CN114681392A

CN114681392A - Sustained-release oral solid composition

Info

Publication number: CN114681392A
Application number: CN202111628754.8A
Authority: CN
Inventors: 李金宇; 刘廷; 李锋; 张钰; 李康健; 孙琼; 卢韵
Original assignee: Jiangsu Hengrui Medicine Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd
Priority date: 2020-12-29
Filing date: 2021-12-28
Publication date: 2022-07-01

Abstract

The present disclosure provides a sustained release oral solid composition. Specifically, the present disclosure provides a sustained release oral solid composition, the sustained release component of which comprises: (a) a core comprising levodopa and/or an ester of levodopa or a salt thereof, carbidopa and at least one pharmaceutically acceptable excipient; (b) an adhesive layer surrounding the core comprising a mucoadhesive polymer; (c) an enteric layer surrounding the adhesive layer, comprising an enteric polymer; and (d) a rate controlling component comprising a rate controlling polymer.

Description

Sustained-release oral solid composition

Technical Field

The disclosure belongs to the field of medicine, and relates to a sustained-release oral solid composition.

Background

Patients suffering from Parkinson's Disease (PD) often exhibit symptoms of dyskinesia, and abnormally low levels of dopamine (neurotransmitters affecting mobility and control of the skeletal-muscular system) are generally considered to be the major cause of these motor symptoms in PD patients. However, dopamine administration is not effective in treating motor symptoms of parkinson's disease because dopamine does not cross the blood brain barrier. To address this problem, Levodopa (LD), a metabolic precursor of dopamine, is typically administered to PD patients, but has some problems.

Over time, patients treated with LD exhibit symptoms of "hypopharmacodynamic (bearingoff)" in which a single dose of levodopa can no longer last as long as the early phase of levodopa therapy (typically 5-10 years after initiation of levodopa therapy). Such patients can develop motor fluctuations manifested as end-of-dose relapse, peak dyskinesia (akanesia), and akinesia. Advanced forms of motion fluctuation (also commonly referred to as the "on-off" phenomenon) are characterized by unpredictable fluctuations from mobility to immobility. Although the cause of these motor fluctuations is not fully understood, advanced patients typically require a treatment regimen that results in a stable plasma level of LD, such as enteral infusion of LD, due to the presence of the motor fluctuations. However, the intestinal infusion treatment of LD is highly demanding, cumbersome to operate, and traumatic. Oral LD is the most accepted treatment regimen for patients, but it is often difficult to control the plasma concentration levels of oral drugs.

On the other hand, although LD crosses the blood-brain barrier and is rapidly converted to dopamine, LD still has some problems because it is rapidly decarboxylated by tissues other than the brain. When administered orally, levodopa is rapidly decarboxylated to dopamine in the extracerebral tissues, so that only a small fraction of LD can be transported into the central nervous system, while remaining in peripheral tissues causes a series of side effects. Decarboxylase inhibitors, such as Carbidopa (CD), inhibit the decarboxylation of LD, and because their decarboxylase inhibitory activity is localized in the extracerebral tissue, the administration of a decarboxylase inhibitor together with levodopa results in increased transport of levodopa into the brain.

In view of the foregoing, there is a clinical need for LD oral dosage forms with minimal 'peak to valley' fluctuations during daily dosing and with stable blood levels. WO2015054302 discloses an enteric oral formulation comprising LD and CD which, although maintaining relatively stable blood levels over a relatively long period of time, also suffers from a high incidence of side effects (Clin Neuropharmacol, 2019; 42(1): 4-8). it discloses that patients taking IPX-203 formulations have an incidence of side effects of 35.7%.

Disclosure of Invention

To overcome the deficiencies of the prior art, the present disclosure provides a sustained release oral solid composition.

The composition provided by the application can reach the levodopa concentration in blood plasma of more than 50% of the peak plasma concentration (Cmax) (the treatment level of the levodopa) in an extremely short time after a patient takes the composition disclosed by the application, and can maintain the levodopa concentration in blood plasma of more than 50% of the Cmax in a time period of at least 4 hours, preferably at least 4.5 hours, more preferably at least 4.7 hours, so that an infusion-shaped levodopa blood concentration distribution can be realized by taking the medicine orally, the patient is ensured to be in an on-state condition in a longer time, and the time of an off-state and dyskinesia is minimized. Meanwhile, carbidopa in the composition has similar slow release characteristics with levodopa, can continuously inhibit peripheral decarboxylation of levodopa during treatment, and further reduces dopaminergic side effects.

In a first aspect, the present disclosure provides a sustained release oral solid composition comprising a sustained release component comprising: (a) a core comprising levodopa and/or an ester of levodopa or a salt thereof, carbidopa and at least one pharmaceutically acceptable excipient; (b) an adhesive layer surrounding the core, comprising a mucoadhesive polymer; (c) an enteric layer surrounding the adhesive layer, comprising an enteric polymer; and (d) a rate controlling component comprising a rate controlling polymer.

