Piracetam as a marker

Abstract

The present invention relates to a composition for the consumption of a subject. The composition comprising piracetam as a monitoring marker for the composition and a substance. The substance is an active pharmaceutical ingredient (API), a placebo material, or a consumer substance. The present invention also relates to use of the composition and methods of monitoring a subject.

Description

[0001] Piracetam as a marker

[0002] Field of the Invention

[0003] The present invention concerns piracetam for non-therapeutic use, in particular in a monitoring marker in medication regimen. More particularly, but not exclusively, this invention concerns piracetam for use as a monitoring marker, for example in monitoring a subject for medical adherence / compliance, in a medication regimen or in a clinical trial set up. The invention also concerns method of monitoring a subject, compositions of piracetam and the method for manufacturing the compositions.

[0004] Background of the Invention

[0005] It is often necessary to monitor a subject, for example a patient or a healthy volunteer, in scenarios such as short-term or long-term medical treatment, clinical trials, or habit or lifestyle tracking.

[0006] In clinical setups, one problem often faced by physicians and other health care providers is that drugs and other pharmaceuticals that are prescribed to subjects are not taken by the subjects, or are not taken properly by the subjects. The reasons for non- compliance or poor compliance vary, and include forgetfulness, cost, inconvenience, lack of follow-up, and fear of taking medications.

[0007] In other setups, monitoring the intake of a subject, for example food or beverage intake, may be useful in obtaining information on the subject’s consumption habit, or in gathering the relevant information of a specific population.

[0008] Several markers for assessing medication adherence / compliance are described in the literature. However, existing markers have various disadvantages / limitations. For example, the measurement of adherence for some markers (for example methylene blue, phenol red, fluorescein, phenazopyridine) was based on urine staining that would be visible to the subject, making discrete monitoring difficult or impossible. In addition, application of some makers (such as phenobarbital) are limited by the occurrence of side effects. Finally, the long half-life of some adherence markers such as bromide and digoxin would limit the application of them with drugs that require more frequent administration, as non-compliance of several days would be masked.

[0009] The ideal marker is non-toxic and potentially detectable in urine or other samples containing body biological fluids at a subtherapeutic dose. Therefore, a substance with a relatively high therapeutic dose, high bioavailability, preferably high unchanged renal clearance and low hepatic metabolism is favourable. Moreover, the half-live of the marker should match the specific intake frequency / pattern.

[0010] The present invention seeks to provide a monitor marker that is useful in monitoring a subject, in particular for medical adherence / compliance, but potentially for other applications too.

[0011] Summary of the Invention

[0012] In a first aspect, the present invention provides a composition for the consumption of a subject, the composition comprising a substance and piracetam as a monitoring marker for the composition, wherein the substance is an pharmaceutical ingredient (API) or a consumer substance.

[0013] Optionally, the substance is an active pharmaceutical ingredient (API), preferably for the treatment or prevention of a disease for which monitoring the consumption of the composition is desirable. Preferably, the API is for the treatment or prevention of a disease for which monitoring the consumption of the composition is essential or vital. For example, in such treatment or prevention of a disease, medical compliance is crucial in ensuring or improving the success of medication / prevention.

[0014] Optionally, the disease is preferably selected from the group consisting of a substance use disorder, an immunodeficiency disorders, a neurological disorder, a mental disorder, a metabolic disease, a cardiovascular disease, or a paediatric disease.

[0015] Optionally, the disease is selected from the group consisting of alcohol use disorder, opioid use disorder, cocaine use disorder, common variable immunodeficiency, chronic granulomatous disease, IgA deficiency, acquired immunodeficiency syndrome, Alzheimer’s, Parkinson’s disease, attention deficit hyperactivity disorder, depression, bipolar disorder, Schizophrenia, post-traumatic stress disorder, diabetes, coronary artery disease, and asthma. For example, the API is for the treatment or prevention of cocaine use disorder, opioid use disorder, or attention deficit hyperactivity disorder.

[0016] Optionally, the composition further comprises an API selected from the group consisting of baclofen, tiagabine, topiramate, disulfiram, modafinil, amphetamine, dextroamphetamine, lisdexamfetamine, serdexmethylphenidate, dexmethylphenidate, methylphenidate, methamphetamine, and combinations and salts thereof. Preferably, the API is dexamphetamine or a salt thereof, and more preferably, the API is dexamphetamine sulfate. Preferably, the composition comprises dexamphetamine sulfate in an amount of 5 to 500 mg, preferably 10 to 200 mg, more preferably 10 to 50 mg, in particular 30 mg.

[0017] Piracetam is used in the composition of the present invention as a monitoring marker. Preferably, the amount of piracetam is substantially lower than, preferably no more than 90% of, more preferably no more than 80% of, even more preferably no more than 70%, for example no more than 50% of, the minimum therapeutic dosage required for the subject. Alternatively or in addition, the amount of piracetam is from 0.01 to 2400 mg, preferably from 0.1 to 1200 mg, even more preferably from 0.1 to 800 mg, typically from 0.1 to 100 mg, in particular from 0.1 to 8 mg.

[0018] Optionally, the substance may be a placebo material. Preferably, the placebo material a sugar or starch, for example lactose, such as lactose monohydrate, for example lactose monohydrate (Supertab).

[0019] The composition may be a single article composition or a combination of two or more articles, and preferably, the composition is a single article composition.

[0020] Preferably, the composition is an oral composition. Also preferably, the composition is a solid dosage form, optionally a solid dosage form selected from the group consisting of tablets, capsules, pills, granules, chewables and powders Preferably, the composition is a tablet. Preferably, the composition is a sustained release composition.

[0021] Optionally, the composition further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of solvents, gelling agents, diluents, disintegrants, lubricants, glidants, fillers, binders, surfactants, colorants / pigments, flavourings, sweeteners, plasticizers, moisturizers, antioxidants, water absorbents, coating agents and preservatives.

