CN117355296A - Prolonged release pharmaceutical composition for oral administration Shu Sai mex - Google Patents

Abstract

The present invention relates to an extended release pharmaceutical composition of Shu Sai m in the form of particles for oral administration, wherein the amount of Shu Sai m in each particle is from 0.5mg to 5.0mg and the particle size of the particles is less than 5000 μm and comprises an outer layer providing extended release of Shu Sai m. The invention also relates to the pharmaceutical composition of the invention for the treatment and/or prevention of epilepsy.

Description

Prolonged release pharmaceutical composition for oral administration Shu Sai mex

Technical Field

The present invention relates to an extended release pharmaceutical composition for oral administration Shu Sai me and its use for preventing and/or treating epilepsy, in particular epilepsy in children and subjects suffering from swallowing disorders.

Background

Epilepsy is a disorder of the central nervous system involving sudden and transient attacks of recurrent, motor, convulsive, sensory, autonomic or psychiatric origin abnormalities. Seizures are almost always associated with abnormal and excessive discharges in the brain, which can be recorded by electroencephalography.

Epilepsy afflicts millions of people worldwide, and is more common in children and the elderly (over 60 years of age) than in adults.

Methods of treatment of seizures have heretofore included medication known as antiepileptic drugs, surgical procedures to ablate a small portion of the brain that leads to an epileptic seizure, implantation of small electronic devices in the body to aid in the manipulation of the seizure, or special diets (ketogenic diets) that can aid in the control of the seizure. Epilepsy is often a life-long condition, and some patients require life-long treatment.

Shu Sai m (sub, also known as Shu Sai oxazine or Shu Saian) is an antiepileptic belonging to the class of cyclic sulfonamides, having the following formula (I):

it is used (especially in europe) for the management of seizures for certain types of seizures. The anti-epileptic activity of Shu Sai is believed to be due primarily to inhibition of various subtypes of Carbonic Anhydrase (CA). In particular, the blockade of cytoplasmic CAII appears to produce a degree of intracellular acidification sufficient to stabilize the neurons responsible for seizures. Furthermore, inhibition of sodium channels may contribute to their antiepileptic efficacy (Dao et al Pharmacology Research & Perspectives,2020,Volume 8,Issue 1,e00558).

Shu Sai is the first therapeutic agent to treat benign seizures (BECTS) in children with central temporal area spikes in some countries, including european countries, which is a common (2% of school-age children) childhood non-pathologic seizures, typically occurring between 3 and 12 years of age. BECTS is characterized by nocturnal orofacial motor or sensory seizures, with or without bilateral transmission. The overall prognosis is good, and the pubertal epilepsy can disappear by itself. Shu Sai America is also used to treat sustained spike and wave-type epilepsy (CSWS epilepsy) (pediatric epilepsy affecting 0.2-0.5%) and refractory Depakine (Depakine) epilepsy during slow sleep. Shu Sai america can also be used to treat the following disorders: landau-kleffner, west, lennox and Rett syndrome, acquired epileptic aphasia, atypical benign partial epilepsy, temporal lobe epilepsy, myoclonus and focal epilepsy.

Shu Sai is reported to be well tolerated and may be more effective than other antiepileptic drugs commonly used for focal seizures, such as carbamazepine, gabapentin or levetiracetam (Dao et al Pharmacology Research & peptides, 2020,Volume 8,Issue 1,e00558).

Suhimei is used in Europe and other countries such as Israel, argentina and AustraliaTrade names are sold. />Is an immediate release coated tablet containing 50mg or 200mg Shu Sai Mei. />It is expected that the administration will be at least 3 times per day, typically at least 4 times per day, with maintenance doses in the range of 5 to 10mg/kg body weight per day. In addition, a stabilization period of about 5-6 days is required to achieve an effective plasma concentration. Notably, the->The dosage forms of (c) do not allow for specific and accurate dose adjustments depending on body weight and subject response to treatment, require multiple daily intake, require a long initial treatment period and may be difficult to swallow. Thus (S)>Is a restrictive treatment regimen and may not be suitable for the lifestyle and needs of certain patients (e.g., children and elderly). />And even considered unsuitable for children under 6 years of age.Another disadvantage of the dosage form is that it does not provide a stable plasma concentration of tebuthimide. In fact, one can observe large fluctuations in the plasma concentration of tebuthimede over time.

The bioavailability of Shu Sai m is poorly understood. To date, it has not been aimed atExtensive pharmacokinetic studies were performed. Recently, dao et al (above) showed that once a single dose of +_ was administered under fasted conditions in healthy subjects>After that, tebuthime has a very strong affinity for erythrocytes. Such high affinities can affect the systemic bioavailability and clearance of the drug. Thus, the idea of formulations and dosage regimens that provide stable Shu Sai plasma levels to promote sustained therapeutic effects is a real challenge.

There is therefore a need to develop a pharmaceutical composition comprising Shu Sai m which addressesAll disadvantages of (2).

Disclosure of Invention

The present invention relates to an extended release pharmaceutical composition for oral administration in the form of granules Shu Sai mex, wherein:

shu Sai Mei in an amount of 0.5mg to 5.0mg per granule, and

the particles have a particle size of less than 5000 μm and comprise an outer layer providing a Shu Sai mei extended release.

Preferably, the particle size is determined by sieve analysis, as described further below.

In some embodiments, the particles comprise a core, a first layer comprising Shu Sai mex surrounding the core, and an outer layer surrounding the first layer.

Preferably, the extended release pharmaceutical composition is characterized by the following in vitro dissolution characteristics:

When the pharmaceutical composition is subjected to an in vitro dissolution test according to European pharmacopoeia 01/2016:20803 at pH 6.8:

-release within 1 hour no more than 20% of Shu Sai me originally present in the composition;

-release 30% to 60%, such as 35% to 55% or 40% to 50% of Shu Sai me originally present in the composition within 6 hours; and

releasing within 14 hours at least 80% of the Shu Sai me originally present in the composition,

in some embodiments, the particles have a maximum particle size of at most 3000 μm, preferably at most 2500 μm, for example at most 2240 μm. In addition, 70 to 100 wt% of the particles may have a particle size of 1000 to 3000 μm, in particular 1400 to 2240 μm, more in particular 1600 to 2240 μm, preferably 1700 to 2240 μm.

The amount of each granule Shu Sai mg is generally 0.5mg to 5.0mg, preferably 0.5mg to 2.5mg, more preferably 1.5mg to 2.5mg.

In a specific embodiment, the extended release pharmaceutical composition is a composition, the outer layer of which comprises at least one hydrophilic polymer and at least one hydrophobic polymer. The weight ratio of hydrophobic polymer to hydrophilic polymer may be 1.5 to 3, preferably 1.8 to 2.5.

In some embodiments, the hydrophilic polymer is polyvinylpyrrolidone and the hydrophobic polymer is ethylcellulose. The outer layer may also contain plasticizers and/or surfactants.