Examples of levodopa include, but are not limited to: levodopa, L-DOPA, L-3, 4-dihydroxyphenylalanine, and (S) -2-amino-3- (3, 4-dihydroxyphenyl) propionic acid.

Examples of carbidopa include, but are not limited to: carbidopa and (S) - α -methyl- α -hydrazino-3, 4-dihydroxyphenylpropionic acid monohydrate.

Examples of esters of levodopa include, but are not limited to: levodopa methyl ester, levodopa ethyl ester, levodopa propyl ester, and levodopa butyl ester. The ester of levodopa may be a salt, including in the case of hydrated salts, in particular, salts of levodopa esters include, but are not limited to: any one of caprylate, myristate, succinate dihydrate, fumarate dihydrate, mesylate, tartrate and hydrochloride.

In some embodiments, the rate controlling component of the sustained release composition: (A) incorporating the core; (B) priming the adhesive layer around the core; (C) doping an adhesion layer; or (D) a combination of any two or three of (A), (B) and (C).

In one embodiment, the rate controlling component surrounds the core and primers the adhesion layer.

In some embodiments, the sustained release component formulation of the present disclosure is formulated as one or more of a powder, a tablet, a mini-tablet, a pill, a bead, or a granule.

In some embodiments, the core of the sustained release component of the present disclosure comprises at least one pharmaceutically acceptable excipient; in some embodiments, the excipient may be selected from one or more of croscarmellose sodium, microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, hydroxypropyl cellulose.

In some embodiments, the adhesion layer of the sustained release component of the present disclosure comprises an anti-tack agent; in some embodiments, the antisticking agent may be selected from one or more of talc, magnesium stearate, glyceryl monostearate.

In some embodiments, the adherent layer of the slow release component of the present disclosure comprises one or more of a plasticizer, an anti-tack agent; in some embodiments, the antisticking agent may be selected from one or more of talc, magnesium stearate, glyceryl monostearate; in some embodiments, the plasticizer may be selected from one or more of triethyl citrate, polyethylene glycol 6000, tributyl citrate, dibutyl sebacate

In yet other embodiments, the compositions of the present disclosure further comprise an immediate release component comprising: levodopa and/or an ester of levodopa or a salt thereof, carbidopa and at least one pharmaceutically acceptable excipient. In some embodiments, the excipient may be selected from one or more of croscarmellose sodium, microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, hydroxypropyl cellulose.

In some embodiments, the immediate release component may be formulated as one or more of a powder, a tablet, a mini-tablet, a pill, a bead, or a granule.

The immediate release component of the present disclosure may further comprise a barrier coating, the coating material may be selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, carnauba wax, methylcellulose, gelatin, cellulose acetate, ethylcellulose, shellac, microcrystalline wax, polyvinyl acetate phthalate, glyceryl behenate, hydroxypropyl methylcellulose phthalate, and hydroxyethyl methylcellulose; in some embodiments, the coating material is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose; in some embodiments, the coating material is hydroxypropyl cellulose.

In some embodiments, the compositions of the present disclosure further comprise an absorption-promoting component comprising a carboxylic acid selected from one or more 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; tartaric acid is preferred. The absorption enhancing component may be formulated as one or more of a powder, tablet, mini-tablet, pill, bead or granule. The absorption promoting component can improve the end absorption of the levodopa and further prolong the time of the blood concentration staying in the therapeutic window.

Examples of rate controlling polymers suitable for use in the sustained release component of the present disclosure include, but are not limited to: ethyl cellulose, cellulose acetate,

And

or mixtures thereof. Preferably, the rate controlling polymer is insoluble in water at neutral pH. In one embodiment, the rate controlling polymer is ethyl cellulose or cellulose acetate; preferably cellulose acetate.

The rate controlling polymer of the present disclosure may comprise 1.0% to 8.0%, preferably 2.0% to 6.0%, more preferably 2.5% to 5%, even more preferably 3.0% to 4.0% by mass of the sustained release component.

To further modulate the release rate, the rate controlling component of the present disclosure may further comprise a pore-forming agent selected from one or more of copovidone, polyethylene glycol, hydroxypropyl methylcellulose, and hydroxyethyl methylcellulose; preferably copovidone.

The pore-foaming agent of the present disclosure may account for 0.5% to 5%, preferably 1% to 3%, more preferably 1.5% to 2% by mass of the sustained-release component.

The mucoadhesive polymer may be composed of a single polymer or a combination of two or more different polymers. Mucoadhesive polymers may have certain characteristics, such as being hydrophilic, hydrophobic, cationic, anionic, and/or biocompatible, for adhering to mucosal surfaces so that the active agent's presence may be extended at the site of absorption to increase bioavailability. In addition, the mucoadhesive polymer may be of natural, synthetic or biological origin. In some embodiments, the size of the polymer may be in the range of 10,000 daltons to 1,000,000 daltons, and more preferably 20,000 daltons to 200,000 daltons.