[0022] Also preferably, the substance is a consumer substance, for example a food or beverage substance or composition.

[0023] Preferably, the composition comprises piracetam, dexamphetamine sulfate, kollidon SR, lactose monohydrate, silica colloidas anhydrica and magnesium stearate, and is optionally a tablet. Also preferably, the composition comprises piracetam, kollidon SR, lactose monohydrate, silica colloidas anhydrica and magnesium stearate, and is optionally a tablet

[0024] According to a second aspect, the present invention provides a method for monitoring a subject. The method comprises: a) providing the subject with the composition according to the first aspect of the present invention; b) collecting an sample from the subject; and c) determining the level of piracetam in the sample collected.

[0025] Preferably, the sample collected is a body biological fluid sample, such as an urine sample or a blood sample.

[0026] Preferably, step b) is performed 12-80 hours after step a).

[0027] Preferably, the method is for the monitoring of medical compliance of a subject.

[0028] Optionally, the method further comprises: d) Issuing medical instructions, or adjusting previous medical instructions, based on the level of piracetam determined.

[0029] According to a third aspect, the present invention provides subtherapeutic dose of piracetam for use as a monitoring marker. The amount of piracetam is substantially lower than, preferably no more than 90% of, more preferably no more than 80% of, even more preferably no more than 70%, for example no more than 50% of, the minimum therapeutic dosage required for the subject. Preferably, the daily dosage of piracetam used is from 0.01 to 2400 mg, preferably from 0.1 to 1200 mg, even more preferably from 0.1 to 800 mg, typically from 0.1 to 100 mg, in particular from 0.1 to 10 mg.

[0030] Optionally, the piracetam is used to monitor a subject in following medication instructions. Preferably, the piracetam is used to monitor medical adherence and / or compliance of a subject.

[0031] According to a fourth aspect, the present invention provides a kit comprising a desiccant capsule and a composition according to the first aspect of the present invention.

[0032] According to a fifth aspect, the present invention provides a composition for the consumption of a subject, the composition comprising piracetam as a monitoring marker for the composition and a placebo material. Preferably, the placebo material a sugar or starch, for example lactose, such as lactose monohydrate, for example lactose monohydrate (Supertab).

[0033] According to a sixth aspect, the present invention provides piracetam for use as a monitoring marker in a composition for the consumption of a subject. The composition further comprises a substance comprising a placebo material, or an active pharmaceutical ingredient (API), or a consumer substance

[0034] It will of course be appreciated that features described in relation to one aspect of the present invention may be incorporated into other aspects of the present invention. For example, the method of the invention may incorporate any of the features described with reference to the apparatus of the invention and vice versa.

[0035] Description of the Drawings

[0036] Embodiments of the present invention will now be described by way of example only with reference to the accompanying schematic drawing of which:

[0037] Figure 1 illustrated the study design of Example 1

[0038] Figure 2 shows the result of piracetam urine concentrations measured in Example 2

[0039] Detailed Description

[0040] According to a first aspect, the present invention provides a composition comprising a substance and piracetam as a monitoring marker for the composition, wherein the substance is an active pharmaceutical ingredient (API) or a consumer substance .

[0041] Piracetam is a drug that has efficacy in medical conditions such as cognitive disorders, vertigo, cortical myoclonus and dyslexia. It is sold as a medication in many European countries, and is registered in the Netherlands for the treatment of vertigo. The daily therapeutic intake of piracetam is 2400 mg with complete bioavailability, no hepatic metabolism and a renal clearance of about 90%. Sub-therapeutic dose of piracetam is non-toxic. The likelihood of interference with prescribed piracetam is relatively low, as only 740 patients used the drug in the Netherlands in 2021. The plasma half life of piracetam is approximately 4-5 hours. These features of piracetam makes it an ideal candidate as a monitoring marker. The composition of the present invention comprising piracetam at a sub-therapeutic dose may be useful for monitoring a subject, in particular monitoring a subject in the consumption of the composition.

[0042] One way of determining the sub-therapeutic doses of piracetam is based on the EMA guidelines on shared manufacturing facilities. This guideline contains acceptance limits of cross-contamination between drugs in multipurpose manufacturing processes. These limits are based on the absence of a therapeutic or toxicological effect of the residues of an API, and the permitted daily exposure (PDE) is calculated using all available pharmacological and toxicological data, including both non-clinical and clinical data, to derive safe thresholds. The PDE represents a substance-specific dose that is unlikely to cause adverse effects if a person is exposed to or below this dose for a lifetime. The PDE for piracetam was calculated to be 8 mg.

[0043] The subtherapeutic dose of piracetam that is safe to use in each application can, however, be determined differently and individually, based on the substance that is to be taken with piracetam and / or the conditions of the subject. Piracetam is used as a monitoring marker. Therefore in general, the amount of piracetam can be anything lower than, or substantially lower than, the minimum therapeutic dosage required for the subject. In other words, the amount of piracetam use in the composition of the present invention is such that it is safe to use for the subject, it does not provide no or substantially no pharmacological effects and it does not interfere with the intended effects of the substance. Preferably, the amount of piracetam is no more than 90% of, more preferably no more than 80% of, even more preferably no more than 70%, for example no more than 50% of, the minimum therapeutic dosage required for the subject. Alternatively or in addition, the amount of piracetam may be from 0.01 to 2400 mg, preferably from 0.1 to 1200 mg, even more preferably from 0.1 to 800 mg, typically from 0.1 to 100 mg, in particular from 0.1 to 10 mg. In a preferred embodiment of the present invention, the composition comprises 1 to 8 mg piracetam, for example 1.25 mg piracetam. It is believed that these preferred embodiments offer both good detectability and safety.

[0044] The subject of the present invention may be a human or an animal, for example a mammal, such as a livestock animal. The human subject of the present invention may be an adult or a child.

[0045] The term “consumption” is used herein in the broad sense to encompass processes where the composition is only partially digested or otherwise in-taken by the subject.