The first layer may also comprise a tackifier and/or a surfactant. The core is generally made of an inert component preferably selected from the group consisting of polysaccharides, silica, calcium carbonate, magnesium carbonate, sugars, polyols and mixtures thereof, preferably cellulose, microcrystalline cellulose and mixtures thereof.

The invention also relates to the use of an extended release pharmaceutical composition as defined above for the prevention and/or treatment of epilepsy in a subject. The extended release pharmaceutical composition may be administered to the subject up to twice daily, for example twice daily, once daily or once every two days.

The subject may be a child, preferably an infant or a child under 7 years old and/or a subject suffering from a swallowing disorder. The extended release pharmaceutical composition may be administered to the subject twice daily.

The average daily dose of Shu Sai Mei may typically be from 0.1mg/kg to 10mg/kg, for example from 0.5mg/kg to 10.0mg/kg.

Drawings

FIG. 1 (FIG. 1) shows(left) and in vitro cumulative dissolution profile of the compositions according to the invention (ADV 6769-right).

FIG. 2 (FIG. 2) showsAnd plasma pharmacokinetic profile of the composition according to the invention at a single dose of 200 mg.

Detailed Description

The inventors contemplate a new Shu Sai mei pharmaceutical composition. The pharmaceutical composition is based on small particles which provide prolonged release of the sultiamide.

The pharmaceutical composition of the present invention provides prolonged and regular release of sultebuthimide in vitro over time (i.e. over at least 12 hours) as demonstrated in the experimental section, whereas the reference drugAbout 90% of the active ingredient is released within 30 min.

The in vitro dissolution profile of the pharmaceutical composition of the invention was shown to be associated with an in vivo prolonged release that improves the Shu Sai mei pharmacokinetics. Notably, the compositions of the present invention are characterized byThus, when administered to healthy adults under fasted conditions in an amount equivalent to 200mg Shu Sai Mei, the median Tmax was about 48 hours and the mean Cmax was about 0.209 μg/mL. In contrast, when applied under the same conditions,providing a Tmax of about 2.5 hours, a Cmax of about 1.763 μg/mL.

In view of these results, the pharmaceutical composition of the present invention is expected to establish a stable and effective plasma concentration of tebuthime with very low fluctuations when administered twice or once a day. In contrast to this, the process is performed,more fluctuating plasma concentrations of sultebuthium are provided and should be administered at least three to four times per day to provide effective plasma levels.

By virtue of its improved pharmacokinetic properties, the pharmaceutical composition of the present invention is expected to provide a more stable plasma concentration of sultebuthime over time, simultaneously with the reference drug The administration frequency can be reduced compared with the prior art. In other words, the pharmaceutical composition of the present invention is expected to provide more effective and more compliant epileptic treatments and have lower side effects than the reference drug. Furthermore, the pharmaceutical composition of the present invention shows several other advantages over the reference drug, such as the possibility of fine-tuning the administered dose taking into account the weight of the subject and his/her responsiveness to the treatment. Furthermore, the pharmaceutical composition of the present invention is particularly suitable for administration to children, even children under 6 years of age and subjects suffering from dysphagia, due to the ease with which small dosage forms thereof are swallowed.

Accordingly, the present invention relates to an extended release pharmaceutical composition for oral administration in the form of granules Shu Sai mex, wherein:

shu Sai Mei in an amount of 0.5mg to 5.0mg per granule, and

particle size less than 5000 μm and comprising an outer layer providing a Shu Sai aesthetic extended release.

The invention also relates to the use of such pharmaceutical compositions for the treatment of epilepsy, in particular epilepsy in children or subjects suffering from dysphagia.

General definition

In the context of the present invention, "pharmaceutically acceptable" means that it is useful for preparing a pharmaceutical composition, i.e. it is generally safe, non-toxic and not biologically or otherwise undesirable, and that it is acceptable for veterinary use as well as for human pharmaceutical use.

In the context of the present invention, a "pharmaceutically acceptable salt" of a compound refers to a pharmaceutically acceptable salt as defined herein, and which has the desired pharmacological activity of the parent compound.

Pharmaceutically acceptable salts include, inter alia:

(1) The target compound is mixed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and the like; or with pharmaceutically acceptable organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid, lactic acid and the like; and

(2) The target compound is mixed with pharmaceutically acceptable organic base such as lysine, arginine, etc.; or addition salts obtained with pharmaceutically acceptable inorganic bases such as sodium hydroxide, calcium hydroxide, etc.

In the context of the present invention, the term "effective amount" refers to an amount of active ingredient effective to achieve the desired therapeutic or prophylactic result, i.e., to prevent, eliminate or reduce the deleterious effects of the disease, within the requisite dosage and period of time. It will be apparent to those skilled in the art that the amount administered may be adjusted depending on the subject to be treated, the nature of the disease, etc. In particular, the dosage and regimen of administration may vary depending on the nature, stage and severity of the condition to be treated, as well as the weight, age and general health of the subject to be treated, as well as the judgment of the physician.

As used herein, the term "treatment" refers to any action, such as treatment, intended to improve the health of a patient. In certain embodiments, the term refers to the amelioration or eradication of a disease or symptom associated with a disease. In other embodiments, the term refers to minimizing the spread or exacerbation of a disease resulting from the administration of one or more therapeutic agents to a subject suffering from such a disease. In the context of epilepsy, these terms refer to any action intended to eradicate the disease or to avoid, minimize or reduce the frequency and severity of seizures.

As used herein, the term "prevent" or "prevention" refers to any action intended to avoid the onset of a disease, such as the prevention and delay of a disease.

In the context of the present invention, the terms "subject", "individual" or "patient" are interchangeable and refer to an animal, preferably a mammal, even more preferably a human. As further defined below, the subject is in need of Shu Sai mei treatment. In particular, the subject suffers from epilepsy. The subject may be of any sex and of any age. Preferably, the subject is selected from children, especially children under 12 years old, preferably children under 6 years old, such as infants and young children, and subjects suffering from dysphagia (i.e. dysphagia). Dysphagia may have a variety of etiologies. Subjects with swallowing disorders include, but are not limited to, elderly subjects, subjects with certain neurological disorders (e.g., neurodegenerative or neurodevelopmental disorders), subjects with damage to the swallowing organs (e.g., subjects receiving oropharyngeal/laryngeal surgical resection or radiation therapy), and subjects receiving anterior cervical surgery.

In the context of the present invention, an "extended release dosage form or composition" refers to a composition that releases an active ingredient over an extended period of at least 4 hours, in particular from 6 to 24 hours in an in vitro dissolution assay as described in the european pharmacopoeia. In contrast, an "immediate release dosage form or composition" releases more than 80% of the active ingredient within 45 minutes in an in vitro dissolution assay as described in the european pharmacopoeia.

In the context of the present invention, the term "granule" or "particulate dosage form" refers to a solid dosage form consisting of a plurality of individual granules, each granule being a small mass of material containing the active ingredient (Shu Sai me or pharmaceutically acceptable salt thereof herein) together with one or more pharmaceutically acceptable excipients. The term "particulate dosage form" includes, but is not limited to, beaded dosage forms and particulate (granule) dosage forms.