In some embodiments, the mucoadhesive polymer is selected from one or more of basic methacrylate copolymers, polycarbophil, carbomers, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyornithine, prolamine, polyimine, hyaluronic acid, alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose.

In some embodiments, the mucoadhesive polymer is an alkaline methacrylate copolymer; preferably aminoalkyl methacrylate copolymers; more preferably butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1) copolymers, e.g.

In some embodiments, the mucoadhesive polymer may comprise from 2.0% to 20.0%, preferably from 5.0% to 15.0%, more preferably from 8.0% to 12.0%, even more preferably from 9.0% to 11.0% by weight of the slow release component.

In some embodiments, the mass ratio of the rate controlling polymer to mucoadhesive polymer in the sustained release component is 1:0.5 to 5, specifically 1:0.5, 1:1, 1:1.5, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1: 5.0; preferably 1: 1-4; more preferably 1:2 to 3.

Enteric polymers are designed to prevent drug release from the solid composition in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine. Thus, the sustained release components of the present disclosure have an in vitro release profile with minimal release of the active ingredient at pH 1.0. In the sustained-release component of the present disclosure, the enteric polymer also provides an additional advantage of preventing the sustained-release component from cohering in the low pH environment of the stomach.

In some embodiments, the enteric polymer is selected from one or more of methacrylic acid copolymer, shellac, cellulose acetate phthalate, cellulose acetate trimellitate, poly (vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate.

And in some embodiments, the enteric polymer of the present disclosure is a methacrylic acid copolymer; may be selected from methacrylic acid-ethyl acrylate (1:1) copolymers (e.g.

Or

) Methacrylic acid-methyl methacrylate (1:1) copolymer (e.g.

) And methacrylic acid-methyl methacrylate (1:2) copolymer (e.g.

) One or more of; one or both of a methacrylic acid-methyl methacrylate (1:1) copolymer and a methacrylic acid-methyl methacrylate (1:2) copolymer are preferable; more preferably a methacrylic acid-methyl methacrylate (1:1) copolymer.

In some embodiments, the enteric polymer may comprise from 2.0% to 15.0%, preferably from 5.0% to 12.0%, more preferably from 6.0% to 11.0%, even more preferably from 8.0% to 10.0% by weight of the sustained release component.

In some embodiments, the mass ratio of mucoadhesive polymer to enteric polymer in the sustained release component is 1: 0.5-3, specifically 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1.0, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1: 3.0; preferably 1:0.6 to 2; more preferably 1:0.7 to 1.5; even more preferably 1:0.75 to 1.2.

The compositions of the present disclosure may be prepared by granulation methods well known in the pharmaceutical art, including but not limited to: wet granulation, fluidized bed granulation or dry granulation. The sustained release component and/or the immediate release component may additionally contain a lubricant, such as talc. The slow release component and/or the fast release component of the present disclosure may also include a surfactant, such as sodium lauryl sulfate.

The components of the composition of the present disclosure may be used sequentially or after mixing, after formulation, by methods including multiparticulates, tablets, caplets, matrix tablets, and capsules, which may be single or multi-layered. In one embodiment, the composition is encapsulated in a capsule.

In some embodiments, the mass ratio of carbidopa to levodopa in the compositions of the present disclosure is 1: 1-10; preferably 1: 2-5; more preferably 1: 3-4; even more preferably 1:4.

The mass or ratio of carbidopa according to the present disclosure is calculated as the equimolar converted mass of anhydrous carbidopa unless otherwise specified, and similarly, the mass or ratio of levodopa according to the present disclosure is calculated as the equimolar converted mass of levodopa unless otherwise specified.

In some embodiments, the mass ratio of levodopa in the quick release component to the sustained release component is 1: 0.5-5, specifically 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1: 5; preferably 1: 1-4; more preferably 1: 2-3; even more preferably 1:3.

In yet other embodiments, the mass ratio of carbidopa in the immediate release component to the sustained release component is 1: 0.1-5, specifically 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1.0, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1: 5; preferably 1:0.2 to 4; more preferably 1:0.5 to 3.

The controlled release components of the present disclosure will exhibit minimal release of levodopa and carbidopa at pH 1.0-2.0 and exhibit a dissolution profile of extended release of levodopa and carbidopa at a pH near neutral, for example at or near pH 7.

The dissolution capacity of the composition or sustained release components of the present disclosure was tested according to the dissolution method specified in the first law of four 0931 of chinese pharmacopoeia 2015 edition, using 900ml of enzyme-free artificial gastric juice at pH 1.6 as dissolution medium at 75 rpm, discarding acid solution at 120min, and then using 900ml of phosphate buffered saline at pH 7.0 as release medium at 75 rpm. In some embodiments, the sustained release component of the compositions of the present disclosure releases up to 10% of levodopa at 120 min; preferably up to 5% levodopa is released; more preferably at most 3% of levodopa is released. In other embodiments, the sustained release component of the compositions of the present disclosure releases up to 10% carbidopa at 120 min; preferably up to 5% carbidopa is released; more preferably up to 3% carbidopa is released.

