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WO2018115888A1 - Nouvelles formulations d'aprépitant - Google Patents

Nouvelles formulations d'aprépitant Download PDF

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Publication number
WO2018115888A1
WO2018115888A1 PCT/GB2017/053864 GB2017053864W WO2018115888A1 WO 2018115888 A1 WO2018115888 A1 WO 2018115888A1 GB 2017053864 W GB2017053864 W GB 2017053864W WO 2018115888 A1 WO2018115888 A1 WO 2018115888A1
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WIPO (PCT)
Prior art keywords
aprepitant
fraction
pharmaceutical composition
composition according
controlled
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2017/053864
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English (en)
Inventor
Paul Charlton Titley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
N4 Pharma UK Ltd
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N4 Pharma UK Ltd
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Filing date
Publication date
Priority claimed from GBGB1621867.9A external-priority patent/GB201621867D0/en
Priority claimed from GBGB1716293.4A external-priority patent/GB201716293D0/en
Application filed by N4 Pharma UK Ltd filed Critical N4 Pharma UK Ltd
Publication of WO2018115888A1 publication Critical patent/WO2018115888A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to new uses, combinations and product line extenders relating to the product aprepitant, which is trademarked as Emend®.
  • Aprepitant is a blockbuster drug discovered, developed and marketed by Merck. It was originally developed as an anti-depressant compound, but was later repurposed and developed and approved by the FDA as a cytotoxic agent induced anti emetic compound.
  • Aprepitant is an antiemetic chemical compound that belongs to a class of drugs called substance P antagonists (SPA). It mediates its effect by blocking the neurokinin 1 (NK1) receptor.
  • SPA substance P antagonists
  • a first aspect of this invention is that it has been found that aprepitant can be used for a whole host of additional new uses that are associated with both substance P antagonists and NK1 receptor antagonists. These are documented in the medical literature and are incorporated herein by reference. Combinations can be formed by selecting two or more of these uses for one product.
  • a particularly preferred aspect of this invention is the provision of new and improved formulations hereinafter described which are adapted for the uses and combinations described and incorporated herein.
  • Such formulations address one or more of the following draw backs to aprepitant i.e. rapidity, longevity and a lack of dose to dose action within the therapeutic window. Preferably all three drawbacks are addressed with one product.
  • the present invention provides new routes and types of administration such as oral and non-oral routes.
  • the present invention relates to variations on new doses of aprepitant optionally in conjunction with new uses or combinations, such new doses are usually less than the normal aprepitant dose of 150mg and gives rise to less side effects, new doses are suitably employed when the issues of poor bioavailability and short half-life are also addressed by employing new and useful product line extenders.
  • Aprepitant is manufactured by Merck and Co under the brand name Emend® for the prevention of acute and delayed chemotherapy induced nausea and vomiting. It is also approved for the prevention of post-operative nausea and vomiting. It was approved by the FDA in 2003.
  • Aprepitant may also be useful in the treatment of cyclic vomiting syndrome & late- stage chemotherapy induced vomiting, but there are few studies to date.
  • Aprepitant is made up of a morpholine core with two substituents attached to adjacent ring carbons. These substitute groups are trifluoromethylated phenyl ethanol and flurophenyl group. Aprepitant also has a third substituent (triazolinone), which is joined to the morpholine ring nitrogen . It has three chiral centres very close together, which combine to produce an amino acetyl arrangement. Its empirical formula is C23H21F7N4O3.
  • the chemical structure of aprepitant i.e. aprepitant free base is as follows:
  • Fosaprepitant which is a prodrug of aprepitant and approved as an intravenous form of aprepitant, has the following chemical structure:
  • Aprepitant is an off-white crystalline solid that has a molecular weight of around 534.53. It is very soluble in water and does have a reasonably high solubility in non-polar molecules such as oils. This would, therefore, suggest that aprepitant as a whole, despite having components that are polar, is a non-polar substance. Aprepitant' s solubility can be improved as can its bioavailability by forming salts with acid based reagents. This forms an aspect of the present invention.
  • the new process begins by enantiopure trifluoromethylated phenyl ethanol being joined to a racemic morpholine precursor. This results in the wanted isomer crystallizing on the top of the solution and the unwanted isomer remaining in the solution. The unwanted isomer is then converted to the wanted one by the chemist controlling the reaction conditions and a process known as crystallization-induced asymmetric transformation occurring. By the end of this step a secondary amine, the base of the drug, is formed.
  • the second step involves the fluorophenyl group being attached to the morpholine ring. Once this has been achieved the third and final step can initiated.
  • This step involved a side chain of triazolinone being added to the ring. Once this step has been successfully completed a stable molecule of Aprepitant has been produced.
  • This more streamlined route yields around 76% more Aprepitant than the original process and reduces the operating cost by a significant amount.
  • the new process also reduces the amount of solvent and reagents required by about 80% and saving an estimated 340,000L per ton of Aprepitant produced.
  • Aprepitant is classified as an NK1 antagonist because it blocks signals given off by NK1 receptors. This, therefore, decreases the likelihood of vomiting in patients.
  • NK1 is a G protein coupled receptors located in the central and peripheral nervous system. This receptor has a dominant ligand known as Substance P (SP). SP is a neuropeptide, composed of 11 amino acids, which sends impulses and messages from the brain. It is found in high concentrations in the brain, and, when activated, it results in a vomiting reflex. In addition to this it also plays a key part in the transmission of pain impulses from the peripheral receptors to the central nervous system.
  • SP Substance P
  • Aprepitant has been shown to inhibit both the acute and delayed emesis induced by cytotoxic chemotherapeutic drugs by blocking substance P landing on receptors in the brain's neurons.
  • Positron Emission Topography (PET) studies have demonstrated that Aprepitant can cross the blood brain barrier and bind to NK1 receptors in the human brain. It has also been shown to increase the activity of the 5 HT3 antagonists ondansetron and the corticosteroid dexamethasone, which are also used to prevent nausea and vomiting caused by chemotherapy.
  • Aprepitant is taken orally in the form of a capsule. Before clinical testing, a new class of therapeutic agent has to be characterized in terms of preclinical metabolism and excretion studies. Average bioavailability is found to be around 60-65%. Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19. Seven metabolites of Aprepitant, which are only weakly active, have been identified in human plasma. As a moderate inhibitor of CYP3A4, Aprepitant can increase plasma concentrations of coadministered medicinal products that are metabolized through CYP3A4.
  • Aprepitant One of the main features of Aprepitant, and a major advantage it has over other chemotherapy-induced side-effect treatments, is its ability to selectively antagonize NK1 receptors, while having very low affinity to other common receptors such as serotonin, dopamine, and corticosteroid. It is estimated that Aprepitant is at least 3,000 times more selective to NK1 receptors compared to these other enzyme transporter, ion channels. The normal dosing of Aprepitant given as 125 mg in the first day after chemotherapy and followed by 80 mg the following 2 days.
  • Emend® sales have climbed steadily over the years following first approval in 2004 in the US to $500mm
  • Aprepitant' s unique mechanism of action and its use as a cytotoxic agent induced antiemetic agent lends its self to repurposing for a raft of new uses.
  • aprepitant' s unique mechanism of action and its approved uses means that aprepitant lends itself to incorporation in combination products.
  • aprepitant is a great compound with powerful biological action, it has a number of drawbacks in it biological profile, i.e., It has a short half-life, it has low bioavailability and it has a number of undesirable side effects.
  • a compound like aprepitant is a prime candidate for incorporation into a life cycle maximisation programme. This is because aprepitant is a very active substance P modulator compound. This means that aprepitant can be used in a raft of uses associated with substance P modulation. In addition, these uses lend themselves to incorporation into combination products where the aprepitant product provides biological basis for incorporation into combination products which treat or prevent illnesses where the biological activity of aprepitant as a substance p modulator lends itself to complementing or augmenting products which have known biological activity in a different medical area. An example would be combinations with oncology products, where a combination with aprepitant would stave off emesis associated with cancer treatment.