In the context of the present invention, the term "beads" or "bead dosage forms" refers to particulate solid dosage forms, in particular spherical. The beads typically comprise a core (e.g., an inert core), typically a spherical core coated with one or more layers, e.g., a drug-containing layer and a controlled release layer (e.g., an extended release layer). Such coated beads (also referred to as multi-layered beads) may be prepared by any conventional method known to those skilled in the art, including, for example, wet mass extrusion, spheronization, layering or spray drying, e.g., on an inert core, and/or coating.

In the context of the present invention, the term "microparticle" or "microparticle dosage form" refers to a particulate solid dosage form, in particular spherical, which is prepared by granulation, for example by high shear granulation and melt granulation processes. The particles may be produced by granulating the active ingredient with a polymer and other excipients to produce modified release particles, such as extended release particles.

In the context of the present invention, the "particle size" and more commonly the "particle size distribution" is determined by sieve analysis, typically by using a stack of sieves, e.g. a plurality of sieves, e.g. 3 to 8 sieves arranged in a stack with increasing mesh size from bottom to top.

Pharmaceutical compositions of the invention

As described above, the present invention relates to an extended release pharmaceutical composition for oral administration in the form of granules Shu Sai me, wherein:

shu Sai Mei is 0.5mg to 5.0mg per granule, and

the particles have a particle size of less than 5000 μm and comprise an outer layer providing a Shu Sai mei extended release.

In the context of the present invention, the term tebuthime includes Shu Sai mei base, pharmaceutically acceptable salts thereof such as sodium tebuthime, and solvates (including hydrates) thereof. According to a specific embodiment, the tebuthimide is Shu Sai mei base having the formula:

The particles of the invention have a size of at most 5000 μm, for example at most 4000, 3500, 3000 or 2500 μm.

In the context of the present invention, a "particle size of at most 5000 μm" means at least 95% of the particles of the pharmaceutical composition, e.g. at least 96%, 97%, 98%, 99%, 99.5%, 99.8% or 99.9% of the particles have a size of at most 5000 μm, the percentages being expressed by weight relative to the total weight of the particles.

In a specific embodiment, the particles of the present invention have a size of 1000 μm to 5000 μm.

In an advantageous embodiment, the particles of the invention have a maximum particle size of at most 5000 μm, advantageously at most 3500 μm, for example 3000 μm, 2800 μm, 2600 μm and preferably at most 2500 μm, or at most 2240 μm.

The size distribution of the particles according to the invention may be determined by any size distribution analysis known to the person skilled in the art. Preferably, the particle size distribution of the particles may be determined by sieve analysis, typically by using a stack of sieves, e.g. a plurality of sieves, e.g. 3 to 8 sieves arranged in a stack with increasing mesh size from bottom to top.

Screen analysis methods are well known to those skilled in the art. For example, any commercially available stainless steel screen mesh equipped with a suitable mechanical vibrator may be used. Typically, the sample to be analyzed is placed on a screen at the top of the stack and is subjected to vertical movement (vibratory screening) and/or horizontal movement (horizontal screening) by means of a mechanical vibrator. In this process, the particle size of the sample is compared to the pore size of each individual screen. The probability of a particle passing through the screen is determined by the ratio of particle size to mesh, the direction of the particle, and the number of encounters between the particle and mesh. Suitable screening methods depend on the fineness of the sample. As in the context of the present invention, the sieve analysis method is the preferred method for a size range between 20 μm and 125 mm.

In the context of the present invention, "maximum particle size" is measured by screen analysis and refers to the size of the largest particle, i.e. the mesh diameter of the screen where the particles are first retained.

In another embodiment, the particles of the present invention have a minimum particle size of at least 1000 μm, advantageously at least 1200 μm, more advantageously at least 1400 μm.

In the context of the present invention, the "minimum particle size" is measured by the screen stack and refers to the size of the smallest particle, i.e. the mesh diameter of the screen that last retains the particle.

In some embodiments, 70 to 100 wt% of the particles have a particle size of 1000 to 2500 μm, specifically 1400 to 2240 μm, more specifically 1600 to 2240 μm, preferably 1700 to 2240 μm.

In particular, 80 to 100% by weight of the particles have a particle size of 1000 to 2500. Mu.m, in particular 1400 to 2240. Mu.m, in particular 1600 to 2240. Mu.m, preferably 1700 to 2240. Mu.m.

Preferably, 90 to 100 wt% of the particles have a particle size of 1000 to 2500 μm, in particular 1400 to 2240 μm, more in particular 1600 to 2240 μm, preferably 1700 to 2240 μm. The percentages are measured by weight relative to the total weight of the particles. According to the invention, this particle size allows for easy administration of the composition of the invention, in particular for children and subjects suffering from dysphagia.

Advantageously, in the composition of the invention, the Shu Sai mg per particle is in an amount of 0.5mg to 5.0mg, preferably 0.5mg to 2.5mg, more preferably 1.5mg to 2.5mg.

According to the invention, the Shu Sai mei amount of each particle allows for dose adjustment of the patient, in particular according to the weight and/or age of the patient, the responsiveness of the patient to the treatment and the stage of the disease. In the art, the recommended maintenance dose for Shu Sai america is in the range of 5 to 10mg/kg body weight per day, and the dose to begin treatment is about 2.5mg/kg body weight per day. Thus, the dosage form of the present invention allows for administration of a sufficient dose even to youngest patients, such as children, including young children and even infants, less than 6 years of age.

The pharmaceutical compositions of the present invention provide extended release of sultiamide. This prolonged release of Shu Sai m can be demonstrated by an in vitro dissolution assay generally performed according to European pharmacopoeia 01/2016:20003.

In general, the pharmaceutical composition of the invention is a composition such that Shu Sai mei initially present in the composition releases no more than 65% within 6 hours when the composition is subjected to an in vitro dissolution test according to the european pharmacopoeia 01/2016:20803 having the following conditions:

Instrument: oar (Instrument 2)

Temperature: 37 c,

dissolution medium: phosphate buffer, 0.05M, pH 6.8,

stirring speed: 100rpm

Typically, 10 particles (e.g., 10 coated beads) of the pharmaceutical composition are placed in 900mL of dissolution medium at pH 6.8, 37 ℃ at a stirring rate of 100 rpm. The release of sulteff in the dissolution medium over time was quantified by UV detection (typically at 245 nm).

In a specific embodiment, the pharmaceutical composition is such that at least 70%, particularly at least 75%, 80%, 85% or 90% of the Shu Sai mei originally present in the composition is released within 14 hours when the composition is subjected to an in vitro dissolution assay as described above.

In another embodiment, the pharmaceutical composition is such that no more than 25%, particularly no more than 20% of the Shu Sai me originally present in the composition is released within 1 hour when the composition is subjected to an in vitro dissolution assay as defined above.

In a preferred embodiment, the pharmaceutical composition is such that:

when the composition is subjected to an in vitro dissolution assay as defined above, it:

releasing within 1 hour no more than 20% of the Shu Sai me originally present in the composition,

-release 30% to 60%, such as 35% to 55% or 40% to 50% of Shu Sai me originally present in the composition within 6 hours; and

-release at least 80% of Shu Sai me originally present in the composition within 14 hours.