The levodopa and carbidopa in the sustained release component are continuously dissolved after the pH of the environment is increased, and according to the dissolution test method described above, in one embodiment, the composition of the present disclosure releases at least 90% of the levodopa within 5 to 7 hours. In another embodiment, the composition of the present disclosure releases at least 80% of carbidopa within 4 to 6 hours.

After a patient takes the composition disclosed by the invention, the concentration of levodopa in blood plasma can reach more than 50% of the peak plasma concentration (Cmax) (the therapeutic level of levodopa) in a very short time, and the blood concentration of levodopa is maintained to be more than 50% of the Cmax in at least 4 hours, preferably at least 4.5 hours, more preferably at least 4.7 hours, so that the blood concentration distribution of levodopa in an infusion form can be realized by orally taking a medicine, the patient is ensured to be in an 'on-state' state in a longer time, and the time of 'off-state' and dyskinesia is minimized. Meanwhile, carbidopa in the composition has similar slow release characteristics with levodopa, can continuously inhibit decarboxylation of levodopa during treatment, and further reduces dopa-like side effects in peripheral tissues.

After patients take the composition disclosed by the invention, the incidence rate of the induced adverse reaction is low, and the composition disclosed by the invention has high safety.

In some embodiments, the ratio of carbidopa: the mass ratio of levodopa is any one selected from the group consisting of: (a)17.5 mg: 70 mg; (b)20 mg: 80 mg; (c)22.5 mg: 90 mg; (d)25 mg: 100 mg; (e)30 mg: 120 mg; (f)35 mg: 140 mg; (g)40 mg: 160 mg; (h)45 mg: 180 mg; (i)52.5 mg: 210 mg; (j)60 mg: 240 mg; (k)70 mg: 280mg or (e)87.5 mg: 350 mg; wherein each value can vary by + -10%

In a second aspect, the present disclosure also provides the use of a composition according to the first aspect for the treatment of a disorder associated with reduced levels of dopamine. Diseases associated with reduced dopamine levels include neurological or movement disorders such as restless leg syndrome, Alzheimer's disease, dystonia, schizophrenia, Parkinson's disease, Huntington's disease, attention deficit/hyperactivity disorder (ADHD), snow-du syndrome (she-Drager syndrome), and conditions caused by brain injury including carbon monoxide or manganese poisoning.

In some embodiments, the composition of the first aspect is used to treat parkinson's disease or parkinsonism.

Moreover, the numerical ranges and parameters setting forth the disclosure are approximate, and numerical values related to particular embodiments are presented herein as precisely as possible. Any numerical value, however, inherently contains certain standard deviations found in their respective testing measurements. Accordingly, unless expressly stated otherwise, it is understood that all ranges, amounts, values and percentages used in this disclosure are by weight modified by "about". As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range.

Detailed Description

1. Experimental reagent

2. Laboratory apparatus

Serial number	Name of instrument	Source
			1	TMG1/6 wet granulator	Glatt
2	IPS-25 extrusion rounding machine	GEA
			3	DPL-II fluidized bed	Chongqing Seiko
4	GPCG1.1 fluidized bed	Glatt

3. Examples of the embodiments

3.1 example 1 preparation of immediate Release granules

The formulation of the immediate release granules is shown in table 1.

TABLE 1 quick-release granule formulation composition

The preparation process comprises the following steps:

1) preparing a soft material: adding the weighed and prepared levodopa, carbidopa (monohydrate), microcrystalline cellulose PH101, croscarmellose sodium and povidone K30 into a granulator, setting the stirring speed to be 200rpm and the cutter speed to be 1500rpm, and carrying out dry mixing. While continuing the mixing, purified water was added as a wetting agent and wet shearing was carried out at a stirring speed of 200rpm and a cutter speed of 2000 rpm.

2) Extruding and rounding to prepare the pellets: extruding and rounding by using an extruding and rounding machine, wherein the screen mesh type is as follows: 0.8 × 0.7, impeller speed 35rpm, stirring speed: 25rpm, spheronization speed: 500 rpm.

3) And (3) drying the pellets: drying the vegetarian ball by using a fluidized bed, setting the air inlet temperature at 70 ℃ and the air inlet frequency at 25Hz until the water content is less than or equal to 2.0 percent.

4) Screening: and (4) screening the dried pellets by using 20-mesh and 30-mesh screens, and taking the pellets between 20 meshes and 30 meshes.