  • New chemical entities have a high risk of failing to obtain approval on efficacy and or safety grounds. Only 1 in 10,000 new chemical entities make it to the market. The cost of finding and developing new compounds is huge, at around lbb dollars each. Finally it takes 10 to 12 years to progress a compound from first discovery through to FDA approval. Since the patent covering the NCE, the commercial formulation, the dose and the medical use is filed immediately following discovery, the time remaining to recoup the massive investment in developing and launching the drug, is only 8 to 10 years. Because it also takes time from first launch to peak year sales, the full commercial potential of the compound is rarely if ever maximised. By the time the compound reaches block buster status, there are usually only 3 to 5 years of commercial life remaining for the innovator company to recoup costs and make a return.
  • Aprepitant is a prime candidate for inclusion as an LCM candidate because it has strong patent cover for several years to come giving time to develop, approve, launch and switch sales prior to patent expiry. There is a compelling technical, commercial and legal rationale for harnessing the full potential of major biologically active compounds with proven safety efficacy and biological potential. Aprepitant is particularly suitable for subjecting to the LCM process because it is capable of being developed for new uses, new combinations and product line extenders. This patent application describes these new uses, combinations and product line extenders and also describes lateral thinking of how robust patent coverage can be obtained using salts, dose or PK profile patenting to bolster the chances of patent cover against ab rated competition.
  • the dose of the active is usually 50 to 100 pc more than necessary to ensure that it works, this leads to side effects. Reducing the dose can give a better product.
  • the present invention provides a number of new uses which are selected from the following, pain, travel sickness, and general emesis.
  • the present invention provides a number of new combinations which are selected from combination from other oncology products and optionally admixed with pain medications and/or other emetic drugs.
  • the present invention also provides a number of patentable product line extenders which augment the action of the underlying active ingredient in aprepitant.
  • aprepitant can be improved by increasing its solubility, by salting or the use of co crystal technologies or Nano particles. Increasing solubility allows the drug to be administered in smaller doses delivering the same therapeutic effect.
  • the aprepitant product provides the basis for the development of a raft of new life cycle maximization products which are effectively like new chemical entities, but have the advantage of having been developed and tested in the mass patient populations albeit for a narrow range of uses and product presentations.
  • the short half-life can be improved using delayed release techniques such as controlled release, prolonged release capsules and other conventional techniques. All of which form an aspect of the present invention.
  • the invention provides multicomponent pharmaceutical compositions which are typically multicomponent solid dosage forms (e.g. multicomponent tablets or capsules) that give the benefit of one or more, typically two or three, of the technical effects selected from longevity, rapidity and dose to dose maintenance within the therapeutic window. Usually, they provide rapidity, longevity and dose to dose maintenance within the therapeutic window.
  • multicomponent solid dosage forms e.g. multicomponent tablets or capsules
  • therapeutic window is defined accordingly, i.e. as the range of drug plasma concentrations that provide efficacy without unacceptable side effects. Hence, blood plasma levels outside the therapeutic window are associated with either a lack of efficacy or unacceptable side-effects.
  • the pharmaceutical composition - which is typically a unit dosage form - is adapted to ensure maintenance of the aprepitant within the therapeutic window from dose to dose.
  • the invention therefore provides a pharmaceutical composition which achieves these effects.
  • the pharmaceutical composition of the invention comprises: a first fraction comprising aprepitant; and a controlled-release fraction comprising aprepitant.
  • the form of the aprepitant in the two fractions is often the same.
  • both fractions may comprise aprepitant free base, or both fractions may comprise a particular pharmaceutically acceptable salt of aprepitant, or both fractions may comprise a particular co-crystal of aprepitant or a particular prodrug of aprepitant, rather than, for example, one fraction comprising aprepitant free base and the other fraction a pharmaceutically acceptable salt, prodrug or co-crystal of aprepitant, or indeed one fraction comprising one pharmaceutically acceptable salt, prodrug or cocrystal of aprepitant and the other fraction comprising a different pharmaceutically acceptable salt, prodrug or cocrystal of aprepitant.
  • the form of the aprepitant in the two fractions is different.
  • the first fraction and controlled-release fraction may comprise two different forms of aprepitant, the forms of aprepitant being selected from aprepitant free base,
  • the aprepitant in the first fraction may be in an amorphous form and the aprepitant in the controlled-release fraction may be in a crystalline form, or vice versa, and/or the aprepitant in the first fraction may be in the form of a pharmaceutically acceptable salt, or in the form of a co-crystal or prodrug, whereas the aprepitant in the controlled-release fraction may be in the free form, or vice versa.
  • aprepitant which can be employed in the first fraction or the controlled-release fraction or both, are discussed herein.
  • Fig. 1 shows the dissolution profile in pH 6.8 buffer and 0.5% cetyl
  • CTAB trimethylammonium bromide
  • Fig. 2 shows the dissolution profile in pH 6.8 buffer and 0.5% CTAB of the sustained-release formulation batch 17CF16-01-B comprising aprepitant free base, as described in the Example. 100% release was achieved at 7 hours.
  • Fig. 3 shows the dissolution profile in pH 6.8 buffer and 0.5% CTAB over 0 to 120 minutes of the immediate-release formulation batch 17CF16-01-C comprising aprepitant free base, as described in the Example. 100% release was achieved at 1 hour.
  • Fig. 4 shows the dissolution profile in pH 6.8 buffer and 0.5% CTAB over 0 to 6 minutes of the immediate-release formulation batch 17CF16-01-C comprising aprepitant free base, as described in the Example. 20% release was achieved at about 3.5 minutes.
  • pharmaceutically acceptable salt thereof refers to salts which are physically, chemically and physiologically acceptable for either human or veterinary use.
  • a pharmaceutically acceptable salt is a salt with a pharmaceutically acceptable acid or base.
  • Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid.
  • Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines.
  • aprepitant includes not only aprepitant free base, but also pharmaceutically acceptable salts and prodrugs thereof, as well as solutions, amorphous forms, and crystalline forms of aprepitant, including solvates, hydrates, co-crystals and polymorphs.
  • the first fraction is, or comprises, a rapid release fraction.
  • the first fraction is usually adapted to provide rapid release of the aprepitant into the bloodstream to provide fast onset of action.
  • rapid release may be achieved by a formulation of the aprepitant comprising a rapidly dispersing wafer containing the aprepitant or a pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids.
  • the wafer is dispersed and/or dissolved over a period of about 1 to 120 seconds, about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 10 seconds.
  • the first fraction may comprise a disintegrating portion comprising said aprepitant.
  • This fraction typically comprises the aprepitant and a disintegrating carrier or excipient.
  • the disintegrating carrier or excipient is typically one which dissolves rapidly in the saliva, for instance within a period of from about 1 to about 120 seconds, typically within a period of from about 1 to about 60 seconds, for instance from about 1 to about 30 seconds, or from about 1 to about 10 seconds.
  • the first fraction may be a conventional formulation of aprepitant, i.e. neither adapted for rapid release nor delayed or prolonged release.
  • the first fraction may be adapted to provide normal release of aprepitant into the bloodstream, to provide conventional onset of action.
  • it is adapted for rapid release of the aprepitant.
  • the pharmaceutical composition of the invention may further comprise other fractions or components in addition to the first fraction and the controlled-release fraction.
  • the pharmaceutical composition of the invention may further comprise a further portion. This further portion is neither a rapid release fraction nor a controlled-release fraction but a conventional release component.