As demonstrated in the examples section, exemplary compositions have in vitro dissolution profiles independent of pH, more preferably substantially the same at pH 6.8 and pH 1.2 or 4.5.

Thus, in some embodiments, the compositions of the invention meet the same in vitro dissolution specifications at pH 1.2 and 4.5 as described above for pH 6.8.

In a specific embodiment, the pharmaceutical composition of the invention is pH independent.

In some further embodiments, the extended release pharmaceutical composition does not release a significant amount of the active ingredient in the stomach. Typically, the extended release composition of the present invention releases less than 15%, preferably less than 10% or 5% of the Shu Sai me originally present in the composition within 1 hour when the pharmaceutical composition is subjected to an in vitro dissolution test at pH 1.0.

As noted above, the improved in vitro dissolution profile of the present invention is expected to be associated with improved in vivo pharmacokinetic profile. Such facts can be demonstrated by standardized pharmacokinetic studies in vivo, for example as shown in the examples section.

As shown in the examples, the compositions of the present invention and when both products are administered to healthy adults in the same dose, a single dose, under fasted conditions A tablet is characterized by a significant increase in median Tmax and a significant decrease in mean Cmax.

Thus, in some further embodiments, the pharmaceutical composition of the invention is characterized by a median Tmax of at least 36 hours, for example 36 hours to 72 hours, preferably about 48 hours, when administered orally to healthy adult subjects under fasted conditions at a once daily dose of 200 mg.

In some other embodiments, the pharmaceutical composition of the invention is characterized by a mean Cmax of less than 0.3 μg/mL, such as 0.1 to 0.3 μg/mL, when administered orally to healthy adult subjects under fasted conditions at a once daily dose of 200 mg.

In a specific embodiment, the pharmaceutical composition of the invention is characterized by an average AUC when administered orally to healthy adult subjects under fasted conditions at a once daily dose of 200mg, respectively _0-t Less than 22h μg/mL, preferably less than 15h μg/mL, e.g. 10 to 15h μg/mL.

In a specific embodiment, the pharmaceutical composition of the invention is adapted to provide a Shu Sai mei pharmacokinetic profile when administered orally to healthy adult subjects under fasted conditions at a once daily dose of 200mg (sufficient number of particles to reach a dose of 200 mg):

(i) Median T _max For at least 36 hours, preferably about 48 hours;

(ii) Average C _max Less than 0.3 μg/mL, such as 0.1 to 0.3 μg/mL; and

(iii) Average AUC _0-t Less than 22h μg/mL, preferably less than 15h μg/mL, e.g. 10 to 15h μg/mL.

Tmax, cmax and AUC0h-t refer to plasma data and are determined from a curve of the concentration of sultebuthime plasma versus time.

According to the present invention, for a given composition containing Shu Sai m, the profile of the concentration of sulteum plasma versus time can be determined by tracking the concentration of sulteum plasma over a desired period of time (e.g., during at least 7 days, such as about 8 days or about 28 days, after a single oral intake of a quantity of the composition corresponding to a 200mg Shu Sai m dose).

A single oral administration of the Shu Sai mei containing composition is performed under fasted conditions, i.e. no food and not close to the meal time (i.e. typically about 10 hours after meal) because food intake can alter the rate of absorption of tebuthime in the gastrointestinal tract. Cmax and Tmax values refer to the maximum plasma concentration of sultebuthime and the time to reach it, respectively, after oral administration of a single dose of the composition of interest. In other words, tmax and Cmax refer to the characteristics of peak plasma concentration of sultebuthime observed after oral ingestion of a single dose of the composition of interest. AUC (AUC) _0-t Corresponding to the time interval [0h-t ]]The area obtained by integrating the concentration of the plasma of tebuthime with respect to time, point "0h" refers to the oral intake of the composition of interest, while point "t" refers to the time until the last quantification of the concentration of the plasma of tebuthime.

Shu Sai Mei average C _max Median T _max And average AUC _0-t Can be determined from raw individual pharmacokinetic data in the plasma of a counted subject by statistical methods well known in the art. Pharmacokinetic studies can be performed as described in the examples section.

To facilitate this prolonged release, the formulation of the invention is expected to provide a stable plasma concentration of sultebuthime when administered up to twice daily, preferably once daily, in maintenance therapy.

Notably, the pharmaceutical compositions of the present invention can reduce the frequency of administration compared to the reference drug, which improves compliance with Shu Sai mei therapy.

Pharmaceutical composition

As defined above, the present invention relates to an extended release pharmaceutical composition for oral administration in the form of granules Shu Sai me, wherein:

shu Sai Mei in an amount of 0.5mg to 5.0mg per granule, and

the particles have a particle size of less than 5000 μm and comprise an outer layer providing a Shu Sai mei extended release.

Advantageously, the composition of the invention is in the form of beads or particles, in particular in the form of beads. More advantageously, the composition of the invention is a multi-layered beaded dosage form.

In a preferred embodiment, the composition of the invention is in the form of a plurality of coated beads, each coated bead comprising a core, a first layer comprising Shu Sai mer surrounding the core, and an outer layer surrounding the first layer.

In the context of the present invention, the term "core", "inert core" or "neutral core" refers to an inert matrix, in particular a spherical matrix, consisting of inert excipients. Thus, the core does not contain any active ingredient, including Shu Sai america. Furthermore, the core does not exhibit any pharmacological activity nor interact in some way with Shu Sai m, which interaction with Shu Sai m may adversely affect its stability and/or effectiveness.

The core, also called inert core, is generally composed of at least one inert pharmaceutical excipient selected from polysaccharides (e.g. cellulose or microcrystalline cellulose), silica, calcium carbonate, magnesium carbonate, sugars (e.g. lactose or sucrose), polyols (e.g. mannitol, sorbitol or maltitol) and mixtures thereof, preferably cellulose, microcrystalline cellulose and mixtures thereof.

In a preferred embodiment, the core is sucrose-free, more preferably free of any disaccharides or monosaccharides.

According to the invention, the particle size of the core is selected such that the desired particle size of the composition of the invention can be obtained while containing a desired amount of Shu Sai m. Advantageously, the particle size of the core is 600 μm to 1000 μm, in particular 700 μm to 850 μm. The size (and more precisely the size distribution of the starting core particles) may be determined by screening methods, such as screening methods as disclosed above for the final particles of the invention.

According to the invention, the core advantageously represents 5% to 15% by weight of the granule, the percentages being expressed by weight relative to the total weight of the granule.

According to the invention, the particles, in particular beads, may comprise a first layer, which is a drug-containing layer comprising Shu Sai m.

According to the invention, the amount of Shu Sai mg in the first layer is advantageously between 0.5mg and 5.0mg, preferably between 0.5mg and 2.5mg, more preferably between 1.5mg and 2.5mg.

