, USP</td><td> 9,45*</td>
<td>Levodopa, USP</td><td> 35,00</td>
<td>Croscarmellose sodium</td><td> 3,46</td>
<td>Povidone</td><td> 1,23</td>
<td>Magnesium stearate</td><td> 0,25</td>
<td>USP purified water</td><td>N / A **</td>
<td colspan="2">Component II</td>
<td>Carbidopa, USP</td><td> 7,43*</td>
<td>Levodopa, USP</td><td> 27,50</td>
<td>Microcrystalline cellulose, NF</td><td> 5,07</td>
<td>Mannitol NF</td><td> 5,07</td>
<td>Sodium starch, glycolate, NF</td><td> 2,53</td>
<td>Sodium lauryl sulfate, NF</td><td> 2,53</td>
<td>Povidone, USP</td><td> 0,50</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 0,62</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 1,24</td>
<td>Triethyl citrate, NF</td><td> 0,53</td>
<td>Talc, USP</td><td> 0,54</td>
<td>Acetone NF</td><td>N / A **</td>
<td>Isopropyl Alcohol USP</td><td>N / A **</td>
<td>USP purified water</td><td>N / A **</td>
<td colspan="2">Component III</td>
<td>Carbidopa, USP</td><td> 34,41*</td>
<td>Levodopa, USP</td><td> 127,50</td>
<td>Microcrystalline cellulose, NF</td><td> 69,39</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 2,79</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 5,72</td>
<td>Triethyl citrate, NF</td><td> 2,45</td>
<td>Talc, USP</td><td> 0,54</td>
<td>Acetone NF</td><td>N / A **</td>
<td>Isopropyl Alcohol USP</td><td>N / A **</td>
<td>USP purified water</td><td>N / A **</td>
<td>Component IV</td><td></td>
<td>Tartaric acid NF</td><td> 88,52</td>
<td>Microcrystalline cellulose, NF</td><td> 22,09</td>
<td>Ethylcellulose NF</td><td> 10,20</td>
<td>Hypromellose, Type 2910 USP</td><td> 2,16</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 7,10</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 14,37</td>
ES 2 804 348 T3
<td>Triethyl citrate, NF</td><td> 6,18</td>
<td>Talc, USP</td><td> 3,86</td>
<td>Acetone NF</td><td>N / A **</td>
<td>Isopropyl Alcohol USP</td><td>N / A **</td>
<td>Purified water, USP</td><td>N / A **</td>
<td>Hard gelatin capsule</td><td>1 unit</td>
<td>Total loaded capsule weight</td><td> 502,13</td>
<td colspan="2">* Carbidopa is supplied as a monohydrate; the amount is equivalent to 8.75, 6.88, 31.87 mg of carbidopa in component I, II and III respectively ** Evaporated during the drying process</td>
I-CD / LD Bead Component Manufacturing Ultra Rapid Release Granules
The required amounts of carbidopa, levodopa, croscarmellose sodium, and povidone were loaded into a high shear granulator and mixed until uniform. The mixed powder was granulated by adding the purified water. The granules were discharged and dried in the oven at 60 ± 10 ° C. The LOD was measured using a moisture analyzer and the drying process was stopped when the LOD value was not higher than a target value. The granules were crushed using a mortar and pestle. The crushed granules were passed through a US # 18 mesh and those granules that passed through the 18 mesh were collected. The collected granules were mixed with magnesium stearate.
Eudragit® S100: L100 (2: 1) Coated Quick Release II-CD-LD Bead Component Fabrication
The manufacturing method and process flow chart of this component beads is the same as that of the component 2 beads of Formulation A in IPX066-AH4, except that the mannitol is replaced by lactose.
Eudragit® S100: L100 (2: 1) Coated Slow Release III-CD-LD Bead Component Fabrication
The manufacturing method and process flow diagram for this component beads is the same as for the component 3 beads of Formulation A in IPX066-AH4.
Manufacture of slow release beads of component IV-TA coated with Eudragit® S100: L100 (2: 1)
The manufacturing method and process flow diagram for this component beads is the same as that for component 5 beads of Formulation A in IPX066-AH4.
Manufacture of IPX066 capsules for IPX066-AH5 (A)
The required amounts of the component beads were filled into hard gelatin capsules according to the specified target fill weights ± 10%.
Table 27. Target fill weights of the capsule test formulation. IPX066
<td>Components (edit)</td><td>IPX066-AH5 (A) mg / capsule</td>
<td>Component I beads</td><td> 46,39</td>
<td>Component II pearls</td><td> 53,56</td>
<td>Component III pearls</td><td> 244,70</td>
<td>Component IV beads</td><td> 154,48</td>
<td>Total loaded capsule weight</td><td> 502,13</td>
Example 9
The example describes the formulations IPX066-AH6 (A) and IPX066-AH6 (B) and the methods for making them.