  • This further portion - the conventional release component - may be part of the first fraction, in addition to a rapid release fraction or a disintegrating portion that is also part of the first fraction.
  • this further portion - the conventional release component - may be a third fraction, which is different from the first fraction and the controlled release fraction.
  • Such a third fraction may for instance be disposed between the first fraction and the controlled release fraction, for example as an intermediate layer between an outer layer which comprises the first fraction and an inner core which comprises the controlled release fraction.
  • the conventional release component may be formulated as described anywhere herein by combining aprepitant with one or more of the conventional excipients described herein.
  • the pharmaceutical composition of the invention may further comprise a conventional release component comprising aprepitant and one or more conventional excipients.
  • the first fraction may therefore comprise (i) a rapid release fraction, which rapid release fraction is adapted to provide rapid release of aprepitant into the bloodstream to provide fast onset of action, and (ii) said conventional release component.
  • the first fraction comprises a disintegrating portion (which can also be referred to as a rapid release fraction), which comprises aprepitant and a carrier or excipient which disintegrates in saliva.
  • the pharmaceutical composition of the invention may further comprise a conventional release component comprising aprepitant and one or more conventional excipients.
  • the first fraction may therefore comprise (i) a disintegrating portion (which can also be referred to as a rapid release fraction), which comprises aprepitant and a carrier or excipient which disintegrates in saliva, and (ii) said conventional release component.
  • the controlled-release fraction is generally suitable for causing delayed or prolonged release of the aprepitant from the controlled-release fraction after administration of the composition to a subject.
  • Delayed release in the context of controlled release or modified release in the context of this specification, is understood to indicate a formulation that is designed to retard the initial release of drug from the dosage form by a pre -determined interval of time. Delayed release may for instance be understood to mean retardation of release, when compared to a currently approved product.
  • Prolonged release in the context of controlled release or modified release in the context of this specification, may be understood to indicate a formulation that is designed to maintain the release of drug over a period of time that is substantially greater than is achieved in the currently marketed formulation.
  • the controlled-release fraction in the pharmaceutical composition of the invention is adapted to provide longevity of action of the aprepitant from dose to dose by causing delayed or prolonged release of the aprepitant from the controlled-release fraction after administration of the composition to a subject.
  • the controlled-release fraction is suitable for causing prolonged release of the aprepitant from the controlled-release fraction after administration of the composition to a subject.
  • the controlled-release fraction may be adapted to provide longevity of action of the aprepitant from dose to dose by causing prolonged release of the aprepitant from the controlled-release fraction after administration of the composition to a subject.
  • the controlled-release fraction is typically adapted to release the aprepitant from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to a subject.
  • all of the aprepitant is released from the controlled-release fraction over the defined period.
  • x is at least 3, so that it takes at least 3 hours for all of the aprepitant to be released from the controlled-release fraction. It will be appreciated that aprepitant has a relatively long half life so will generally remain in the bloodstream for hours after all of the aprepitant has been released from the controlled-release fraction.
  • x may be at least 4, or, for instance, at least 6 so that it takes at least 6 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 4 to 16, so that it takes from 4 to 16 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 6 to 14, or from 8 to 12. Often, x is at least 6, so that it takes at least 6 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be at least 8, for example at least 10, at least 12, or at least 14. x may for instance be from 6 to 24, or from 6 to 16, or for instance from 6 to 14, or from 6 to 12.
  • x is at least 8, so that it takes at least 8 hours for all of the aprepitant to be released from the controlled-release fraction.
  • x may be at least 9, or, for instance, at least 10, so that it takes at least 9 hours, or at least 10 hours, for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 8 to 24, so that it takes from 8 to 24 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 8 to 15, or from 8 to 12.
  • x may for example be at least 12, so that it takes at least 12 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be at least 15, for example at least 17, at least 18, or at least 20. x may for instance be from 12 to 24, or from 15 to 24, or for instance from 17 to 24, or from 20 to 24.
  • the controlled-release fraction is usually adapted to ensure maintenance of the aprepitant within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.
  • the controlled-release fraction is often adapted to ensure maintenance of the aprepitant within the therapeutic window for a certain percentage - y % - of the time during the dosing interval.
  • the dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject.
  • z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24.
  • other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values.
  • z may for instance be 6, 8 or 12, or even 48.
  • z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24.
  • y is at least 50, such that the aprepitant is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75. Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the aprepitant is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose.
  • z is 24 and y is at least 50. More preferably, z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.
  • the controlled-release fraction is usually adapted to maintain the aprepitant at or above a drug plasma level, 1, in a subject for a certain percentage (q %) of the time during the dosing interval.
  • the dosing interval may in this case be defined as t hours beginning with administration of the composition to the subject.
  • drug plasma level of the aprepitant refers to the plasma concentration of the active form of the aprepitant. This is often aprepitant as administered to the subject, but it may be an active metabolite thereof.
  • the drug plasma level, 1, of the aprepitant, at or above which the controlled-release fraction is adapted to maintain the aprepitant for q % of the time during the dosing interval may be any drug plasma level within the therapeutic window. Alternatively, it may be the plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo. This is known as the IC50, and as the skilled person will appreciate, an IC50 value is specific to a particular drug and to the therapeutic effect that is desired and therefore the condition being treated by the drug.
  • the drug plasma level, 1, of aprepitant, at or above which the controlled-release fraction is adapted to maintain the aprepitant for q % of the time during the dosing interval is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.
  • IC50 plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo that is obtainable by aprepitant.
  • the drug plasma level, 1, may for instance be the plasma concentration (IC50) required for obtaining 50% of a maximum anti -emetic effect in vivo. This is generally the plasma concentration required for obtaining 50% of a maximum anti -emetic effect in vivo that is obtainable by aprepitant.
  • IC50 plasma concentration
  • the pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing.
  • t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24.
  • other dosing frequencies may of course be employed, depending on the patient and condition being treated, and t may therefore have other values.
  • t may for instance be 6, 8 or 12, or even 48.
  • t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24.
  • q is at least 40, such that the aprepitant is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the aprepitant is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose.
  • t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100.
  • the pharmaceutical composition of the invention is a dosage form, for instance a unit dosage form.
  • the dosage form is typically a solid dosage form. It is typically an oral dosage form, for instance a tablet or capsule. It is often a tablet.
  • the dosage form which is typically an oral dosage form, for instance a tablet, often comprises an outer layer which comprises the first fraction, which outer layer is disposed on all or part of the surface of the controlled-release fraction.
  • the dosage form which is typically an oral dosage form, for instance a tablet, often comprises an outer layer which comprises the first fraction, and an inner region.
  • the inner region comprises the controlled-release fraction.
  • the outer layer is typically disposed on all or part of the surface of the inner region.
  • the inner region is often completely within the outer layer.
  • the oral dosage form may have a core-shell structure wherein the controlled-release fraction defines a core and the first fraction is disposed on the surface of the core to form a shell which surrounds the core.
  • the first fraction i.e. the outer layer, or shell, in the above-mentioned embodiments, is typically capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds. It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 90 seconds, particularly from about 1 second to about 60 seconds, for instance from about 1 second to about 45 seconds or, for example, from about 1 second to about 30 seconds, and preferably from about 1 second to about 10 seconds.
  • It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds, for instance within a period of from about 15 seconds to about 120 seconds, particularly from about 30 seconds to about 90 seconds, or from about 30 seconds to about 60 seconds.
  • the first fraction i.e. the outer layer, or shell, in the above-mentioned embodiments, is typically therefore suitable for sublingual administration.
  • the first fraction is typically suitable for disintegrating in saliva within a period as defined above, and the first fraction typically, in this embodiment, comprises the aprepitant and a disintegrant.