Advantageously, the tebuthimide in the first layer comprises 60 to 85% by weight of the total weight of the first layer.

The Shu Sai American amount in the composition of the invention is generally 45 to 60% by weight of the total weight of the composition of the invention.

The first layer may also comprise one or more pharmaceutically acceptable excipients. The one or more excipients may be selected from binders, surfactants, diluents, tackifiers, and mixtures thereof. Pharmaceutically acceptable excipients that may be used are described in particular in the pharmaceutical excipients handbook, american society for pharmacy (Pharmaceutical Press; ninth revision, 2020). In some embodiments, the first layer further comprises a surfactant and/or a tackifier.

Examples of surfactants include, but are not limited to, glycerol monooleate, sodium lauryl sulfate, lauric acid, myristyl alcohol, glycerol monooleate, polyoxyethylene alkyl ethers, polyoxyethylene and/or polyethylene glycol and/or hydrogenated castor oil derivatives, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polyoxyethylene stearate, polyoxylglycerides, sorbitan esters, and combinations thereof.

According to the invention, the preferred surfactant is a pegylated hydrogenated castor oil or polysorbate 80, preferably a pegylated hydrogenated castor oil.

Examples of viscosity enhancers include, but are not limited to, acacia, agar, alginic acid, bentonite, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carrageenan, carob bean gum, cetostearyl alcohol, chitosan, colloidal silicon dioxide, cyclomethicone, ethylcellulose, gelatin, glycerin, guar gum, hectorite, hydrogenated vegetable oil type I, hydrophobic colloidal silicon dioxide, hydroxyethyl cellulose, hydroxyethyl methylcellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methylcellulose, magnesium aluminum silicate, maltodextrin, methylcellulose, myristyl alcohol, polydextrose, polyethylene glycol, poly (methyl vinyl ether/maleic anhydride), polyvinyl alcohol, potassium chloride, povidone, propylene glycol alginate, soapstone, sodium alginate, sodium chloride, starch, stearyl alcohol, sucrose, tragacanth, and xanthan gum.

According to the invention, the viscosity increasing agent is preferably hydroxypropyl methylcellulose (HPMC) or povidone, more preferably HPMC.

Advantageously, the first layer comprises a surfactant, such as pegylated hydrogenated castor oil, and a viscosity enhancing agent, such as HPMC.

The surfactant may comprise 5 wt% to 10 wt% of the total weight of the first layer and the tackifier may comprise 10 wt% to 25 wt% of the total weight of the first layer.

The excipients present in the first layer generally constitute from 15 to 40% by weight of the total weight of the first layer.

According to the invention, the first layer advantageously represents 60% to 80% by weight of the particles, the percentages being expressed by weight relative to the total weight of the particles.

According to the invention, the particles, in particular beads, comprise an outer coating layer providing an extended release of Shu Sai m.

The outer coating layer typically comprises a controlled release agent that provides an extended release of Shu Sai me. Examples of controlled release agents include, but are not limited to, hydrophilic polymers, hydrophobic polymers, and wax materials.

In a preferred embodiment, the outer coating layer comprises at least one hydrophilic polymer and at least one hydrophobic polymer as controlled release agents. In particular, in the context of the present invention, the balance between hydrophilic and hydrophobic polymers determines the release of Shu Sai aesthetic. In fact, the more hydrophobic the outer coating layer, the slower the Shu Sai aesthetic release. Accordingly, one skilled in the art should be careful to select the weight ratio of hydrophobic polymer to hydrophilic polymer. Advantageously, the weight ratio of hydrophilic polymer to hydrophobic polymer is from 1.5 to 3, preferably from 1.8 to 2.5, for example from 1.9 to 2.4.

Advantageously, in the outer coating layer, the hydrophilic polymer is selected from polyvinylpyrrolidone (povidone), hydroxypropyl methylcellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, carbomers, potassium pectate (potassium pectate), potassium pectate (potassium pectinate) and mixtures thereof.

In particular, the hydrophilic polymer is polyvinylpyrrolidone.

Advantageously, the amount of hydrophilic polymer in the outer coating layer is from 50% to 70% by weight relative to the total weight of the outer layer. The hydrophilic polymer in the outer layer may comprise from 5% to 20% by weight of the total weight of the composition of the invention.

Advantageously, in the outer layer, the hydrophobic polymer is selected from ethylcellulose, hydroxyethylcellulose, ammonio methacrylate copolymers(RL or->RS), methacrylic acid copolymer (++>L or->S), methacrylic acid-ethyl acrylate copolymer (+.>L100-5), methacrylate neutral copolymerNE 30D), dimethylaminoethyl methacrylate-methacrylate copolymer (++>E100) Vinyl methyl ether/maleic anhydride copolymers, their salts and esters >And mixtures thereof.

In particular, the hydrophobic polymer is ethylcellulose.

Preferably, the hydrophobic polymer is ethylcellulose having a viscosity in the range of 6 to 22mpa.s, in particular 6 to 11mpa.s, for example 6 to 8mpa.s. The viscosity of ethylcellulose can be determined by capillary viscometer as described in the european pharmacopoeia ethylcellulose monograph. Typically, 5g of dry ethylcellulose is dissolved in 95g of a mixture comprising ethanol (96%)/toluene in a weight ratio of 20/80. The viscosity was then measured using a capillary viscometer at 25 ℃.

Advantageously, the amount of hydrophobic polymer in the outer coating layer is from 20% to 40% by weight relative to the total weight of the outer layer.

The amount of hydrophobic polymer in the composition of the invention is generally from 3% to 10% by weight relative to the total weight of the composition of the invention.

Advantageously, the outer coating layer further comprises a further excipient selected from plasticizers, surfactants, colorants or pigments, glidants, flavoring agents, viscosity enhancers, and mixtures thereof. Pharmaceutically acceptable excipients that may be used are described in particular in the pharmaceutical excipients handbook of the american pharmaceutical association (Pharmaceutical Press; sixth revision, 2009).

Advantageously, the additional excipient of the outer coating layer is a mixture of at least a plasticizer and a surfactant.

Examples of plasticizers include, but are not limited to, acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, castor oil, chlorobutanol, dextrin, dibutyl sebacate, glycerin, glyceryl monostearate, mannitol, mineral oil, palmitic acid, petrolatum, polyethylene glycol, propylene glycol, pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and combinations thereof.

The plasticizer is preferably castor oil. The plasticizer may comprise 1 to 10% by weight of the total weight of the coating.

Examples of surfactants include, but are not limited to, all of the surfactants listed above.

The preferred surfactant is a pegylated hydrogenated castor oil. The surfactant in the coating may comprise from 1% to 8% by weight of the total weight of the coating.

The weight ratio of plasticizer to surfactant in the coating may be 1 to 2.

Advantageously, the outer coating layer is free of active ingredients, i.e. free of sulfenamide. More advantageously, the outer coating layer is free of Shu Sai m and comprises polyvinylpyrrolidone and ethylcellulose as controlled release agents, castor oil as plasticizer and pegylated hydrogenated castor oil as surfactant.