Table 28
<td>Formulation</td><td rowspan="3"> %</td><td>IPX066-AH6 (A)</td><td>IPX066-AH6 (B)</td>
<td>Dose strength</td><td>245 mg</td><td>195 mg</td>
<td>Ingredients</td><td>mg / capsule</td><td>mg / capsule</td>
<td>Carbidopa</td><td> 10,21</td><td> 66,14<sup>α</sup></td><td> 52,64<sup>α</sup></td>
<td>Levodopa</td><td> 37,84</td><td> 245,00</td><td> 195,00</td>
<td>Tartaric acid</td><td> 17,63</td><td> 132,53</td><td> 105,48</td>
ES 2 804 348 T3
<td>Microcrystalline cellulose</td><td> 19,23</td><td> 124,63</td><td> 99,20</td>
<td>Mannitol</td><td> 1,01</td><td> 6,43</td><td> 5,12</td>
<td>Ethylcellulose</td><td> 2,03</td><td> 15,27</td><td> 12,15</td>
<td>Hypromellose type 2910</td><td> 0,43</td><td> 3,23</td><td> 2,57</td>
<td>Sodium starch glycolate</td><td> 0,50</td><td> 3,21</td><td> 2,55</td>
<td>Sodium lauryl sulfate</td><td> 0,50</td><td> 3,21</td><td> 2,55</td>
<td>Povidone</td><td> 0,34</td><td> 2,52</td><td> 2,01</td>
<td>talcum powder</td><td> 1,36</td><td> 9,45</td><td> 7,52</td>
<td>Ac copolymer, methacrylic, Type A (Eudragit® L100)</td><td> 2,09</td><td> 14,84</td><td> 11,81</td>
<td>Ac copolymer, methacrylic, Type B (Eudragit® S100)</td><td> 4,25</td><td> 30,11</td><td> 23,97</td>
<td>Triethyl citrate NF</td><td> 1,82</td><td> 12,93</td><td> 10,29</td>
<td>Croscarmellose sodium</td><td> 0,69</td><td> 5,31</td><td> 4,23</td>
<td>Magnesium stearate</td><td> 0,05</td><td> 0,38</td><td> 0,30</td>
<td>Purified water</td><td>N / A **</td><td>N / A **</td><td>N / A **</td>
<td>Isopropyl alcohol</td><td>N / A **</td><td>N / A **</td><td>N / A **</td>
<td>Acetone</td><td>N / A **</td><td>N / A **</td><td>N / A **</td>
<td>Ethyl alcohol</td><td>N / A **</td><td>N / A **</td><td>N / A **</td>
<td>Total</td><td> 100%</td><td> 675,19</td><td> 537,39</td>
<td>Hard gelatin capsules</td><td></td><td>1 unit (size 00)</td><td>1 unit (size 0EL)</td>
<td colspan="4">* Carbidopa is supplied as a monohydrate; thus, the amount is equivalent to 61.25.48.75 mg of carbidopa * * Evaporated during the drying process</td>
Manufacturing Test Formulation
Four different component beads were made for test formulation IPX066-AH6 (A) and AH6 (B). The qualitative and quantitative compositions for each component seed are summarized in Table 29.
Table 29. Qualitative and quantitative composition for 4-component beads in capsule formulation
IPX066
<td></td><td>IPX066-AH6 (A)</td><td>IPX066-AH6 (B)</td>
<td>Ingredients</td><td>mg / capsule</td><td>mg / capsule</td>
<td colspan="3">Component I</td>
<td>Carbidopa, USP</td><td> 14,50*</td><td> 11,54*</td>
<td>Levodopa, USP</td><td> 53,71</td><td> 42,75</td>
<td>Croscarmellose sodium</td><td> 5,31</td><td> 4,23</td>
<td>Povidone</td><td> 1,89</td><td> 1,50</td>
<td>Magnesium stearate</td><td> 0,38</td><td> 0,30</td>
<td>USP purified water</td><td>N / A **</td><td>N / A **</td>
<td colspan="3">Component II</td>
<td>Carbidopa USP</td><td> 9,42*</td><td> 7,50*</td>
<td>Levodopa USP</td><td> 34,87</td><td> 27,75</td>
<td>Microcrystalline cellulose, NF</td><td> 6,43</td><td> 5,12</td>
<td>Mannitol NF</td><td> 6,43</td><td> 5,12</td>
<td>Sodium starch, glycolate, NF</td><td> 3,21</td><td> 2,55</td>
<td>Sodium lauryl sulfate, NF</td><td> 3,21</td><td> 2,55</td>
<td>Povidone, USP</td><td> 0,63</td><td> 0,51</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 0,79</td><td> 0,63</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 1,57</td><td> 1,25</td>
<td>Triethyl citrate, NF</td><td> 0,67</td><td> 0,53</td>
<td>Talc, USP</td><td> 0,68</td><td> 0,54</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td>
<td>USP purified water</td><td>N / A *</td><td>N / A *</td>
<td colspan="3">Component III</td>
<td>Carbidopa, USP</td><td> 42,22*</td><td> 33,60*</td>
<td>Levodopa, USP</td><td> 156,42</td><td> 124,50</td>