[0046] Administration (or non-administration) of the composition of the present invention can be confirmed by the presence (or the absence) of piracetam in body biological fluid samples, for example in urine or blood samples, collected. The samples may be collected 24 to 72 hours after the administration of the composition is expected. Scenario in which monitoring a subject is either necessary or beneficial include, for example, when medical adherence is vital for the control of health conditions of a subject, when studying an investigational medicinal product, or when doing clinical trials.

[0047] The substance of the composition of the present invention may be an active pharmaceutical ingredient (API) or a consumer substance, for example a food / beverage sub stance / comp ositi on .

[0048] Preferably, the API is for the treatment and / or prevention of a disease. The disease may be a disorder or an infection disease. The disease may be any disease for which monitoring medical compliance is desirable, beneficial or vital. Alternatively, the API may be for the treatment and / or prevention of any disease, when the composition is used in a scenario where monitoring compliance is desirable, for example during a clinical trial or investigation.

[0049] Preferably, the disease is selected from the group consisting of a substance use disorder, an immunodeficiency disorders, a neurological disorder, a mental disorder, a metabolic disease, a cardiovascular disease, or a paediatric disease. Treatment and / or prevention of these diseases often requires long-term medication, where non-adherence to medical protocols is common. It can be intentional, unintentional, or both. Compositions comprising a combination of sub-therapeutic dose of piracetam and an API can be used to monitor medical adherence of patients in a safe and discreet manner.

[0050] Preferably, the API is for the treatment and / or prevention of a disease selected from the group consisting of alcohol use disorder, opioid use disorder, cocaine use disorder, common variable immunodeficiency, chronic granulomatous disease, IgA deficiency, acquired immunodeficiency syndrome, Alzheimer’s, Parkinson’s disease, attention deficit hyperactivity disorder (ADHD), depression, bipolar disorder, Schizophrenia, post-traumatic stress disorder, diabetes, coronary artery disease, and asthma. More preferably, the composition comprises an API for the treatment and / or prevention of cocaine use disorder, opioid use disorder, or attention deficit hyperactivity disorder.

[0051] Substance misuse can directly impair judgement about health behaviors, and poor adherence to psychiatric medication regimens is also major obstacle to the effective care of persons who have chronic mental illness. Persons who have both a mental illness and a substance use disorder appear to have the highest risk of poor adherence. The composition of the present invention is therefore particularly useful when comprising APIs for the treatment and / or prevention of common substance use disorders and neurological and mental disorders.

[0052] Preferably, the API is selected from the group consisting of baclofen, tiagabine, topiramate, disulfiram, modafinil, amphetamine, dextroamphetamine, lisdexamfetamine, serdexmethylphenidate, dexmethylphenidate, methylphenidate, methamphetamine, and combinations and salts thereof, and preferably, the API is dexamphetamine or a salt thereof. More preferably, the API is dexamphetamine or a salt thereof. In a preferred embodiment of the present invention, the composition comprises piracetam and dexamphetamine sulfate as the API. Preferably, the composition comprising piracetam and dexamphetamine sulfate as the API is for the treatment and / or prevention of cocaine use disorder.

[0053] Dexamphetamine is the D-i someric form of amphetamine, and is registered for the treatment of narcolepsy and ADHD. Amphetamines have a stimulating effect on the central nervous system. Previous studies have shown that dexamphetamine can be used as agonist replacement therapy to manage cocaine dependence. Dexamphetamine sulfate is one of its salt forms commonly used in pharmaceutical compositions. Dexamphetamine (sulfate) may be used in a dosage of 10 to 100 mg, preferably 20 to 90 mg, more preferably 30 to 90 mg, for example 30 or 60 or 90 mg, daily.

[0054] The amount of the API in the composition is based on registered / licensed / recommended dosage of the API used. The skilled person can, based on the pharmacological kinetics of said API, easily determine a suitable formulation for the composition including a suitable amount of the API, based on common general knowledge and the teaching of the current application. When the API is dexamphetamine sulfate, the amount of it is preferably from 10 to 500 mg, even preferably from 50 to 200 mg, more preferably from 80 to 150 mg. In a preferred embodiment of the present invention, the composition comprises dexamphetamine sulfate in an amount 30 mg. For example, a composition of the present invention comprises 30 mg dexamphetamine and 1.25 mg piracetam.

[0055] Alternatively, the substance in the composition of the present invention comprises a placebo material. It has been widely recognized that insuring proper medication ingestion or administration by individuals are very important in defending against unnecessary sickness, deaths and other problems. And these issues are even more problematic in a clinical trial setting where a lack of adherence to a particular assigned protocol may influence eventual approval of a particular drug therapy, potentially denying a valuable drug to the public and resulting in possible rejection of drugs. Additionally, failure to adhere to prescribed protocols in clinical drug trials may result in poor data collection and evaluation, thus resulting in the above mentioned deaths from failure for trials to identify potentially life-threatening side effects. The compositions of the present invention are also useful for the controlled arm in a clinical trial, when placebos are assigned.

[0056] A placebo (sometimes called dummy pill) is otherwise the same as the medication being tested but has an inert (inactive) substance instead of the API. Typical placebo material include, for example, sugar and starch. The skilled person will be able to design the composition of a placebo based on the corresponding medication being tested. Optionally, the placebo material is a sugar. The term “sugar” is used herewith to encompass natural sugars, sugar substitutes and sugar alcohols, as well as salts thereof. Sugar or starch based excipients have enjoyed broad acceptance as ingredients in various dosage forms of pharmaceutical compositions, and therefore are advantageous to use as placebo material. Optionally, the placebo material is selected from the group consisting of sucrose, glucose, fructose, galactose, maltose, arabimose, lactose, inositol, mannose, ribose, trehalose, xylose, salts thereof, and combinations thereof. In one embodiment of the present invention, the composition comprises piracetam and lactose as the placebo material. The composition of the present invention may further comprise one or more pharmaceutically acceptable excipients. The one or more excipients each may have a function in facilitating the formation of the desirable dosage form, achieving or maintaining the desirable stability, solubility and / or bioavailability, and / or delivering the content of the composition in a desirable manner.