  • the first fraction (the outer layer, or shell, in the above-mentioned
  • composition of the invention which is typically an oral dosage form
  • the composition of the invention is administered sublingually, i.e. placed under the tongue, or between the cheek and gum. It may for instance be capable of dispersing or dissolving within a period of from about 1 second to about 90 seconds, particularly from about 1 second to about 60 seconds, for instance from about 1 second to about 45 seconds or, for example, from about 1 second to about 30 seconds, and preferably from about 1 second to about 10 seconds, after the composition of the invention is administered sublingually, i.e. placed under the tongue, or between the cheek and gum.
  • It may for instance be capable of dispersing or dissolving in buccal fluid within a period of from about 1 second to about 120 seconds, for instance within a period of from about 15 seconds to about 120 seconds, particularly from about 30 seconds to about 90 seconds, or from about 30 seconds to about 60 seconds, after the composition of the invention is administered sublingually, i.e. placed under the tongue, or between the cheek and gum.
  • the first fraction (the outer layer, or shell, in the above-mentioned embodiments) may be one which is suitable for enteral administration.
  • the compostion is simply swallowed rather than being placed under the tongue, and the first fraction releases the aprepitant in the gastrointestinal tract.
  • the first fraction (the outer layer, or shell, in the above-mentioned embodiments) may be capable of releasing all of the aprepitant from the first fraction in vivo within a period of 60 minutes from the time of administration of the composition to a subject, for instance within 30 minutes from the time of administration, or for example within 10 minutes from the time of administration. It may for instance be capable of releasing all of the aprepitant from the first fraction in vivo within 5 minutes from the time of administration, or, for instance, within 2 minutes from the time of administration, for instance within a period of from about 15 seconds to about 120 seconds, particularly from about 30 seconds to about 90 seconds, or from about 30 seconds to about 60 seconds after administration.
  • the first fraction may be capable of releasing at least 50% of the aprepitant from the first fraction in vivo within 10 minutes of the time of administration of the composition to a subject, and it is often capable of releasing at least 50% of the aprepitant from the first fraction in vivo within 5 minutes from the time of administration, for instance within 2 minutes from the time of administration, or, for example, within 30 seconds from the time of administration.
  • the dosage form may advantageously further comprise a coating for delaying exposure of the aprepitant in the controlled-release fraction to the buccal, gastric, or intestinal fluids.
  • a coating which may be an enteric coating
  • the coating for delaying exposure of the aprepitant is typically disposed on the surface of the inner region, which comprises the controlled-release fraction. It may then delay release of the aprepitant from the controlled-release fraction but not adversely affect rapid release of the aprepitant from the first component.
  • the coating may advantageously therefore be disposed between the first fraction and the controlled-release fraction, in a core shell structure wherein the controlled-release fraction defines a core and the first component is a shell disposed around that core.
  • the coating which may be an enteric coating, may advantageously be disposed between the core and the shell.
  • the ratio of the mass of the aprepitant in the controlled-release fraction to the mass of the aprepitant in the first fraction is typically from 80:20 to 20:80.
  • the first fraction comprises from 20% to 80% by mass of the total amount of the aprepitant in the first fraction and the controlled-release fraction
  • the controlled-release fraction comprises from 80% to 20% by mass of the total amount of the aprepitant in the first fraction and the controlled-release fraction.
  • the mass here refers to the mass of aprepitant in the free base form, irrespective of whether the aprepitant is present in the composition in salt form, co-crystal form, or indeed as the free base. This is to allow for the possibility that the aprepitant may be present in different forms in the first fraction and the controlled-release fraction, for instance it may be present in the free base form in one fraction and in a salt form in the other fraction. Thus, masses herein are quoted on a "free base" basis.
  • aprepitant is in the free base form (as opposed to a salt form or in the form of a co-crystal or prodrug)
  • reference to "80mg" of aprepitant, as used herein, means 80mg of aprepitant in the free base form.
  • the aprepitant is in the form of a salt, cocrystal or prodrug
  • reference to "80mg" of aprepitant does not mean 80mg of that salt, cocrystal or prodrug; rather, it refers to the particular amount of that salt, cocrystal or prodrug that would provide 80mg of aprepitant in the free base form. In other words, it refers to the mass of the salt, co-crystal or prodrug of aprepitant which is the molar equivalent of 80mg of aprepitant free base.
  • the ratio of the number of moles of aprepitant in the controlled-release fraction to the number of moles of aprepitant in the first fraction is typically from 80:20 to 20:80.
  • the first fraction comprises from 20 mol. % to 80 mol. % of the total amount of aprepitant in the first fraction and the controlled-release fraction
  • the controlled-release fraction comprises from 80 mol. % to 20 mol. % of the total amount of aprepitant in the first fraction and the controlled-release fraction.
  • the total amount of the aprepitant in the first fraction and the controlled-release fraction typically corresponds to the total amount of aprepitant in the pharmaceutical composition itself.
  • the first fraction and the controlled-release fraction are typically the only fractions in the composition that comprise aprepitant.
  • the terms "total amount of aprepitant in the first fraction and the controlled-release fraction” and “total mass of aprepitant in the first fraction and the controlled-release fraction”, as used herein, are interchangeable with the terms “total amount of aprepitant in the pharmaceutical composition” and “total mass of aprepitant in the pharmaceutical composition” respectively.
  • the ratio of the mass of the aprepitant in the controlled-release fraction to the mass of the aprepitant in the first fraction is from 70:30 to 30:70.
  • the ratio of the number of moles of aprepitant in the controlled-release fraction to the number of moles of the aprepitant in the first fraction is from 70:30 to 30:70.
  • the ratio of the mass of the aprepitant in the controlled-release fraction to the mass of the aprepitant in the first fraction may for instance be from 60:40 to 40:60, or for example from 55:45 to 45:55.
  • the ratio of the number of moles of the aprepitant in the controlled-release fraction to the number of moles of the aprepitant in the first fraction may be from 60:40 to 40:60, or for example from 55:45 to 45:55.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction is typically from 10 mg to 200 mg.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction may for instance be from 20 mg to 160 mg, for instance from 50 mg to 150 mg. As discussed above, these values also generally correspond to the total amount of aprepitant in the pharmaceutical composition itself.
  • Examples of the total masses of aprepitant that are commonly employed in the composition of the invention include 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 125 mg, 140 mg, 150 mg and 160 mg.
  • these total masses of aprepitant are distributed between the first fraction and the controlled-release fraction in accordance with the ratios defined above.
  • composition comprising 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 125 mg, 140 mg, 150 mg or 160 mg of aprepitant in total, the ratio of the mass of aprepitant in the controlled- release fraction to the mass of aprepitant in the first fraction is typically from 80:20 to 20:80. It is often from 70:30 to 30:70, and may for instance be from 60:40 to 40:60. It may for example be from 55:45 to 45:55, for instance about 50:50.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction is typically from 10 mg to 200 mg, for instance from 20 mg to 160 mg, or from 20 mg to 150 mg. This typically also corresponds to the total mass of the aprepitant in the pharmaceutical composition itself.
  • the ratio of the mass of aprepitant in the controlled-release fraction to the mass of aprepitant in the first fraction is from 80:20 to 20:80. It is often from 70:30 to 30:70, and may for instance be about 60:40 to 40:60, for example from 55:45 to 45:55, or about 50:50.
  • aprepitant is employed in the first fraction and the remainder of the total mass of the aprepitant is employed in the controlled-release fraction.
  • aprepitant may be employed in the first fraction and the remainder of the total mass of the aprepitant is employed in the controlled-release fraction.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction is 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 125 mg, 140 mg, 150 mg or 160 mg. This typically also corresponds to the total mass of the aprepitant in the pharmaceutical composition itself.