According to the invention, the outer coating layer advantageously represents from 15% to 25% by weight of the granule, the percentages being expressed by weight relative to the total weight of the granule.

In an advantageous embodiment of the invention, the pharmaceutical composition is in the form of a multi-layered bead having a particle size of 1500 μm to 2500 μm (preferably a maximum particle size of not more than 3000 μm), each bead comprising or consisting of:

-a spherical core;

-a first layer surrounding the spherical core comprising Shu Sai mg in an amount of 0.5 to 2.5mg, and optionally at least one excipient selected from the group consisting of binders, surfactants, tackifiers, and combinations thereof; and

an outer layer surrounding the first layer, which is Shu Sai mesh free and comprises at least one hydrophobic polymer such as ethylcellulose and at least one hydrophilic polymer such as polyvinylpyrrolidone (PVP), the weight ratio of hydrophilic polymer to hydrophobic polymer being from 1.5 to 3, and optionally at least one additional excipient such as a plasticizer and/or a surfactant.

Preferably, the spherical core accounts for 5-15%, the first layer accounts for 60-80%, and the outer coating layer accounts for 15-25%; percentages are expressed by weight relative to the total weight of the particles. Suhime preferably comprises 45 to 60 wt% of the total weight of the granule

In an advantageous embodiment of the invention, each bead comprises or consists of:

-a spherical core preferably made of microcrystalline cellulose;

-a first layer surrounding a spherical core comprising Shu Sai mg in an amount of 0.5 to 2.5mg, a viscosity increasing agent such as hydroxypropyl methylcellulose (HPMC) and a surfactant such as pegylated hydrogenated castor oil; and

an outer coating which is Shu Sai-free and comprises a hydrophobic polymer such as ethylcellulose and a hydrophilic polymer such as polyvinylpyrrolidone (PVP), a plasticizer such as castor oil and a surfactant such as pegylated hydrogenated castor oil, wherein the weight ratio of hydrophobic polymer to hydrophilic polymer is from 1.5 to 3.

Preferably, the spherical core comprises 5% to 15%, the first layer comprises 60% to 80%, wherein the tebuthimide present in the first layer comprises 45% to 60%, and the outer coating layer comprises 15% to 25%; percentages are expressed by weight relative to the total weight of the particles.

In another advantageous embodiment of the invention, the beads comprise or consist of:

-a spherical core made of microcrystalline cellulose, preferably having a particle size ranging from 650 μm to 900 μm, preferably from 710 μm to 850 μm;

-a first layer surrounding a spherical neutral core comprising sultebuthime, hydroxypropyl methylcellulose (HPMC) as a viscosity enhancer and pegylated hydrogenated castor oil as a surfactant in an amount of 0.5mg to 2.5 mg; and

-an outer coating free of Shu Sai mex and comprising ethylcellulose as hydrophobic polymer and polyvinylpyrrolidone (PVP) as hydrophilic polymer, castor oil as plasticizer and pegylated hydrogenated castor oil as surfactant, wherein the weight ratio of ethylcellulose to PVP is from 1.5 to 3.

Preferably, 70 to 100 wt% of the particles have a particle size of 1400 to 2240 μm.

Preferably, the spherical core comprises 5% to 15%, the first layer comprises 60% to 80%, wherein the tebuthimide present in the first layer comprises 45% to 60%, and the outer coating layer comprises 15% to 25%; percentages are expressed by weight relative to the total weight of the particles.

In the above embodiments, the beads are further characterized by:

the spherical cores are made of microcrystalline cellulose and constitute from 5% to 10% by weight of the total weight of the beads,

shu Sai Mei is present only in the first layer and constitutes 50 to 60% by weight of the total weight of the beads, and/or

The HPMC present in the first layer is 10 to 15% by weight of the total weight of the beads, and/or

The pegylated hydrogenated castor oil in the first layer comprises 3% to 8% by weight of the total weight of the beads, and/or

The ethylcellulose in the coating represents 2 to 10% by weight of the total weight of the beads, and/or

The castor oil in the coating represents 0.5% to 2% by weight of the total weight of the beads, and/or

The povidone in the coating represents 5 to 20% by weight of the total weight of the beads, and/or

The pegylated hydrogenated castor oil in the coating represents 0.1% to 2% by weight of the total weight of the beads.

Preparation method

The pharmaceutical compositions of the present invention may be prepared by conventional methods well known to those skilled in the art of pharmaceutical composition manufacture.

In particular, when the particles according to the invention are in the form of coated beads, they may be prepared by any conventional method known to the person skilled in the art, including for example wet mass extrusion, spheronization, spray drying, layering and/or coating. Furthermore, when the granules of the invention are in particulate form, they may be prepared by any granulation method known to those skilled in the art, for example by high shear granulation or melt granulation methods.

When the pharmaceutical composition is in the form of coated beads, the beads can generally be prepared by performing the following steps:

step (a) preparing a suspension or solution to be coated as a drug-containing layer;

step (b) coating the core with the suspension prepared in step (a);

step (c) optionally, sieving the particles

Step (d) preparing a suspension for an outer layer;

step (e) coating the particles obtained after step (b) or (c) with the suspension prepared in step (d); and

step (f) is sieved to recover particles having a maximum particle size of at most greater than 5000 μm, in particular at most 3500 μm, 3000 μm or 2500 μm, advantageously at most 2240 μm.

According to the invention, step (a) generally comprises preparing a suspension to be sprayed as a medicated layer. The suspensions may be prepared by methods known to those skilled in the art. In particular, the suspension comprises all components of the first layer, i.e. the sultebuthium and optionally other excipients, such as surfactants and viscosity enhancers, in a suitable solvent, such as water or a water-alcohol solution. The composition of the first layer is particularly defined as above.

In a specific embodiment, step (a) can be carried out by incorporating the sultebuthimide and additional excipients into the solvent with high speed agitation.

According to the invention, steps (b) and (e) are carried out in a manner known to the person skilled in the art. In particular, coating steps (b) and (e) may be performed in solid trays, side vented trays, fluid bed machines, full-perforated drums and continuous coating machines. Advantageously, steps (b) and (e) are carried out in a fluidised bed.

According to the invention, steps (c) and (f) are carried out in a manner known to the person skilled in the art. Specifically, steps (c) and (f) are performed by sieving, typically using a vibrating screen. In some embodiments, step (c) is performed to recover pre-coated particles having a particle size below 5000 μm, preferably below 3000 μm.

According to the invention, step (d) advantageously involves preparing the suspension to be sprayed as an extended release outer layer. The suspensions may be prepared by methods known to those skilled in the art. In particular, the suspension comprises all components of the outer layer, i.e. the controlled release agent and optionally other excipients (e.g. surfactants and plasticizers), in a suitable solvent such as water, alcohols (e.g. isopropanol) or other organic solvents (e.g. acetone) and combinations thereof. The composition of the outer layer is particularly defined as above.

The conditions (temperature, concentration, solvent, reactants, equivalents of reactants) of each of the above steps can be adjusted by one skilled in the art using his/her general background of galenic formulation.