[0057] Pharmaceutically acceptable excipients are well known to the skilled person. Optionally, the one or more pharmaceutically acceptable excipients is selected from the group consisting of solvents, gelling agents, diluents / fillers, disintegrants, lubricants, glidants, binders, surfactants, colorants / pigments, flavourings, sweeteners, plasticizers, moisturizers, antioxidants, water absorbents, coating agents and preservatives.

[0058] Binders may be used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. In some embodiments, the binder is selected from the group consisting of microcrystalline cellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose. In specific embodiments, the binder is microcrystalline cellulose, e.g. Avicel® PHI 05. When present, binders may comprise from about 0 wt% to about 15 wt%, or from about 0.2 wt% to about 10 wt% of the composition. In some embodiments, the binder comprises about 5 wt% to about 10 wt% of the composition. In particular embodiments, the binder comprises about 10 wt% of the composition.

[0059] Solid dosage forms frequently contain one or more lubricants. Examples of lubricants include magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, mixtures of magnesium stearate with sodium lauryl sulfate, or mixtures of two or more of these. In some embodiments, the lubricant is magnesium stearate and / or sodium stearyl fumarate. In some preferred embodiments, the lubricant is magnesium stearate. In some such embodiments, the solid dosage form is a tablet comprising magnesium stearate. When present, lubricants frequently comprise from about 0.25 wt% to about 10 wt%, preferably from about 0.5 wt% to about 6 wt% of the composition. In one preferred embodiment, the composition is a tablet comprising about 0.5 wt% magnesium stearate as lubricant. Tablets may also compromise glidants, for example silicon dioxide, colloidal silicon dioxide, silica colloidas anhydrica, magnesium silicate, magnesium trisilicate, talc, and other forms of silicon dioxide, such as aggregated silicates and hydrated silica. In some embodiments, the glidant is silica colloidas anhydrica. When present, glidants may comprise from about 0.01 wt% to about 10 wt%, preferably from about 0.1 wt% to about 5 wt%, or from about 0.5 wt% to about 2 wt% of the tablet. In one preferred embodiment, the composition is a tablet comprising about 0.2 wt% silica colloidas anhydrica as glidant.

[0060] Tablets may optionally include surface-active agents, such as sodium lauryl sulfate and polysorbate 80. When present, surface-APIs may comprise from 0 wt% to 10 wt%, or preferably 0.2 wt% to 5 wt% of the tablet.

[0061] As used herein, a “diluent” or “filler” is an excipient that adds bulkiness to a composition. Examples of fillers include lactose, sorbitol, celluloses, calcium phosphates, starches, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.

[0062] The composition of the present invention may comprise piracetam and the substance in a single article composition, or as a combination of two or more different articles. For example, the composition may comprise a piracetam tablet and an API or tablet. Preferably, the composition is a single article composition. In a preferred embodiment of the present invention, the composition is a single article composition comprising piracetam and an API.

[0063] The composition may be a composition for oral administration, for sublingual administration, for parenteral administration, for topical administration, or for inhaler administration. Preferably, the composition is an oral composition for oral administration. Oral compositions are easy to take, allow for medication at home, and piracetam has high bioavailability when administered orally. Alternatively, the composition may be a sublingual composition. The composition of the present invention may be of any dosage form, for example a solid dosage form, a liquid dosage form, a semi-solid dosage form or a gaseous dosage form. For example, the composition may be a solid dosage form selected from the group consisting of tablets, capsules, pills, granules, chewables and powders. The composition may be a liquid dosage form selected from the group consisting of elixirs, emulsions, suspensions, solutions and syrups. The composition may be a semi-solid dosage form selected from the group consisting of ointments, creams, paste and gels. The composition may be a gaseous dosage form selected from the group consisting of aerosols, inhalations and sprays.

[0064] When the composition is a combination of two or more articles, each of the articles may be of the same or different dosage forms.

[0065] Preferably, the composition is a solid dosage form, for example a tablet. In one preferred embodiment of the present invention, the composition is a single tablet comprising piracetam and an API or a placebo material. In an exemplary embodiment of the present invention, the composition is a single tablet comprising piracetam and dexamphetamine sulfate as the API. In another exemplary embodiment of the present invention, the composition is a single tablet comprising piracetam and lactose monohydrate as the placebo material.

[0066] In general, the solid dosage forms of the invention are prepared according to methods usual in pharmaceutical chemistry. Selected excipients may be incorporated along with the API into either or both of the extragranular or intragranular compartments.

[0067] The composition of the present invention may be an immediate release composition, or a sustained release composition, or a delayed release composition. The skilled person can determine and formulate the composition with desirable release profile based on applications (for example the API used and the medical conditions).

[0068] When the composition is a combination of two or more articles, each of the articles may be of the same or different release patterns. Preferably, the composition is a sustained release composition, for example a single sustained release composition. In one preferred embodiment of the present invention, the composition is a sustained release piracetam composition, for example a sustained release piracetam tablet. The sustained release composition of the present invention may comprise sustained release agent, for example a sustained release matrix, which helps to prolong and control the release of the content of the composition. A matrix system consists of active and inactive ingredients that are homogeneously dispersed and mixed in the dosage form.