  • the ratio of the mass of aprepitant in the controlled-release fraction to the mass of aprepitant in the first fraction is from 80:20 to 20:80. It is often from 70:30 to 30:70, and may for instance be about 60:40 to 40:60, for example from 55:45 to 45:55, or about 50:50.
  • from 35 mg to 55 mg, from 30 mg to 50 mg, or for instance about 40 mg, of the aprepitant may be employed in the first fraction and the remainder of the total mass of the aprepitant is employed in the controlled-release fraction.
  • the controlled-release fraction typically comprises said aprepitant (typically in a particular defined dose amount as discussed above) and a matrix suitable for promoting prolonged release of the aprepitant.
  • the controlled-release fraction often further comprises a filler. It may also comprise a glidant, a lubricant, or both.
  • the matrix may be a hydrophilic matrix or an erodible matrix. Suitable hydrophilic and erodible matrix materials which may be employed are discussed further herein.
  • the matrix may for instance be a hydrophilic matrix, which may for instance comprise a hydrophilic polymer, for instance a water-soluble polymer. Suitable polymers include cellulose ether and xanthan gum. Accordingly, the hydrophilic matrix may for example comprise a polymer which is a cellulose ether or xanthan gum.
  • the controlled-release fraction typically comprises a hydrophilic polymer which is a cellulose ether.
  • a hydrophilic polymer which is a cellulose ether.
  • Cellulose ethers are available from Dow under the trade name Methocel and are suitable for use for controlled release of drugs in hydrophilic matrix systems.
  • the cellulose ether may be selected from carboxymethylcellulose (CMC), methylcellulose (MC) and derivatives thereof, hydroxyethylcellulose (HEC) and derivatives thereof, hydroxylpropyl cellulose (HPC), hydroxypropylmethylcellulose, and ethylcellulose (EC). Often, however, the cellulose ether is hydroxypropylmethylcellulose or ethylcellulose.
  • Hydroxypropylmethylcellulose in particular, is usually employed.
  • the controlled-release fraction may comprise the aprepitant in an amount of from 5 wt. % to 20 wt. % based on the total weight of the controlled-release fraction, or for instance in an amount of from 8 wt. % to 17 wt. %, for example from 11 wt. % to 15 wt. %.
  • the controlled-release fraction may additionally comprise the matrix suitable for promoting prolonged release of the aprepitant (which is typically a hydrophilic matrix, for instance a hydrophilic polymer as defined above, and may suitably be a cellulose ether, such as, for example, hydroxypropylmethylcellulose or ethylcellulose) in an amount of from 15 wt.
  • the matrix suitable for promoting prolonged release of the aprepitant which is typically a hydrophilic matrix, for instance a hydrophilic polymer as defined above, and may suitably be a cellulose ether, such as, for example, hydroxypropylmethylcellulose or ethylcellulose
  • the controlled- release fraction may for instance comprise the matrix in an amount of from 15 wt. % to 35 wt. %.
  • the controlled-release fraction may for example comprise the matrix in an amount of from 25 wt. % to 35 wt. %, for instance from 28 wt. % to 32 wt. %, based on the total weight of the controlled-release fraction.
  • the controlled-release fraction may comprise the matrix in an amount of from 15 wt. % to 25 wt. %, for instance from 18 wt. % to 22 wt. %, based on the total weight of the controlled-release fraction.
  • the hydrophilic polymer is said cellulose ether
  • the controlled-release fraction comprises the aprepitant in an amount of from 5 wt. % to 20 wt. % and comprises the cellulose ether in an amount of from 15 wt. % to 35 wt. %, and preferably in an amount of from 25 wt. % to 35 wt. %, based on the total weight of the controlled-release fraction.
  • the controlled-release fraction may additionally comprise a glidant.
  • the controlled- release fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a glidant, for instance from 0.1 wt. % to 0.9 wt. % of a glidant, or for example from 0.3 wt. % to 0.7 wt. % of the glidant, based on the total weight of the controlled-release fraction.
  • suitable glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc. Often, however, silicon dioxide (silica) is employed as a glidant in the controlled-release fraction. This is typically hydrophilic silica. It is often for instance hydrophilic fumed silica, which is commercially available under the trade name Aerosil 200.
  • the controlled-release fraction may additionally comprise a lubricant.
  • the controlled- release fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the controlled-release fraction.
  • Suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the controlled-release fraction.
  • the balance of the controlled-release fraction typically comprises, and often consists of, one or more fillers.
  • suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • the fillers employed in the controlled-release fraction are selected from lactol,
  • the balance of the controlled-release fraction typically comprises, and often consists of, a filler which comprises lactose.
  • the filler is often for instance anhydrous lactose, which is commercially available from DFE Pharma under the trade name SuperTab® 24AN.
  • the balance of the controlled-release fraction may comprise, for instance consist of, a filler which comprises cellulose.
  • the filler is often for instance microcrystalline cellulose, which is commercially available as Microcrystalline Cellulose PH102 under the trade name Avicel® from FMC Corporation.
  • the controlled-release fraction may for instance comprise, or consist of, the following:
  • the aprepitant in an amount of from 5 wt. % to 20 wt. % based on the total weight of the controlled-release fraction;
  • hydrophilic polymer in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction
  • a lubricant in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction
  • a glidant in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction
  • the filler typically makes up the balance of the controlled-release fraction.
  • the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler usually comprises microcrystalline cellulose or anhydrous lactose, typically anhydrous lactose.
  • the aprepitant may be as further defined anywhere herein, i.e. it may be in free base, salt, cocrystal or prodrug form. Often, however, it is aprepitant free base.
  • the controlled-release fraction may for instance comprise, or consist of, the following:
  • a lubricant optionally up to 2 wt. % of a lubricant
  • glidant optionally up to 2 wt. % of a glidant
  • the filler typically makes up the balance of the controlled-release fraction.
  • the percentages by weight here are the percentages by weight of the components in the controlled-release fraction, based on the total weight of the controlled-release fraction.
  • the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually microcrystalline cellulose or anhydrous lactose.
  • the filler may comprise, of for instance consist of, lactose, usually anhydrous lactose.
  • the aprepitant may be as further defined anywhere herein, i.e. it may be in free base, salt, cocrystal or prodrug form. Often, however, it is aprepitant free base.
  • the controlled-release fraction may for instance comprise, or consist of, the following:
  • a lubricant optionally up to 2 wt. % of a lubricant
  • glidant optionally up to 2 wt. % of a glidant
  • the filler typically makes up the balance of the controlled-release fraction.
  • the percentages by weight here are the percentages by weight of the components in the controlled-release fraction, based on the total weight of the controlled-release fraction.
  • the hydrophilic polymer is typically a cellulose ether, for instance hydroxypropylmethylcellulose or ethylcellulose; the lubricant, when present, is typically a stearate, for instance magnesium stearate; the glidant, when present, is typically hydrophilic silica; and the filler is usually microcrystalline cellulose or anhydrous lactose.
  • the aprepitant may be as further defined anywhere herein, i.e. it may be in free base, salt, cocrystal or prodrug form. Often, however, it is aprepitant free base.
  • the first fraction may be adapted to provide rapid release of aprepitant into the bloodstream to provide fast onset of action.
  • the first component may comprise a rapid release fraction.
  • the first fraction typically comprises said aprepitant (typically in a particular defined dose amount as discussed above) and a disintegrating agent, also known as a disintegrant.
  • the disintegrant renders the whole of the first fraction, or part of the first fraction, rapidly disintegrable so that the first fraction, or at least part of the first fraction, disperses rapidly on contact with aqueous fluids.