Use of the same

Another aspect of the invention is the use of the pharmaceutical composition of the invention as a medicament, in particular for the treatment and/or prevention of epilepsy.

In particular, the present invention relates to a pharmaceutical composition of the invention for use in the treatment and/or prevention of epilepsy in a subject.

In one embodiment, the present invention relates to a method for treating and/or preventing epilepsy in a subject in need thereof, comprising the step of administering to the subject an effective amount of a pharmaceutical composition of the invention.

In one embodiment, the present invention relates to the use of a pharmaceutical composition of the invention in the manufacture of a medicament for the treatment and/or prevention of epilepsy in a subject.

In the context of the present invention, the epilepsy to be treated or prevented is advantageously selected from benign pediatric epilepsy (BECTS) accompanied by central temporal area spike, continuous spike and wave type epilepsy during slow sleep (CSWS epilepsy), refractory debau epilepsy, landau-kleffner, west, lennox and Rett syndrome (Rett syndrome), acquired epileptic aphasia, atypical benign partial epilepsy, temporal lobe epilepsy, myoclonus and focal epilepsy. More advantageously, the epilepsy to be treated or prevented is childhood Benign Epilepsy (BECTS) with central temporal area spikes.

According to the invention, the composition is administered by the oral route. The dosage may be determined according to criteria that are generally considered when establishing a treatment appropriate for the patient, such as the age or weight of the patient, the severity of his/her general condition, tolerance to treatment, and adverse effects noted. In particular, according to the invention, the number of particles administered daily and per intake may be determined according to criteria generally considered for the treatment of epilepsy and suitable for the subject.

The daily dose of Shu Sai m.p. to be administered may be from 0.5mg/kg body weight to 10.0mg/kg body weight, for example from 0.5mg/kg to 1.0mg/kg, from 1.0 to 1.5mg/kg or from 1.5mg/kg to 6.0mg/kg. In particular, the daily initial dose to be administered (at the beginning of the treatment) is advantageously between 1.0mg/kg body weight and 3.5mg/kg body weight, for example 2.5mg/kg body weight. The daily maintenance dose to be administered (once steady state is reached) may be 2.0mg/kg body weight to 6mg/kg body weight, for example 4mg/kg body weight to 6mg/kg body weight. Thus, according to the invention, the number of particles to be administered is measured by taking into account the Shu Sai mei amount per particle and the dose per intake, in particular taking into account the weight of the subject and the stage of the treatment.

The compositions of the present invention may be administered with or without food.

It is contemplated that the compositions of the present invention may allow for a shortened treatment adaptation period, which is presently about 5 to 6 days. Thus, in some embodiments, for the compositions of the present invention, the daily initial dose should be administered during the first three days of treatment, i.e., during the first 72 hours, preferably during the first 48 hours. In another embodiment, no initial treatment with the composition of the present invention is required.

Advantageously, the pharmaceutical composition of the invention is administered to the subject at most twice daily, i.e. once or twice daily, preferably once or twice daily.

Advantageously, the subject is a person or child suffering from dysphagia, preferably an infant or a child under 7 years old. In some other embodiments, the subject with a swallowing disorder is an elderly subject, e.g., at least 65 years old.

Carbonic Anhydrase Inhibitors (CAIs) have been used clinically for decades to manage a variety of disorders, including anti-tumor therapies. Shu Sai, a member of the class of sulfonamides with potent CA inhibitors, may have anti-tumor activity, particularly in hypoxic tumors over-expressed by carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII. Thus, in a further aspect, the present invention relates to the use of a composition according to the invention as an anti-tumour agent, for example in the treatment of hypoxic tumours in which the carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are overexpressed. As described above, the compositions are administered by the oral route. The dosage may be determined according to criteria that are generally considered when establishing a treatment appropriate for the patient, such as the age or weight of the patient, the severity of his/her general condition, tolerance to treatment, and adverse effects noted.

In another embodiment of the invention, the pharmaceutical composition of the invention for use according to the invention may be administered in combination with another therapeutic agent, for example in combination with another antiepileptic or anticancer drug (e.g. histone deacetylase inhibitors, alkylating agents, antimetabolite nucleosides, angiogenesis inhibitors and immune checkpoint inhibitors), depending on the therapeutic effect sought (i.e. treatment of epilepsy or tumors).

The effective amount of the combination or the relative proportions of the two active ingredients may vary depending on the condition of the subject. As previously mentioned, the amount of each compound in the combination to be administered or the pharmaceutical composition comprising the combination must be determined by standard procedures well known to those of ordinary skill in the art. Appropriate dosages must be determined taking into account the physiological data of the patient (e.g., age, body size, and weight) in order to administer a therapeutically effective amount of such combinations to the patient. The pharmaceutical combination according to the invention is more particularly intended for simultaneous, separate or sequential administration, preferably simultaneous administration, of the active ingredients.

The invention also relates to a pharmaceutical kit comprising a pharmaceutical composition in the form of particles according to the invention and a device adapted to dispense a predetermined number or volume of said particles, wherein the predetermined number of particles is an integer preferably from 1 to 25, preferably an integer from 1 to 10, such as 1, 2, 3, 4 or 5.

Examples

The invention will be better understood from the following examples, which are provided for illustrative purposes only.

Example 1: preparation of the pharmaceutical composition (ADV 6769) of the invention

An extended release composition in the form of beads comprising sulteff is obtained by two steps:

1-immediate release beads comprising Shu Sai m by laminating a suspension core comprising Shu Sai m to a neutral core (by spray drying); and

2-prolonged release beads comprising Shu Sai Mei were made by coating with a prolonged release outer layer.

Preparation of 1-IR beads

A suspension to be coated on microcrystalline cellulose cores was prepared by mixing sultebuthium with a viscosity increasing agent and a surfactant in water under high speed stirring.

The resulting suspension is then spray dried on the microcrystalline cellulose core in a fluidized bed coater to obtain immediate release beads (e.g., pre-beads comprising the first layer). The compositions are shown in Table 1.

Table 1: component of IR beads

Preparation of 2-PR beads

After sieving, the IR beads obtained previously were coated with a coating suspension in a fluid bed coater by spray drying, thereby forming an outer layer on the IR beads.

The coating suspension is obtained by mixing the hydrophobic polymer, the hydrophilic polymer, the plasticizer and the surfactant in a mixture of volatile solvents such as acetone, isopropanol and water under stirring.

Table 2: components of PR beads

Example 2: in vitro dissolution assay

Dissolution testing by uv monitoring according to european pharmacopoeia 01/2016:20803 is performed under the following conditions:

bath temperature: 37 DEG C

Stirring mode, namely paddle type

Stirring speed: 100rpm

Dissolution medium: phosphate buffer 0.05m, ph 6.8, dissolution volume: 900mL

Ultraviolet detection-wavelength: λ=245 nm

Cell path length: 1cm

Test operation: 10 beads as obtained in example 1

The results are shown in FIG. 1. FIG. 1 also shows that obtained under the same dissolution conditionsIn vitro dissolution profile of film coated tablets.