[0069] Exemplary controlled release agents can be selected from the group consisting of acetate succinate, a polyvinyl derivative (for example, polyvinyl alcohol, polyvinyl acetate, polyvinyl acetate phthalate, a copolymer of vinyl acetate and vinyl pyrrolidone, a copolymer of vinyl acetate and crotonic acid, polyvinylpyrollidone), polyethylene oxide, polyacrylic acid, polysaccharides (for example, modified starch, cross-linked high amylose starch, hydroxypropyl starch, hydroxypropyl methylcellulose phthalate, cellulose and cellulose derivatives (for example, microcrystalline cellulose, carboxymethylethyl cellulose, cellulose acetate, methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose phthalate, cellulose acetate, cellulose acetate phthalate, cellulose acetate propionate, cellulose-acetate succinate, cellulose acetate butyrate, cellulose-acetate trimellitate)), poloxamer, povidone, alginic acid, sodium alginate, polyethylene glycol, polyethylene glycol alginate, gums (for example, xanthan gum), polymethacrylates (including, for example, a copolymer of methacrylic acid and methyl-methacrylate, and a copolymer of methacrylic acid and ethyl acrylate), a copolymer of methacrylic acid and ethyl acrylate, a copolymer of polymethyl vinyl ether and malonic acid anhydride, a copolymer of polymethyl vinyl ether and malonic acid or the ethyl-, isopropyl-, n-butylesters thereof, zein, and mixtures of the foregoing.

[0070] Further examples of controlled release film-coating polymers include, but are not limited to, methylcellulose, ethylcellulose (for example, Aquacoat® type from FMC Corp.), methylhydroxyethylcellulose, methylhydroxypropylcellulose (for example, Pharmacoat® type from Shin Etsu Corp.), ethylhydroxyethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose or methylcarboxymethylcellulose, acrylic polymers, polyvinylacetates, polyvinyl chlorides, polymethylmetacrylates or a terpolymer of vinylchloride, vinylalcohol and vinylacetate, hydroxypropylmethylcellulose phthalate (for example, HP type from Shin Etsu), hydroxypropylmethylcellulose acetate succinate (for example, Aqoat from Shin Etsu), cellulose acetate phthalate (for example, Aquacoat CPD from FMC Corp, or C- A-P NF from Eastman Chemical), polyvinyl acetate phthalate (for example, Sureteric from Colorcon), carboxymethylethylcellulose, and co-polymerized methacrylic acid / methacrylic acid methyl esters (for example, Eudragit from DegussaZEvonik Industries or Kollicoat from BASF or Acryl-Eze from Colorcon or Eastacryl from Eastman Chemical).

[0071] When present, the controlled release agents comprise from 30 wt% to 80 wt%, or preferably 50 wt% to 70 wt% of the composition.

[0072] In a preferred embodiment of the present invention, the composition is a single tablet comprising piracetam and Kollidon SR. For example, preferred embodiment of the present invention comprises 65 wt% Kollidon SR. Kollidon SR is a sustained release matrix forming agent consisting of polyvinyl acetate and polyvinylpyrrolidone. A typical composition of Kollidon SR comprises 80 wt% polyvinyl acetate, 19 wt% povidone, 0.8 wt% luryl sulfate and 0.2 wt% silica. It has free-flowing, non- hygroscopic and direct compressibility properties (high dry binding capacity). Further, in vitro drug release profiles of tablet formulations with Kollidon SR as sustained release matrix forming agent are not influenced by the compression force used, pH and ionic strength of the dissolution media, and speed of agitation. This unique property of Kollidon SR makes it one of the most promising sustained release matrix forming agents especially where pH independent drug release is desired.

[0073] In one preferred embodiment of the present invention, the composition is a sustained release composition comprising piracetam and dexamphetamine sulfate as the API, for example a sustained release piracetam tablet comprising piracetam and dexamphetamine sulfate. The composition may preferably comprise Kollidon SR as the sustained release matrix and further comprises lactose monohydrate as filler, silica colloidas anhydrica as glidant and magnesium stearate as lubricant. In another preferred embodiment of the present invention, the composition is a sustained release composition comprising piracetam and lactose monohydrate as placebo material, for example a sustained release piracetam tablet comprising piracetam and lactose monohydrate. The composition may preferably comprise Kollidon SR as the sustained release matrix and further comprises additional amount of lactose monohydrate as filler, silica colloidas anhydrica as glidant and magnesium stearate as lubricant.

[0074] The composition of the present invention may also be a food / beverage composition. It may be a food / beverage composition for the consumption of the general public, or a food / beverage composition for the consumption of a designated group of people. For example, the food composition of the present invention may comprise a sweetener and is to be consumed as a sugary product. It is of course also within the scope of the present invention that the food composition comprises a different flavouring and is to be consumed as a savoury product. The food composition of the present invention can be either hot food or cold food. The term “food” is used herein in a broad sense to encompass meals, snacks and food supplements. The food composition of the present invention may be in any form that is edible. For example, it can be a cake, a biscuit, a chewable, a tablet, a capsule, or powders.

[0075] The beverage composition of the present invention may be alcoholic or nonalcoholic beverage. For example the beverage composition of the present invention may be a liquor such as gin, vodka, whiskey, tequila, rum, brandy, a wine, a beer, or any combinations thereof. Alternatively, the beverage composition of the present invention may be a diary drink, a fizzy drink, a tea or coffee drink, or any combinations thereof. The beverage composition of the present invention can also be a cocktail drink.

[0076] The food / beverage composition of the present invention may be useful for habit tracking and / or for monitoring the consumption of food / beverage. For example, it can be used for the purpose of monitoring the consumption of a specific drink or food item. In addition to piracetam, the food / beverage composition of the present invention comprises the main food or beverage item, and may further comprise excipients and additives commonly used in food and beverage. The present invention further provides a method for monitoring a subject, for example monitoring a subject in following medical instructions. Preferably, the method of the present invention may be used for monitoring a subject on medical adherence, either during treatment medication regimen or during clinical trials (either in the control arm or in the intervention (treatment) arm). Alternatively, the method of the present invention may also be used for habit tracking. For example, it may be used to track sugar-consumption in patients with diabetes, or subjects susceptible to diabetes, or may be used to track alcohol-consumption. Preferably, the subject is a human. Preferably, the subject is a patient. Alternatively, the subject is a healthy volunteer. The subject could also be a person subject to life-style / habit monitoring / tracking.