  • the first fraction, or at least part of the first fraction is typically capable of dispersing or dissolving in an aqueous fluid, in particular in buccal fluid, such as saliva, within a period of from about 1 second to about 120 seconds. Often, the period is from about 1 second to about 90 seconds, for instance from about 1 second to about 60 seconds, or for example from about 1 second to about 30 seconds.
  • the first fraction often further comprises one or more fillers. It may also comprise a glidant, a lubricant, or both. It may also comprise one or more agents selected from taste masking agents and flavouring agents.
  • Any suitable disintegrant may be employed.
  • a wide range of disintegrants are known to the skilled person. Examples of these include, but are not limited to, sodium starch glycolate, polyvinylpyrrolidone (PVPP, crospovidone), alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate.
  • PVPP polyvinylpyrrolidone
  • PVP polyvinylpyrrolidone
  • PVP polyvinylpyrrolidone
  • the disintegrant may be a swelling agent.
  • a modified starch for instance sodium starch glycolate, is employed as the disintegrant.
  • the disintegrant is sodium starch glycolate
  • the first fraction comprises the aprepitant in an amount of from 3 wt. % to 15 wt. % and comprises the sodium starch glycolate in an amount of from 1 wt. % to 10 wt. %, based on the total weight of the first fraction.
  • the disintegrant may be sodium starch glycolate
  • the first fraction may comprises the aprepitant in an amount of from 5 wt. % to 11 wt. % and comprises the sodium starch glycolate in an amount of from 2 wt. % to 6 wt. %, based on the total weight of the first fraction.
  • the first fraction may further comprise one or more agents selected from taste masking agents and flavouring agents.
  • the one or more agents may for instance comprise: a flavouring agent and one or more sweeteners.
  • a peppermint flavouring agent may for instance be employed as the flavouring agent.
  • An example of a suitable peppermint flavouring agent is Peppermint Flavour 501500 TP0504.
  • Suitable sweeteners include natural sweeteners, for instance natural sugars and stevia (e.g. TASTEVA®), or artificial sweeteners. Any artificial sweetener may be employed, for instance a synthetic sugar substitute, such as, for example, sucralose.
  • the one or more agents may for example comprise: a flavouring agent, a natural sweetener and an artificial sweetener.
  • the one or more agents may for instance comprise stevia (e.g. TASTEVA®), sucralose and a peppermint flavouring agent (e.g.
  • Peppermint Flavour 501500 TP0504 Peppermint Flavour 501500 TP0504.
  • the total amount of the one or more agents selected from taste masking agents and flavouring agents in the first fraction is typically up to 7 wt %, for instance up to 5 wt. %, based on the total weight of the first fraction. It may for instance be from 0.1 wt. % to 5 wt. %, based on the total weight of the first fraction, for instance from 0.5 wt. % to 5 wt. %, or from 1.5 wt. % to 3 wt. %.
  • the first fraction may additionally comprise a lubricant.
  • the first fraction typically comprises up to 2 wt. %, for instance up to 1 wt. %, of a lubricant, for instance from 0.1 wt. % to 0.9 wt. % of a lubricant, or for example from 0.3 wt. % to 0.7 wt. % of the lubricant, based on the total weight of the first fraction.
  • Suitable lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate. Often, however, a stearate, usually a metal stearate, and typically magnesium stearate, is employed as a lubricant in the first fraction.
  • the balance of the first fraction typically comprises, and often consists of, one or more fillers.
  • suitable fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium,
  • carboxymethylcellulose sodium compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil-type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, a sugar alcohol, a disaccharide sugar alcohol, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • the filler employed in the first component comprises a sugar alcohol.
  • the sugar alcohol filler may be a disaccharide sugar alcohol, for instance isomalt.
  • the balance of the first fraction typically comprises, and often consists of, a filler which comprises isomalt.
  • a suitable isomalt filler which is commercially available is Isomalt 721.
  • the first fraction may for instance comprise, or consist of, the following:
  • the aprepitant in an amount of from 3 wt. % to 15 wt. % based on the total weight of the first fraction;
  • a disintegrant which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 1 wt. % to 10 wt. % based on the total weight of the first fraction;
  • one or more agents selected from taste masking agents and flavouring agents which may be as further defined above (e.g. a flavouring agent, a natural sweetener and an artificial sweetener), wherein the total amount of the one or more agents in the first fraction is from 0.1 wt. % to 5 wt. %, based on the total weight of the first fraction;
  • a lubricant which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the first fraction; and a filler, which may be as further defined above, optionally wherein the filler makes up the balance of the first fraction.
  • the first fraction may for instance comprise, or consist of, the following:
  • the aprepitant in an amount of from 5 wt. % to 11 wt. % based on the total weight of the first fraction;
  • a disintegrant which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 2 wt. % to 6 wt. % based on the total weight of the first fraction;
  • one or more agents selected from taste masking agents and flavouring agents which may be as further defined above (e.g. a peppermint flavouring agent, stevia and sucralose), wherein the total amount of the one or more agents in the first component is from 1.5 wt. % to 3 wt. %, based on the total weight of the first fraction;
  • a lubricant which may be as further defined above (e.g. magnesium stearate), in an amount of up to 2 wt. % based on the total weight of the first fraction; and a filler, which may be a disaccharide sugar alcohol, optionally isomalt, optionally wherein the filler makes up the balance of the first fraction.
  • the percentages by weight here are the percentages by weight of the components in the first fraction, based on the total weight of the first fraction.
  • the disintegrant is typically a modified starch, for instance sodium starch glycolate;
  • the lubricant when present, is typically a stearate, for instance a metal stearate such as magnesium stearate;
  • the one or more agents selected from taste masking agents and flavouring agents typically comprise a peppermint flavouring agent, stevia and sucralose;
  • the filler usually comprises a disaccharide sugar alcohol, typically isomalt.
  • the filler may comprise, or for instance consist of, the disaccharide sugar alcohol, typically isomalt.
  • the aprepitant may be as further defined anywhere herein, i.e. it may be in free base, salt, cocrystal or prodrug form. Often, however, it is aprepitant free base.
  • controlled-release fraction is as defined above under the heading "controlled release fraction embodiments" and the first fraction is as defined above under the heading “first fraction embodiments”.
  • the controlled-release fraction comprises:
  • the aprepitant in an amount of from 5 wt. % to 20 wt. % based on the total weight of the controlled-release fraction;
  • a hydrophilic polymer which may be a cellulose ether or xanthan gum, but is typically a cellulose ether, in an amount of from 15 wt. % to 35 wt. % based on the total weight of the controlled-release fraction; optionally, a lubricant which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; optionally, a glidant, which may for instance be hydrophilic silica, in an amount of up to 2 wt. % based on the total weight of the controlled-release fraction; and
  • a filler which may be as further defined above for the controlled-release fraction, optionally wherein said filler makes up the balance of the controlled-release fraction; and - the first fraction comprises:
  • the aprepitant in an amount of from 3 wt. % to 15 wt. % based on the total weight of the first fraction;
  • a disintegrant which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 1 wt. % to 10 wt. % based on the total weight of the first fraction; one or more agents selected from taste masking agents and flavouring agents, which may be as further defined above (e.g. a flavouring agent, a natural sweetener and an artificial sweetener), wherein the total amount of the one or more agents in the first fraction is from 0.1 wt. % to 5 wt. %, based on the total weight of the first fraction;
  • a disintegrant which may be as further defined above (e.g. sodium starch glycolate), in an amount of from 1 wt. % to 10 wt. % based on the total weight of the first fraction
  • agents selected from taste masking agents and flavouring agents which may be as further defined above (e.g. a flavouring agent, a natural sweetener and an artificial sweetener), wherein the total amount of the one or more
  • a lubricant which may be as further defined above (e.g. a metal stearate), in an amount of up to 2 wt. % based on the total weight of the first fraction; and
  • a filler which may be as further defined above for the first fraction, optionally wherein the filler makes up the balance of the first fraction.