<td>Microcrystalline cellulose, NF</td><td> 85,13</td><td> 67,76</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 3,42</td><td> 2,72</td>
ES 2 804 348 T3
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 7,02</td><td> 5,59</td>
<td>Triethyl citrate, NF</td><td> 3,01</td><td> 2,39</td>
<td>Talc, USP</td><td> 2,99</td><td> 2,38</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td>
<td colspan="3">Component IV</td>
<td>Tartaric acid NF</td><td> 132,53</td><td> 105,48</td>
<td>Microcrystalline cellulose, NF</td><td> 33,07</td><td> 26,32</td>
<td>Ethylcellulose NF</td><td> 15,27</td><td> 12,15</td>
<td>Hypromellose, Type 2910 USP</td><td> 3,23</td><td> 2,57</td>
<td>Ac copolymer, methacrylic, type A, NF (Eudragit® L100)</td><td> 10,63</td><td> 8,46</td>
<td>Ac copolymer, methacrylic, type B, NF (Eudragit® S100)</td><td> 21,52</td><td> 17,13</td>
<td>Triethyl citrate, NF</td><td> 9,25</td><td> 7,37</td>
<td>Talc, USP</td><td> 5,78</td><td> 4,60</td>
<td>Acetone NF</td><td>N / A *</td><td>N / A *</td>
<td>Isopropyl Alcohol USP</td><td>N / A *</td><td>N / A *</td>
<td>Purified water, USP</td><td>N / A *</td><td>N / A *</td>
<td>Hard gelatin capsule</td><td>1 unit</td><td>1 unit</td>
<td>Total loaded capsule weight</td><td> 675,19</td><td> 537,39</td>
<td colspan="3">** Carbidopa is supplied as a monohydrate * evaporated in the drying process</td>
I-CD / LD Component Bead Manufacturing Ultra Rapid Release Granules
The manufacturing method and process flow chart of the beads of this component is the same as that of the beads of Component 1 of Formulation A in IPX066-AH5, except that the beads were dried with GPCG-I instead of in an oven, and ground in a Fitzmill rather than by mashing with pestle and mortar.
Eudragit® S100: L100 (2: 1) Coated Quick Release Component II-CD-LD Beads Fabrication
The manufacturing method and process flow chart of this component beads is the same as that of the component 2 beads of Formulation A in IPX066-AH5.
Eudragit® S100: L100 (2: 1) Coated Slow Release Component III-CD-LD Beads Fabrication
The manufacturing method and process flow diagram for this component beads is the same as for the formulation A component 3 beads in IPX066-AH5.
Manufacture of slow release beads of component IV-TA coated with Eudragit® S100: L100 (2: 1)
The manufacturing method and process flow diagram for this component beads is the same as that for component 4 beads of Formulation A in IPX066-AH5.
Manufacture of IPX066 capsules for IPX066-AH6 (A) and (B)
The required amounts of the component beads were filled into hard gelatin capsules according to the specified target fill weights ± 10%.
Table 30. Target fill weights of the IPX066 capsule test formulation
Components (edit) IPX066-AH6 (A) mg / capsule IPX066-AH6 (B) mg / capsule Component I beads 75.79 60.32 Component II pearls 67.91 54.05 Component III pearls 300.21 238.94 Component IV beads 231.28 184.08 Total loaded capsule weight 675.19 537.39
Contents41
50 members in 13 offices
Priority claims3
| Document | Office | Kind | Date |
|---|---|---|---|
| 9457 | United States of America | – | |
| 945707 | United States of America | A | |
| 2008014080 | United States of America | W |
Members50
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| EP2234963A4 | European Patent Office (EPO) | A4 | |
| ZA201005309B | South Africa | B | |
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| KR101752080B1 | Republic of Korea | B1 | |
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| IL263053A | Israel | A | |
| EP2234963B1 | European Patent Office (EPO) | B1 | |
| ES2804348T3This record | Spain | T3 |
Numbers
- Publication
- 2804348
- Application
- 8866933
Titles2
- Spanish
- Formulaciones de liberación controlada de levodopa y usos de las mismas
- English
- Controlled-release formulations of levodopa and uses thereof
Classification
- IPC, 4
- A61K9 22
- A61K31 198
- A61K45 06
- C07C229 00