[0077] Optionally, the subject may be a single person. Alternatively, the subject may be a population. The method of the present invention may be used for monitoring the collective consumption of the composition of the present invention in a population. When the subject is a population, it can be a population of patients, a population of healthy volunteers, or a combination of both.

[0078] The composition of the present invention may be used in a clinical trial. For example, in a clinical trial, the composition of the present invention comprising piracetam and a placebo material is used for the control arm. Additionally or alternatively, the composition of the present invention comprising piracetam and an API is used for the treatment arm. If piracetam is used for both the composition of the control arm and the composition of the treatment arm, the amount of piracetam used in the compositions may be the same or different.

[0079] The present invention also provides piracetam for use as a monitoring marker in a composition for the consumption of a subject. The composition further comprises a substance as described herein.

[0080] The method of the present invention comprises: a) providing the subject with the composition according to the present invention; b) collecting an sample from the subject; and c) determining the level of piracetam in the sample collected. The method of the present invention provides a safe and discrete way of monitoring a subject. The information obtained (for example whether the subject has followed medical instructions given, or the level of piracetam measured from the sample collected, optionally in comparison with a standard or benchmark) may help researchers, medical practitioners and / or other personals to issue medical instructions, or to adjust previous medical instructions, accordingly.

[0081] The sample collected may be any body biological fluid of the subject. Preferably, the sample collected is an urine sample, a blood sample, an excreta sample, a sweat sample, a saliva sample, a tissue or tissue fluid sample. The type of sample collected may depend on the specific API used in the composition. Preferably, the sample collected is an urine sample or a blood sample, more preferably a urine sample. When the subject is a population, the sample may be a collection of samples collected from each member of the population, or selective (either randomly or criteria-based) members of the population. The collected samples (if more than one) can be analysed separately, or mixed.

[0082] In one preferred embodiment of the present invention, the sample collected is a urine sample of the subject.

[0083] Alternatively, the sample collected may be a sample containing a body biological fluid of the subject. For example, the sample collected may be waste or sewage containing a body biological fluid of the subject.

[0084] Preferably, step b) is performed 10 to 100 hours, preferably 12 to 80 hours, more preferably 24 to 72 hours, after step a). In other words, the sample is collected 10 to 100 hours, preferably 12 to 80 hours, more preferably 24 to 72 hours, most preferably 24 hours, after the administration or the consumption of the composition comprising piracetam. Piracetam is a plasma half life of 4 to 5 days. If the amount of piracetam is measured in urine samples, a sample collected between 2 to 3 days after the consumption of the composition of the present invention provides the best basis for detecting the presence (or absence, or the level) of piracetam in the collected sample. Of course, the release behavior of piracetam in a specific composition may also be affected by the excipients and / or carriers used. Pharmacokinetic behaviour of piracetam may also be different in different biomatrix. The skilled person will be able to choose a window during which a sample should be collected from the subject, based on individual applications. In general, when the purpose is detecting the presence (or absence) of piracetam in the collected sample, the sample collection can enjoy a wider time window as long as the residue piracetam is above detection limit.

[0085] In a preferred embodiment of the present invention, the subject is a healthy volunteer and the sample collected is a urine sample collected 24 or 72 hours after the administration (consumption) of the composition.

[0086] Optionally, the piracetam concentration in a urine sample collected 24 hours after the oral administration of a composition of the present invention is from 20 to 7500 ng / mL, preferably from 50 to 5000 ng / mL, for example from 100 to 3500 ng / mL. Preferably, the piracetam concentration in a urine sample collected 72 hours after the oral administration of a composition of the present invention is no more than 500 ng / mL, no more than 400 ng / mL, no more than 300 ng / mL, no more than 200 ng / mL, for example no more than 100 ng / mL. Preferably, the piracetam concentration in a urine sample collected 24 hours after the oral administration of a composition of the present invention is at least 5000, at least 4000, at least 3000, at least 2000, at least 1000, at least 800, at least 500, at least 400, at least 200, at least 100, times the piracetam concentration in a urine sample collected 72 hours after oral administration of a composition of the present invention.

[0087] Step c) of the method of the present invention may be performed using any suitable analytical method, for example by HPLC-MS / MS method. The skilled person can, based on the type of sample collected and / or the contents of the composition used, determine a suitable method for measuring the level of piracetam in the sample.

[0088] The present invention further provides sub-therapeutic dose of piracetam for use as a monitoring marker. Preferably, the piracetam as a monitoring marker is used in an amount from 0.1 to 2400 mg, preferably from 0.1 to 1200 mg, from 0.1 to 800 mg, from 0.1 to 500 mg, from 0.1 to 200 mg, more preferably from 0.5 to 50 mg from 0.5 to 20 mg, from 0.5 to 10 mg, from 1 to 8 mg, daily. In an example of the present invention, the piracetam is used as a monitoring marker in amount of 1.25 mg daily. The piracetam for use as a monitoring marker may be used in a composition of the present invention as described herein, or in a method of the present invention as described herein.

[0089] Preferably, the piracetam for use as a monitoring marker is used for monitoring medical adherence / compliance of a subject, either a patient or a healthy volunteer. Alternatively, the piracetam for use as a monitoring marker is used for monitoring the consumption of a food or beverage item for the purpose of, for example, generating survey data or as pre-requisition for subsequent medical intervention.

[0090] The present invention also provides a composition for use in the treatment or improvement of a substance use disorder, for example opioid use disorder or cocaine use disorder. The composition comprises piracetam as a monitoring marker and dexamphetamine or a salt thereof as an active pharmaceutical ingredient.

[0091] It should be understood that numerical values used herein are intended to encompass the recited value and the range which would be included by rounding up or down to that figure as well, considering significant figures, and the range which would encompass the recited value plus or minus 20%.

[0092] A preferred composition according to the invention comprises:

[0093] Table 1 - Exemplary composition of the present invention (Drug) Another preferred composition according to the invention comprises:

[0094] Table 2 - Exemplary composition of the present invention (Placebo)

[0095] Examples

[0096] The invention will be explained in more detail in the following, non-limiting examples.