  • the hydrophilic polymer is a cellulose ether and is present in an amount of from 25 wt. % to 35 wt. % based on the total weight of the controlled-release fraction, preferably in an amount of from 28 wt. % to 32 wt. %.
  • the hydrophilic polymer is a cellulose ether and is present in an amount of from 15 wt. % to 25 wt. % based on the total weight of the controlled-release fraction, preferably in an amount of from 18 wt. % to 22 wt. %.
  • the disintegrant comprises sodium starch glycolate
  • the filler in the first fraction comprises isomalt
  • the one or more agents selected from taste masking agents and flavouring agents comprise a peppermint flavouring agent, stevia and sucralose
  • the lubricant in the first and controlled-release fractions comprises magnesium stearate
  • the hydrophilic polymer comprises a cellulose ether
  • the glidant comprises hydrophilic silica
  • the filler in the controlled-release fraction comprises anhydrous lactose.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction may for instance be from 20 mg to 160 mg, but is more typically from 40 mg to 150 mg, or from 80 mg to 125 mg.
  • the total mass of the aprepitant in the first fraction and the controlled-release fraction may for instance be from 20 mg to 160 mg, and: (i) the ratio of the mass of the aprepitant in the controlled-release fraction to the mass of the aprepitant in the first fraction is from 80:20 to 30:70, preferably from 60:40 to 40:60; or (ii) the mass of the aprepitant in the first fraction is from 20 mg to 60 mg.
  • rapid release may be achieved by a dosage form of aprepitant comprising a rapidly dispersing wafer containing the aprepitant or a pharmaceutically acceptable salt thereof which is placed on the tongue and dissolves in the mouth, for example within the buccal fluids.
  • the wafer is dispersed and/or dissolved over a period of about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 10 seconds.
  • the wafer is made from a freeze-dried compact containing the aprepitant or a pharmaceutically acceptable salt thereof, in a matrix of a buccal fluid-dispersible polymer such as gelatine and a polysaccharide such as mannitol.
  • the aprepitant is dissolved or dispersed into a suspension of mannitol and gelatine prior to filling into blister cavities.
  • rapid release of the aprepitant may be provided by the blending and compression of the aprepitant with water soluble excipients, such as a sugar such as but not limited to mannitol, and an effervescence agent, at low compression forces.
  • water soluble excipients such as a sugar such as but not limited to mannitol
  • effervescence agent an effervescence agent
  • the low compression forces lead to the formation of a highly porous tablet which disintegrates rapidly. Rapid disintegration is further aided by the inclusion of the effervescence agent, which in the context of this specification is defined as one or more agents which produce carbon dioxide upon contact with buccal, gastric, or intestinal fluids.
  • effervescence is derived by the reaction which takes place between alkali metal carbonates or bicarbonates and organic acids such as citric acid or tartaric acid to release carbon dioxide.
  • effervescent agents are effervescent couples such as an organic acid and a metal carbonate or bicarbonate.
  • Suitable organic acids include but are not limited: citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and alginic acid, and anhydrides and acid salts.
  • Suitable carbonates and bicarbonates include, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate.
  • only the base component of the effervescent couple may be present.
  • Effervescence may also result from the inclusion of a carbonate or bicarbonate alone to react with acidic gastrointestinal fluids.
  • the porous tablet disperses over a period of about 1 to 60 seconds, preferably about 1 to 45 seconds, most preferably about 1 to 30 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000), M J Rathbone, J Hadgraft & M S Roberts in Modified Release Drug Delivery Systems, Marcel Dekker, New York, 2003, US Patent No. 5, 178,878 and US Patent No 5,607,697 which are incorporated herein by reference.
  • rapid release of the aprepitant may be achieved by blending and compressing the aprepitant with a suitable sugar such as but not limited to sucrose which has been melt-spun to form a mass of thin filaments with a high surface area.
  • a suitable sugar such as but not limited to sucrose which has been melt-spun to form a mass of thin filaments with a high surface area.
  • the resulting tablets are highly porous. Upon contact with buccal fluids, they disintegrate rapidly as the mass of thin filaments dissolves. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent No 4,855,326 which are incorporated herein by reference.
  • rapid release of the aprepitant may be achieved by blending and compressing the aprepitant with a low mould ability saccharide (e.g. such as but not limited to lactose and mannitol) which has been granulated using a high mould ability saccharide (e.g. such as but not limited to maltose and maltitol) as a binder.
  • a low mould ability saccharide e.g. such as but not limited to lactose and mannitol
  • a high mould ability saccharide e.g. such as but not limited to maltose and maltitol
  • the resulting tablets possess characteristics which enable them to dissolve rapidly on contact with aqueous fluids, typically within about 1 to 60 seconds, preferably about 1 to 30 seconds, most preferably about 1 to 15 seconds. Details of this technology are described in the scientific and patent literature, for example W Habib et al in Critical Reviews in Therapeutic Drug Carrier Systems, Vol 17 (1) 61-72 (2000) and US Patent
  • rapid release of the aprepitant may be achieved by blending and compressing the aprepitant with a disintegrating agent (e.g. such as but not limited to carboxymethylcellulose) and a swelling agent (e.g. such as but not limited to modified starch, e.g. Sodium Starch Glycolate) to produce a rapidly disintegrable tablet which preferably on contact with aqueous fluids disperses over a period of about 1 to 90 seconds, preferably about 1 to 60 seconds, most preferably about 1 to 30 seconds.
  • a disintegrating agent e.g. such as but not limited to carboxymethylcellulose
  • a swelling agent e.g. such as but not limited to modified starch, e.g. Sodium Starch Glycolate
  • One way of augmenting the rapid release achievable by a suitable choice of formulation is to utilise a salt of the aprepitant which is very soluble in saliva or in gastric fluid.
  • amorphous form of a salt of the aprepitant or the aprepitant in the free base form may be dispersed or adsorbed in a thin layer over a high surface area inert substrate.
  • Suitable substrates include but are not limited to: Amberlite ®
  • Activated carbon Activated carbon Darco ®, Activated carbon Darco ® G-60, Activated carbon Darco ® KB, Activated carbon Darco ® KB-B, Activated carbon Norit ®, silica gel high purity grades with high pore volume, for example about 0.75 cc/g and average pore diameter 6 ⁇ .
  • Controlled release may be provided in the form of prolonged release.
  • a prolonged release dosage form may consist of a matrix dosage unit, such as a hydrophilic and/or an erodible matrix, usually in tablet form. Release from such a unit can be controlled by a number of mechanisms, such as dissolution, erosion, diffusion, osmotic pressure or any combination thereof.
  • Embodiment of prolonged release dosage forms may utilise excipients which control release of the aprepitant by more than one formal mechanism.
  • An erosion controlled prolonged release dosage unit can be achieved by compressing the aprepitant with a slowly dissolvable and/or erodable polymeric material into a tablet form. Release of the aprepitant occurs as the polymer dissolves and/or erodes away.
  • Suitable polymers include but are not restricted to glyceryl monostearate, acrylic resins, ethylcellulose, stearyl alcohol, hydroxypropylcellulose, carboxymethylcellulose, hypromellose,
  • a diffusion controlled prolonged release dosage form may be produced by compressing a water-swellable hydrophilic polymer in combination with the aprepitant drug substance.
  • Such systems are often referred to as "hydrophilic matrices" or “swellable-soluble” systems. Water continues to penetrate the matrix causing the swelling of the hydrophilic polymer. The gelatinous layer that is formed, retards the rate of ingress of water into the matrix and the flux of drug out of the matrix. The aprepitant is released from such matrices either by diffusion through the gel layer or by erosion and/or dissolution of the gel layer.