5) Coating: water at 70 ℃ was added to the vessel and stirring was started, while stirring, hypromellose was slowly added to the vortex of solvent and mixing was continued until the copolymer was completely dissolved. After calibration of the spray rate, glaster GPCG1.1 equipped with a worster insert was used for coating at an inlet temperature of 45 ℃, an atomization gas pressure of 1.5bar and a worster septum height of 20 mm. After spraying the target amount of coating solution, it was dried at an inlet temperature of 50 ℃.

3.2 example 2 preparation of sustained Release granules

The formulation of the sustained release granules is shown in table 2.

TABLE 2 sustained Release granule formulation

The preparation process comprises the following steps:

1) soft mass preparation, 2) pellet preparation by extrusion spheronization, 3) pellet drying and 4) sieving the same as in example 1.

4) Coating a film control layer: cellulose acetate and copovidone (Kollidon VA64) were completely dissolved in a mixed solution of acetone and isopropanol solution. After calibration of the spray rate, glaster GPCG1.1 equipped with a worster insert was used for coating at an inlet temperature of 30 ℃, an atomization gas pressure of 1.5bar and a worster septum height of 20 mm. After spraying the target amount of coating solution, it was dried at an inlet temperature of 30 ℃.

5) Yutex E100 coating: dissolving Eiteqi E100 in ethanol under stirring, adding pulvis Talci to form suspension, and stirring continuously during coating process. After calibration of the spray rate, glaster GPCG1.1 equipped with a worster insert was used for coating at an inlet temperature of 30 ℃, an atomization gas pressure of 1.5bar and a worster septum height of 20 mm. After spraying the target amount of coating solution, the coated beads were dried at an air inlet temperature of 30 ℃.

6) Enteric coating: completely dissolving Eiteqi L100 in ethanol under stirring, adding triethyl citrate and pulvis Talci to form suspension, and stirring continuously during coating process. After calibration of the spray rate, glaster GPCG1.1 equipped with a worster insert was used for coating at an inlet temperature of 30 ℃, an atomization gas pressure of 1.5bar and a worster septum height of 20 mm. After spraying the target amount of coating solution, it was dried at an air inlet temperature of 30 ℃.

3.3 example 3 preparation of absorption promoting particles

The formulation of the absorption enhancing particles is shown in table 3.

TABLE 3 prescription composition of absorption-promoting granules

The preparation process comprises the following steps:

1) soft mass preparation, 2) extrusion spheronization for pellet preparation, 3) pellet drying and 4) sieving the pellets as in example 1, with the only difference that the spheronization speed is 700 rpm.

5) Coating of the slow release layer: separately, a prescribed amount of HPMC (E5) was dissolved in hot water, a prescribed amount of ethylcellulose was dissolved in absolute ethanol, and after complete dissolution, the two solutions were mixed together and stirred. Glaster GPCG1.1 equipped with a worsted insert was used for coating at an inlet air temperature of 30 ℃, an atomisation air pressure of 1.5bar and a worsted septum height of 20 mm. After spraying the target amount of coating solution, it was dried at an inlet temperature of 30 ℃.

6) Enteric coating: adding the Eudragit L100 and S100 into 95% ethanol, adding triethyl citrate and talcum powder after completely dissolving to form a suspension, and continuing stirring. After calibration of the spray rate, glaster GPCG1.1 equipped with a worster insert was used for coating at an inlet temperature of 30 ℃, an atomization gas pressure of 1.5bar and a worster septum height of 20 mm. After spraying the target amount of coating solution, it was dried at an inlet temperature of 30 ℃.

3.4 example 4 preparation of composition capsules

The capsules were obtained by filling according to the proportions in table 4.

TABLE 4 fill-in amount of capsules (specification: carbidopa/levodopa ═ 43.75 mg: 175mg)

Code for preparation	Immediate release granules/mg	Sustained release granule/mg	Absorption promoting granule/mg
				T1	Prescription A73.62	Prescription I298.54	/
T2	Prescription A73.62	Prescription II 299.80	/
				T3	Prescription A73.62	Prescription I298.54	Prescription a 175
T4	Prescription A73.62	Prescription I298.54	Prescription b 267.19
				T5	Prescription A73.62	Prescription III 269.32	/
T6	Prescription B93.96	Prescription IV 271.09	/

3.5 preparation of T7 capsules

Immediate release and sustained release granules were prepared in a similar manner to examples 1 and 2 in accordance with the proportions of formulation C shown in table 5 and formulation V shown in table 6, and filled in a capsule according to the proportion of formulation C70.94 mg/formulation V252.89 mg (specification: carbidopa/levodopa-43.75 mg: 175mg) to obtain T7 capsules.

TABLE 5 prescription composition of immediate release granules of T7

TABLE 6 prescription composition of sustained-release granules of T7

Biological test evaluation

The present invention is further described and illustrated below in conjunction with specific examples thereof, which are not intended to limit the scope of the present invention.