In vitro dissolution assays were repeated at different acidic pH values. Notably, the in vitro dissolution profile obtained for the compositions of the present invention was substantially the same at 1.2 and 4.5 as at pH 6.8. Thus, the acidic pH has no effect on the in vitro dissolution release rate of Shu Sai m in the compositions of the invention.

Example 3: exploring the compositions of the present invention (named ADV 6769) and reference productsRandom, control, parallel group, open-label clinical study compared to pharmacokinetic profile, pharmacodynamics, safety and tolerability in healthy subjects.

Development stage: first stage

The main object is:

characterization of the Pharmacokinetic (PK) profile of Shu Sai Mei, including the release profile of sultebuthium from the formulations of the invention (ADV 6769) in plasma after oral administration of single doses of 50, 200 and 400mg of ADV6769 in healthy subjects, compared to 200mg

Study design:

random, control, parallel, open label studies with three doses of ADV6769 (50, 200 and 400 mg) or one dose(200 mg) and 2 fractions (fraction A random, fraction B). />

Eligible subjects will be randomly assigned to one of the following 3 treatment groups: ADV6769 50mg, ADV6769 200mg or200mg (part A).

The following data for these 3 treatment groups were reviewed prior to inclusion of eligible subjects into treatment group ADV6769 400mg (part B).

Study period: during this period the subject was allowed to enter the unit for at least 72 hours, from day-2 evening to day 2 (at least 36 hours) after administration of a single dose of one of the study products.

End of study: day 29 after study product administration.

Study constraints and limitations: no drinks containing alcohol, coffee, fruit or herbal tea were consumed during the study, no smoking, no fasting from 10 hours before IMP administration to 4 hours after IMP administration, standardized diet during hospitalization, from day-2 to day 2 t36 hours. The recommended contraceptive method must be used during the study period, for female subjects up to 33 days after the study treatment, and for male subjects up to 93 days after the study treatment.

Study population:

Number of subjects: 24 subjects, 6 subjects in each group

Main qualification criteria:

healthy adult subjects, female or male, aged 18 to 55 years, with BMI of 18 to 27kg/m ² Between which are located

Subjects without significant medical history or long term treatment

Study product:

activity study product: ADV6769, an extended release granule formulation, three doses (50 mg, 200mg and 400 mg) were administered orally.

Commercially available200mg of oral tablet.

And (3) application: single oral administration of each study product (ADV 6769 50, 200 and 400mg,200mg)。

study endpoint:

main evaluation criterion

Pharmacokinetics of

ADV6769 formulations and methods of use calculated using non-compartmental methodsShu Sai main PK parameters of (v):

area under the curve up to time t (AUC 0-t)

Maximum concentration (Cmax)

Time to reach Cmax (Tmax)

Statistical analysis

Plasma concentrations will be summarized as treatment and over time, individual concentrations and average ± SD concentrations will be tabulated and presented graphically.

Plasma PK parameters will be treated by conventional non-compartmental methods (i.e. 3 doses of each of ADV6769 and200 mg) including the following parameters:

area under concentration curve up to time t (AUC 0-t): both trapezoidal and logarithmic trapezoidal rule calculations will be used.

Maximum concentration (Cmax)

Time to reach Cmax (Tmax)

Results

Table 3 summarizes the doses of 50, 200 and 400mg of ADV6769 and the dose of 200mgShu Sai mei pharmacokinetic data in plasma of PK population. It can be seen that the composition of the invention (ADV 6769) provides an extended release in vivo of Shu Sai m.p. characterized by reference to the drug when administered at a dose equivalent to 200mg Shu Sai m.pA significantly higher Tmax and a lower Cmax.

Table 3: results of pharmacokinetic studies

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Claims (14)

1. A Shu Sai mei extended release pharmaceutical composition in the form of a granulate, wherein:

shu Sai Mei in an amount of 0.5mg to 5.0mg per granule, and

the particles have a particle size of less than 5000 μm and comprise an outer layer providing a Shu Sai mei extended release.

2. The extended release pharmaceutical composition of claim 1, wherein the particle comprises a core, a first layer comprising Shu Sai mer surrounding the core, and an outer layer surrounding the first layer.

3. The extended release pharmaceutical composition according to claim 1 or 2, wherein:

when the pharmaceutical composition is subjected to an in vitro dissolution assay according to European pharmacopoeia 01/2016:20803 at pH 6.8:

-release within 1 hour no more than 20% of Shu Sai me originally present in the composition;

-release 30% to 60%, such as 35% to 55% or 40% to 50% of Shu Sai me originally present in the composition within 6 hours; and

-release at least 80% of Shu Sai me originally present in the composition within 14 hours.

4. The extended release pharmaceutical composition according to any one of claims 1 to 3, wherein the particles have a maximum particle size of at most 3000 μm, preferably at most 2500 μm, such as at most 2240 μm, and advantageously 70 to 100 wt% of the particles have a particle size of 1000 μm to 3000 μm, in particular 1400 μm to 2240 μm, more in particular 1600 μm to 2240 μm, preferably 1700 μm to 2240 μm.

5. The extended release pharmaceutical composition according to any one of claims 1 to 4, wherein the Shu Sai mei amount per particle is 0.5 to 5.0mg, preferably 0.5 to 2.5mg, more preferably 1.5 to 2.5mg.

6. The extended release pharmaceutical composition according to any one of claims 1 to 5, wherein the outer layer comprises at least one hydrophilic polymer and at least one hydrophobic polymer, and advantageously wherein the weight ratio of the hydrophobic polymer to the hydrophilic polymer is from 1.5 to 3, preferably from 1.8 to 2.5.

7. The extended release pharmaceutical composition of claim 6, wherein the hydrophilic polymer is polyvinylpyrrolidone and the hydrophobic polymer is ethylcellulose.

8. The extended release pharmaceutical composition according to any one of claims 1 to 7, wherein the outer layer further comprises a plasticizer and/or a surfactant.

9. The extended release pharmaceutical composition according to any one of claims 2 to 8, wherein the first layer further comprises a tackifier and/or a surfactant.

10. The extended release pharmaceutical composition according to any one of claims 2 to 9, wherein the core is made of an inert component selected from the group consisting of polysaccharides, silica, calcium carbonate, magnesium carbonate, sugars, polyols and mixtures thereof, preferably cellulose, microcrystalline cellulose and mixtures thereof.

11. An extended release pharmaceutical composition as defined in any one of claims 1 to 10 for use in the prevention and/or treatment of epilepsy in a subject.

12. The extended release pharmaceutical composition for use according to claim 11, wherein the subject is a child, preferably an infant or a child under 7 years old and/or a subject suffering from a swallowing disorder.

13. The extended release pharmaceutical composition for use according to claim 11 or 12, which is administered in a subject up to twice daily, in particular once daily or once every two days.

14. The extended release pharmaceutical composition for use according to any one of claims 11 to 13, wherein the daily dose of Shu Sai mg/kg is 0.1mg/kg to 10.0mg/kg, such as 0.5mg/kg to 10.0mg/kg.