[0097] Example 1 - manufacturing of piracetam 1.25 mg sustained-release tablets as placebo

[0098] Piracetam 1.25 mg sustained release tablets were manufactured. The composition of the tablets is as shown in Table 2 above.

[0099] First, piracetam was grinded. Silica colloidalis anhydrica and powder of the grinded piracetam were passed through a screen and mixed with Kollidon SR and lactose monohydrate in a tumbling mixer. After the mixing step, the powder mixture is sampled at various locations for content and content uniformity. The assay of piracetam must show between 95.0% and 105.0% of the desired content, the relative standard deviation between the samples of piracetam must be no more than 5.0%. The powder mixture was held for a maximum of 1 week after mixing before being used for compression of piracetam 1.25 mg sustained release tablets in a low density polyethylene (LDPE) bag, surrounded by an LDPE outer bag, placed in a closed high density polyethylene (HDPE) container with six desiccant bags and stored at 15-25 °C, protected from light. Shortly prior to compression, magnesium stearate was mixed into the intermediate powder mixture in a tumbling mixer. Subsequently, the final powder mixture was compressed into tablets using a rotary tablet press. Throughout the compression process, in-process-controls were taken at regular intervals, inspected visually and tested for hardness, mass and mass variation.

[0100] Before the piracetam 1.25 mg sustained release tablets were manufactured from the powder blend using direct compression, the powder blend was analyzed for QC. Since the piracetam content is only 0.62% of total weight of the tablet, content and content uniformity of the powder mixture after mixing were considered as Critical Quality Attributes (CQAs). In addition, appearance and identity tests are performed on the intermediate powder mixture (Table 3 below).

[0101] Table 3 : Tests, acceptance criteria and results for the intermediate powder blend

[0102] ^Development batches were used to define final mixing settings for the clinical batch size

[0103] A development batch (1,000 tablets) and two validation batches (5,000 and 10,000 tablets, respectively) of piracetam 1.25 mg sustained release tablets were produced to confirm the feasibility and robustness of the manufacturing process. These batches were subjected to full Quality Control tests as described in Table 4 below and all complied to the specifications. On the basis of these results, a clinical batch size of 10,000 tablets was selected.

[0104] Table 4: In-process and release specifications for the piracetam 1.25 mg sustained release tablets

[0105] Example 2 - clinical test of placebo The composition used in Example l is a piracetam sustained-release tablet (1.25 mg piracetam tablet) whose content is as described in Table 5 above. In this single center, open-lable, uncontrolled study, participating healthy volunteers (n=10) were required to administer the composition under supervision once weekly according to the following scheme:

[0106] Table 5 - administration scheme of Example

[0107] Urine samples were collected 24 hours and 72 hours after administration of the weekly dose.

[0108] An illustration of the study design is shown in Figure 1. The piracetam urine concentrations measured in Example 1 are shown in Figure 2. All administered doses of piracetam resulted in detectable concentrations in urine after 24 hours. Moreover, measured concentrations after 2 days of non-administration (72 hours) for all doses were distinguishable from concentrations after 24 hours. The result demonstrated that the administration (or the non-administration) of the composition can be successfully monitored.

[0109] Example 3 - manufacturing of dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets

[0110] Dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets were manufactured. The composition of the tablets is as shown in Table 1 above.

[0111] First, piracetam was grinded. Dexamphetamine sulfate, silica colloidalis anhydrica and piracetam were passed through a screen and mixed with Kollidon SR and lactose monohydrate in a tumbling mixer. After the mixing step, the obtained intermediate powder mixture was sampled at various locations for content and content uniformity. The assay of both piracetam and dexamphetamine sulfate must show between 95.0% and 105.0% of the desired content. The relative standard deviation between the samples of both drug substances must be no more than 5.0%. The powder mixture was held for a maximum of 1 week after mixing before being used for compression of dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets in a low density polyethylene (LDPE) bag, surrounded by an LDPE outer bag, placed in a closed high density polyethylene (HDPE) container with six desiccant bags and stored at 15-25 °C, protected from light.

[0112] Shortly prior to compression, magnesium stearate was mixed into the intermediate powder mixture in a tumbling mixer. Subsequently, the final powder mixture was compressed into tablets using a rotary tablet press. Throughout the compression process, in-process-controls were taken at regular intervals, inspected visually and tested for hardness, mass and mass variation.

[0113] Appearance and identity tests are performed on the intermediate powder mixture (Table 6 below).

[0114] Table 6: Tests, acceptance criteria and results for dexamphetamine sulfate / piracetam intermediate powder mixture

[0115] *Powder mixture was used immediately for tablet manufacture. Tablets made with this powder mixture did comply.

[0116] A development batch (1,000 tablets) and two validation batches (5,000 and 10,000 tablets, respectively) of dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets were produced to confirm the feasibility and robustness of the manufacturing process.

[0117] The batches were subject to full quality control tests as described in Table 7 below and all complied to the specifications. Table 7: In-process and release tests and specifications for dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets

[0118] Piracetam

[0119] Example 4

[0120] Dexamphetamine sulfate / piracetam 30 / 1.25 mg sustained release tablets obtained according to the process as described in Example 2 were tested for stability. Stability of the tablets in the clinical container closure system (packed per 3 tablets in the “clinical container closure systems”, which are 15 ml HDPE Duma® Twist-Off pharmaceutical tablet containers (Gerresheimer model 35015, (D*E[) 36mm x 46mm, with 21mm neck) closed with Duma® Twist-Off Pharmaceutical childresistant screw caps with guarantee closure and a desiccant capsule (Gerrasheimer model 2829D, suitable for 21mm neck) was examined according to the stability study plan given in Table 8. Acceptance criteria and results for stability studies are given in Table 8. All tests listed was performed at each time point.