1. Experimental reagent

Serial number	Reagent	Source
			1	Hydrochloric acid	SINOPHARM CHEMICAL REAGENT Co.,Ltd.
2	Sodium hydroxide	Shanghai Lingfeng Chemicals Co., Ltd
			3	Sodium dihydrogen phosphate dihydrate	SINOPHARM CHEMICAL REAGENT Co.,Ltd.
4	Sodium chloride	SINOPHARM CHEMICAL REAGENT Co.,Ltd.
			5	FaSSIF/FeSSIF/FaSSGF	Biorelevant.com Ltd

2. Laboratory apparatus

Serial number	Instrument for measuring the position of a moving object	Source
			1	AT-7smart dissolution instrument	SOTAX
2	708-DS dissolution instrument	Agilent

3. Test example

3.1 in vitro dissolution test

According to the dissolution determination method (first method of 0931 in four parts of the Chinese pharmacopoeia 2015 edition), 900ml of enzyme-free artificial gastric juice with pH of 1.6 is used as dissolution medium, the rotation speed is 75 r/min, the acid solution is discarded at 120min, 900ml of phosphate buffer with pH of 7.0 is used as release medium, and the rotation speed is 75 r/min. The cumulative release of each component of the capsules of formulations T1 to T3 and T5 to T6 is shown in table 7; the cumulative release of each ingredient from the capsules of formulations T4 and T7 is shown in table 8.

TABLE 7 cumulative release (%) -of the capsules T1 to T3 and T5 to T6

TABLE 8 cumulative Release (%) -of T4 and T7 capsules

The cumulative release profiles of sustained release granule formulations I and II were determined according to the above dissolution test method, and the results are shown in Table 9.

TABLE 9 cumulative Release (%)

The basic methacrylate copolymer contained in the adhesive layer and the methacrylic acid copolymer contained in the enteric layer contain amino groups, so that ionic interaction can occur between the two polymers, and the viscosity, swelling behavior and the like of the polymers can change along with the difference of the types and the proportions of the polymers, which is proved by related documents (J Control Release, 2005; 103: 191-198). The sustained release component of the present disclosure further comprises a rate controlling component, which further comprises a polymer containing carboxyl groups, which forms a more complex carboxyl-amino-carboxyl ionic interaction system with the adhesion layer and the enteric layer, and in addition, the active component also comprises acidic and basic groups, which makes the swelling and release characteristics of the sustained release component as a whole more difficult to predict.

The composition disclosed by the invention has more excellent carbidopa sustained release data compared with a control on the basis of stable and long-acting levodopa release characteristics, which suggests that the carbidopa in the prescription disclosed by the invention can continuously inhibit the decarboxylation of the levodopa for a relatively long time, and thus the side effects of peripheral tissues caused by the decarboxylation of the levodopa are greatly relieved.

3.2 in vivo pharmacokinetic testing

3.2.1 run 1

The study adopts a single-center, random, open, four-cycle cross test design, and a 3-day cleaning period is used in the cycle. Subject: 12 healthy subjects were planned for selection, with no restriction.

The test method comprises the following steps: the study is divided into 6 stages of screening period, 1 st period, 2 nd period, 3 rd period, 4 th period and post-test physical examination. And (3) screening period: and (3) the subjects are fully informed 7 days before the administration to 1 day before the administration, and are screened and checked after signing an informed consent book, and are subjected to a group test after the subjects are qualified. Cycle 1: subjects were admitted to phase i ward 1 day prior to dosing and fasted for at least 10 hours prior to dosing. Drugs T1, T2 or IPX-066 were tested orally on a single fasting basis on a random schedule on the morning of the day of administration. Drinking water is prohibited before and 1 hour after taking medicine, and fasting is performed within 4 hours after taking medicine. About 4mL of elbow venous blood was collected at 0h before administration (within 1h before administration) and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 10.0, 12.0, 14.0h after administration; vital signs were measured at enrollment, within 1h prior to dosing and 2 (+ -1) h, 4 (+ -1) h, 8 (+ -1) h, 14 (+ -1) h post-dosing, and adverse events were recorded during the course of the experiment. The first cycle procedure was repeated for the second, third and fourth cycles, with a 3-day wash period between cycles.

Administration dose: the test preparation T1, T2, T3350 mg or the reference preparation IPX-066 (trade name) were administered according to a random schedule every cycle

)245mg。

The results of the pharmacokinetic experiments are shown in table 10.

TABLE 10 sample in vivo pharmacokinetic test data

As can be seen from the test results, T1, T2 and T3 all achieved longer than the reference formulation IPX-066>The blood concentration fluctuation degree of the 50% Cmax time and T1 and T2 is lower than that of the reference preparation; cmax and AUC of T1, T2, T3 and reference preparation converted to equal dosage_0-tData are comparable, Cmax and AUC for T1 formulations_0-tHas significantly lower inter-individual variation (RSD%) than that of ginsengThe preparation is prepared.

3.2.2 run 2

The study adopts a single-center, random, open, four-cycle cross test design, and a 3-day cleaning period is used in the cycle. Subject: 16 healthy subjects were scheduled for inclusion, with no restriction.

The test method comprises the following steps: the study is divided into 6 stages of screening period, 1 st period, 2 nd period, 3 rd period, 4 th period and post-test physical examination. And (3) screening period: and (3) the subjects are fully informed 7 days before the administration to 1 day before the administration, and are screened and checked after signing an informed consent book, and are subjected to a group test after the subjects are qualified. Cycle 1: subjects were admitted to the hospital 1 day prior to dosing and fasted for at least 10 hours prior to dosing. Test drugs T5, T6, control or reference formulation IPX-066 were administered orally on a single fasting basis on a random schedule on the morning of the day of administration. Drinking water is forbidden before and 1 hour after the medicine is taken, and fasting is not carried out within 4 hours after the medicine is taken. About 4mL of elbow venous blood was collected at 0h before administration (within 1h before administration) and at 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 7.0, 8.0, 10.0, 12.0, 14.0h after administration; vital signs were measured at enrollment, within 1h prior to dosing, and 2 (+ -1) h, 4 (+ -1) h, 8 (+ -1) h, 14 (+ -1) h post-dose, and adverse events were recorded during the course of the experiment. The first cycle procedure was repeated for the second, third and fourth cycles, with a 3-day wash period between cycles. Administration dose: the test preparation T5, T6, T7350 mg or the reference preparation IPX-066 (trade name) were administered according to a random schedule every cycle

)390 mg. The results of the pharmacokinetic experiments are shown in table 11.

TABLE 11 sample in vivo pharmacokinetic test data

The incidence of adverse reactions is shown in table 12.

TABLE 12 incidence of adverse reactions

Product name	Incidence of treatment-induced adverse reactions	Remarks for note
			IPX-203 (literature)	35.7％	A total of 28 patients with advanced PD participating in the study
T5	18.75％	Participating in the study a total of 16 healthy subjects
			T6	12.5％	Participating in the study a total of 16 healthy subjects
T7	31.25％	Participating in the study a total of 16 healthy subjects
			Reference formulation IPX-066	18.75％	A total of 16 healthy subjects participated in the study

Note: adverse reactions concerned in this study were fatigue, dizziness, lacrimation, fever, muscle soreness, headache, dyspepsia and pregnancy;

it can be seen from the test results that T5, T6 and T7 all achieved > 50% Cmax maintenance times longer than the reference formulation IPX-066, the blood levels of T5, T6 and T7 fluctuated less than the reference formulation and the inter-individual variability (RSD%) was significantly lower than the reference formulation. Meanwhile, the incidence of adverse reactions induced by the treatment of T5, T6 and T7 is lower than that of IPX-203.

Claims

1. An extended release oral solid composition comprising an extended release component comprising: (a) a core comprising levodopa and/or an ester of levodopa or a salt thereof, carbidopa and at least one pharmaceutically acceptable excipient; (b) an adhesive layer surrounding the core comprising a mucoadhesive polymer; (c) an enteric layer surrounding the adhesive layer, comprising an enteric polymer; and (d) a rate controlling component comprising a rate controlling polymer.

2. The composition of claim 1, wherein the rate controlling component: (A) incorporating the core; (B) priming the adhesive layer around the core; (C) doping an adhesion layer; or (D) a combination of any two or three of (A), (B) and (C).

3. The composition of claim 1 or 2, wherein the rate controlling component surrounds the core and primers the adherent layer.

4. The composition according to any one of claims 1 to 3, wherein the sustained release component is formulated as one or more of a powder, a tablet, a mini-tablet, a pill, a bead or a granule.

5. The composition of any one of claims 1-4, further comprising an immediate release component comprising: levodopa and/or an ester of levodopa or a salt thereof, carbidopa and at least one pharmaceutically acceptable excipient.

6. The composition of claim 5, wherein the immediate release component comprises excipients selected from one or more of croscarmellose sodium, microcrystalline cellulose, polyvinylpyrrolidone, sodium lauryl sulfate, and hydroxypropyl cellulose.

7. The composition of claim 6, wherein the immediate release component is formulated as one or more of a powder, a tablet, a mini-tablet, a pill, a bead, or a granule.

8. The compound according to any one of claims 1-7, further comprising an absorption-promoting component comprising a carboxylic acid selected from one or more 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; tartaric acid is preferred.

9. The composition of any of claims 1-8, wherein the rate controlling polymer is ethyl cellulose or cellulose acetate; preferably cellulose acetate.

10. The composition of any one of claims 1-9, the rate controlling component further comprising a porogen selected from one or more of copovidone, polyethylene glycol, hydroxypropyl methylcellulose, and hydroxyethyl methylcellulose; preferably copovidone.