[0121] Table 8 Sampling time points for stability studies Thus far, tablets have been shown stable for 12 months at 25°C / 60% RH (see Table 9 below). Also, to account for short term temperature excursions, accelerated stability at 40°C / 75% RH was examined for 2 weeks and tablets were found stable for this period of time. No extension of the stability study at this storage condition was examined as it is known that the Kollidon SR excipient phylically alters due to the glass transition temperature (Tg) of approximately 30 °C of the polyvinyl acetate component, which may affect release characteristics of the matrix.

[0122] Table 9 Acceptance criteria for stability studies and development batch stability study results of dexamphetamine sulfate / piracetam 30 mg / 1.25 mg sustained release tablets.

[0123] ■ / : compliance

[0124] On the basis of these results, a shelflife of 12 months at +15-25 °C was assigned to the dexamphetamine sulfate / piracetam 30 / 1.25 mg sustained release tablet (in the clinical container closure system as described above).

[0125] Whilst the present invention has been described and illustrated with reference to particular embodiments, it will be appreciated by those of ordinary skill in the art that the invention lends itself to many different variations not specifically illustrated herein. By way of example only, certain possible variations will now be described.

[0126] Any feature that has been described above in relation to any one aspect or embodiment of the invention is also disclosed hereby in relation to all other aspects and embodiments. Likewise, all combinations of two or more of the individual features or elements described above may be present in any aspect or embodiment.

[0127] For brevity, all possible features and combinations have not been recited in relation to all aspects and embodiments, but they are expressly contemplated and hereby disclosed.

Claims

Claims1. A composition for the consumption of a subject, the composition comprising piracetam as a monitoring marker for the composition and a substance, wherein the substance is an active pharmaceutical ingredient (API) or a consumer substance.

2. The composition of claim 1, wherein the substance comprises an active pharmaceutical ingredient (API), preferably for the treatment or prevention of a disease for which monitoring the consumption of the composition is desirable.

3. The composition of claim 1 or 2, wherein the API is for the treatment or prevention of a disease selected from the group consisting of a substance use disorder, an immunodeficiency disorders, a neurological disorder, a mental disorder, a metabolic disease, a cardiovascular disease, or a paediatric disease; and / or wherein the API is for the treatment or prevention of a disease selected from the group consisting of alcohol use disorder, opioid use disorder, cocaine use disorder, common variable immunodeficiency, chronic granulomatous disease, IgA deficiency, acquired immunodeficiency syndrome, Alzheimer’s, Parkinson’s disease, attention deficit hyperactivity disorder, depression, bipolar disorder, Schizophrenia, post-traumatic stress disorder, diabetes, coronary artery disease, and asthma .

4. The composition of any one of claims 1 to 3, wherein the substance is selected from the group consisting of baclofen, tiagabine, topiramate, disulfiram, modafinil, amphetamine, dextroamphetamine, lisdexamphetamine, serdexmethylphenidate, dexmethylphenidate, methylphenidate, methamphetamine, and combinations and salts thereof, and preferably, the substance is dexamphetamine or a salt thereof.

5. The composition of any one of claims 1 to 4, wherein the substance is dexamphetamine sulfate, preferably in an amount of 5 to 500 mg, preferably 10 to 200 mg, more preferably 10 to 50 mg, in particular 30 mg.

6. The composition of any one of claims 1 to 5, wherein the amount of piracetam is substantially lower than, preferably no more than 90% of, more preferably no more than 80% of, even more preferably no more than 70%, for example no more than 50% of, the minimum therapeutic dosage required for the subject; and / or wherein the amount of piracetam is from0.01 to 2400 mg, preferably from 0.1 to 1200 mg, even more preferably from 0.1 to 800 mg, typically from 0.1 to 100 mg, in particular from 0.1 to 8 mg.

7. The composition according to any one of claims 1 to 6, wherein the composition is a single item composition or a mixture of two or more items, and preferably, the composition is a single item composition.

8. The composition according to any one of claims 1 to 7, wherein the composition is an oral composition, and / or wherein the composition is a solid dosage form, and / or wherein the composition is a sustained release composition.

9. The composition according to any one of claims 1 to 8, wherein the composition is a dosage form selected from the group consisting of tablets, capsules, pills, granules, chewables and powders; and preferably, the composition is a tablet.

10. The composition according to any one of claims 1 to 9, further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of solvents, gelling agents, diluents, disintegrants, lubricants, glidants, fillers, binders, surfactants, colorants / pigments, flavourings, sweeteners, plasticizers, moisturizers, antioxidants, water absorbents, coating agents and preservatives.

11. The composition according to any of claims 1 to 10, wherein the composition comprises piracetam, dexamphetamine sulfate, kollidon SR, lactose monohydrate, silica colloidas anhydrica and magnesium stearate.

12. A method for monitoring a subject, the method comprising: a) providing the subject with the composition according to any one of claims 1 to 11; b) collecting a sample from the subject; and c) determining the level of piracetam in the sample collected.

13. The method according to claim 12, wherein the sample collected is a body biological fluid sample, preferably an urine sample or a blood sample or a saliva sample.

14. The method according to any one of claims 12 or 13, further comprising:d) Issuing medical instructions, or adjusting previous medical instructions, based on the level of piracetam determined.

15. A composition for use in the treatment or improvement of a substance use disorder, for example opioid use disorder or cocaine use disorder, wherein the composition comprises piracetam as a monitoring marker and dexamphetamine or a salt thereof as an active pharmaceutical ingredient.

16. A composition for the consumption of a subject, the composition comprising piracetam as a monitoring marker for the composition and a substance, wherein the substance is a placebo material, preferably a sugar or starch, more preferably lactose, such as lactose monohydrate.

17. The composition according to any one of claims 1 to 11, and / or the composition of claim 16, for use in a clinical trial.

18. Use of piracetam as a monitoring marker in a composition for the consumption of a subject, wherein the composition further comprises a substance comprising a placebo material, or an active pharmaceutical ingredient (API), or a consumer substance.

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