11. The composition according to any one of claims 1 to 10, wherein the mucoadhesive polymer is selected from one or more of the group consisting of alkaline methacrylate copolymers, polycarbophil, carbomer, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyornithine, prolamine, polyimine, hyaluronic acid, alginate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose.

12. The composition of any of claims 1-11, wherein said mucoadhesive polymer is an alkaline methacrylate copolymer; preferably aminoalkyl methacrylate copolymers; more preferred is a butyl methacrylate-dimethylaminoethyl methacrylate-methyl methacrylate (1:2:1) copolymer.

13. The composition of any of claims 1-12, wherein the mass ratio of the rate-controlling polymer to mucoadhesive polymer in the sustained-release component is 1:0.5 to 5; preferably 1: 1-4; more preferably 1:2 to 3.

14. The composition according to any one of claims 1 to 13, wherein the enteric polymer is selected from one or more of methacrylic acid copolymer, shellac, cellulose acetate phthalate, cellulose acetate trimellitate, poly (vinyl acetate phthalate), hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.

15. The composition of any of claims 1-14, wherein the enteric polymer is a methacrylic acid copolymer; preferably one or more selected from methacrylic acid-ethyl acrylate (1:1) copolymer, methacrylic acid-methyl methacrylate (1:1) copolymer and methacrylic acid-methyl methacrylate (1:2) copolymer; more preferably one or both of a methacrylic acid-methyl methacrylate (1:1) copolymer and a methacrylic acid-methyl methacrylate (1:2) copolymer; even more preferably a methacrylic acid-methyl methacrylate (1:1) copolymer.

16. The composition of any of claims 1-15, wherein the weight ratio of mucoadhesive polymer to enteric polymer in the sustained release component is 1:0.5 to 3; preferably 1:0.6 to 2; more preferably 1:0.7 to 1.5; even more preferably 1:0.75 to 1.2.

17. The composition of any one of claims 1-16, wherein the composition is encapsulated in a capsule.

18. The composition according to any one of claims 1 to 17, wherein the mass ratio of carbidopa to levodopa is 1:1 to 10; preferably 1: 2-5; more preferably 1: 3-4; even more preferably 1:4.

19. The composition according to any one of claims 1 to 18, wherein the mass ratio of the levodopa in the quick release component to the sustained release component is 1: 0.5-5; preferably 1: 1-4; more preferably 1: 2-3; even more preferably 1:3.

20. The composition of any of claims 1-19, wherein the mass ratio of carbidopa in the immediate release component to carbidopa in the sustained release component is 1:0.1 to 5; preferably 1:0.2 to 4; more preferably 1:0.5 to 3.

21. The composition according to any one of claims 1-20, wherein 900ml of the enzyme-free artificial gastric juice having a pH of 1.6 is used as dissolution medium at 75 rpm according to the dissolution method specified in the first law of the fourth 0931 of the pharmacopoeia 2015 edition of china, the acid solution is discarded at 120min, and 900ml of phosphate buffer having a pH of 7.0 is used as release medium at 75 rpm; the sustained release component releases up to 10% of levodopa at 120 min; preferably up to 5% levodopa is released; more preferably at most 3% of levodopa is released.

22. The composition of claim 21, wherein said sustained release component releases up to 10% carbidopa at 120 min; preferably up to 5% carbidopa is released; more preferably up to 3% of carbidopa is released.

23. The composition according to any of claims 1-22, wherein 900ml of enzyme-free artificial gastric fluid at pH 1.6 is used as dissolution medium at 75 rpm, the acid solution is discarded at 120min, followed by 900ml of phosphate buffered saline at pH 7.0 as release medium at 75 rpm, according to the dissolution method specified in the first law of the four 0931 parts of the chinese pharmacopoeia 2015 edition; the composition releases at least 90% of levodopa within 5-7 hours.

24. The composition of claim 23, wherein said composition releases at least 80% carbidopa within 4 to 6 hours.

25. The composition according to any of claims 1-24, wherein the in vivo levodopa plasma concentration is maintained at or above 50% Cmax for at least 4 hours, preferably at least 4.5 hours, more preferably 4.7 hours.

26. The composition of any one of claims 1-25, wherein the ratio of carbidopa: the mass ratio of levodopa is any one selected from the group consisting of:

(a)17.5 mg: 70 mg; (b)20 mg: 80 mg; (c)22.5 mg: 90 mg; (d)25 mg: 100 mg; (e)30 mg: 120 mg; (f)35 mg: 140 mg; (g)40 mg: 160 mg; (h)45 mg: 180 mg; (i)52.5 mg: 210 mg; (j)60 mg: 240 mg; (k)70 mg: 280mg or (e)87.5 mg: 350 mg; wherein each value can vary by ± 10%.

27. Use of a composition according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of a condition associated with reduced levels of dopamine.

28. Use of a composition according to any one of claims 1 to 26 in the manufacture of a medicament for the treatment of parkinson's disease or parkinsonism.