  • Suitable materials would include any pharmaceutically acceptable excipient which can swell and form a gelatinous mass upon hydration, for example, hydroxypropylmethylcellulose, and xanthan gum. Further information and descriptions of such dosage forms can be found in
  • An osmosis controlled prolonged release dosage form may be produced by compressing the aprepitant in combination with an osmagent into a tablet matrix core formulation.
  • This matrix core is then in part coated with a semi-permeable membrane in known manner, utilising such polymers such as methacrylates, ethylcellulose, and cellulose acetate.
  • Aqueous fluids are drawn by osmosis from the exterior environment across the membrane at a controlled rate into the core, causing dissolution of both the aprepitant and the osmogent and increased pressure within the matrix core. The pressure forces the solubilised aprepitant out through a specially created aperture or passageway.
  • osmagents include but are not restricted to sodium chloride, potassium chloride, lithium chloride, magnesium chloride, magnesium sulphate, lithium sulphate, sodium sulphate, potassium sulphate, citric acid, mannitol, ribose, arabinose, galactose, leucine, glycine, fructose, sucrose, sodium and other bicarbonates.
  • Prolonged release can also be achieved by applying a porous or semipermeable membrane coat onto a tablet surface by the application of such polymers such as methacrylates, ethylcellulose, and cellulose acetate. Release from such systems can occur by more than one of the mechanisms described above, for example a combination of dissolution, diffusion, erosion, and osmosis.
  • prolonged release can be achieved by coating multiparticulates with semipermeable membranes.
  • the multiparticulates include drug -coated substrates, such as lactose beads, and drug-containing substrates, such as drug-containing lactose spheres.
  • Delayed release of the aprepitant can be achieved by means of a physical barrier or coating which delays exposure of the active material to the buccal, gastric, or intestinal fluids.
  • One technique which provides delayed release involves the application of a coating of a fluid resistant barrier to a single dosage unit, or to a multiparticulate dosage unit, for example one composed of beadlets, pellets, spheroids, minitablets and/or granules.
  • These coatings can be designed to dissolve at a specific pH range, for example an enteric coating which dissolves at a pH greater than 5.0.
  • Typical pH-dependent polymers suitable for coating dosage forms include the following:
  • hydroxypropylmethylcellulose phthalate 50 which dissolves at about pH 4.8
  • hydroxypropylmethylcellulose phthalate 55 which dissolves at about pH 5.2
  • polyvinylacetate phthalate which dissolves at about pH 5.0
  • methacrylic acid-methyl methacrylate copolymer (1 : 1) which dissolves at about pH 6.0 methacrylic acid-methyl methacrylate copolymer (2: 1), which dissolves at pH 6.5-7.5 methacrylic acid-ethyl acrylate copolymer (2: 1), which dissolves at about pH 5.5
  • hydroxypropylmethylcellulose acetate succinate which dissolves at about pH 7.0
  • poly(methylvinylether/maleic acid) monoethylester which dissolves at pH 4.5 -5.0
  • poly(methylvinylether/maleic acid)n-butyl ester which dissolves at about pH 5.4
  • non-pH-dependant coating may be used, which initially impedes the ingress of aqueous fluid, but subsequently erodes and/or dissolves to expose the active agent to dissolution.
  • Typical non-pH-dependent polymers suitable for coating dosage forms (single or multiparticulate) to provide a fluid resistant barrier which subsequently erodes or dissolves include, but are not restricted to acacia, alginate, amylase, beeswax, carboxymethylcellulose, carnuba wax, cellulose acetate, cholesterol, ethylcellulose, fatty acids, gelatine, glyceryl behenate, glyceryl monostearate, glyceryl monodistearate, glyceryl tripalmitate,
  • hypromellose hydroxypropylcellulose, hydrogenated vegetable oil, lecithin, methylcellulose, paraffin wax, pectin, polyethylene glycol, polycaprolactone, polyglycolic acid, polylactic acid, polyglyclide-co-lactide co-polymers, polyvinylprroylidone, starch, stearic acid, stearyl alcohol, partially hydrogenated cottonseed oil/soyabean oil (melting at 51-55°C), partially hydrogenated palm oil (melting at 58-63°C), partially hydrogenated cottonseed oil (melting at 61-65°C), partially hydrogenated soyabean oil (melting at 67-71°C), partially hydrogenated castor oil (melting at 85-88°C), polyethylene glycol 3350 (melting at 54-58°C).
  • Delayed release of the aprepitant may also be achieved by a fluid resistant barrier which combines one or more pH-dependant polymers optionally with one or more non-pH- dependant polymers.
  • delayed release dosage forms include enteric coated tablets or enteric coated multiparticulate formulations, in which drug-loaded multi-particulate spheres are coated with methacrylic acid-methyl methacrylate co-polymers such as Eudragit LI 00-55, Eudragit L30D-55, or Eudragit FS 30D or Eudragit S100/S 12.5.
  • methacrylic acid-methyl methacrylate co-polymers such as Eudragit LI 00-55, Eudragit L30D-55, or Eudragit FS 30D or Eudragit S100/S 12.5.
  • Such formulations will not release the aprepitant in the acidic environment of the stomach but only on exposure to the higher pH typically found in the small and large intestine (pH range 5 to 8).
  • An enteric coated tablet illustrating one aspect of this invention may be a single-layer tablet or a multilayer tablet, such as a bi- or tri-layer tablet, wherein the active agent is present in one or more discrete layers within the compressed tablet form.
  • the discrete tablet layers can be arranged to provide modified or non-modified release of active agent.
  • General descriptions and methods for the preparation of suitable tablets may be found in Aqueous polymeric coatings for pharmaceutical dosage forms, J W McGinty (ed), Marcel Dekker, 1989, New York, and in in Microencapsulation and related drug processes, P Deasy, Marcel Dekker, 1984, New York, which publications are incorporated herein by reference.
  • a capsule can be prepared in which the active dose is provided in the form of beads of the aprepitant and is divided into two or more parts, each part having a non-pH- dependant protective coat of different thickness, which takes a different time to erode.
  • compositions of the invention are in unit dosage form.
  • Unit dosage forms for oral administration may be in tablet or capsule form and may as necessary contain conventional excipients such as binding agents, fillers, lubricants, glidants, disintegrants, effervescent agents, and wetting agents.
  • binding agents include but are not limited to: acacia, alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, dextrin, dextrose, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, polyvinylpyrrolidone, pregelatinised starch, sodium alginate, sorbitol, starch, syrup, tragacanth.
  • fillers include but are not limited to: calcium carbonate, calcium phosphate, calcium sulphate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, confectioner's sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, dibasic calcium phosphate, fructose, glyceryl palmitostearate, glycine, hydrogenated vegetable oil- type 1, kaolin, lactose, maize starch, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, microcrystalline cellulose, polymethacrylates, potassium chloride, powdered cellulose, pregelatinised starch, sodium chloride, sorbitol, starch, sucrose, sugar spheres, talc, tribasic calcium phosphate, xylitol.
  • lubricants include but are not limited to: calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, microcrystalline cellulose, sodium benzoate, sodium chloride, sodium lauryl sulphate, stearic acid, sodium stearyl fumarate, talc, zinc stearate.
  • glidants include but are not limited to: colloidal silicon dioxide, powdered cellulose, magnesium trisilicate, silicon dioxide, talc.
  • disintegrants include but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone, polacrilin potassium, pregelatinised starch, sodium alginate, sodium lauryl sulphate, sodium starch glycolate.
  • effervescent agents are effervescent couples as described hereinbefore.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tableting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are conventional in the art.
  • the tablets may be coated according to methods known in normal pharmaceutical practice. For example see Pharmaceutical dosage forms: tablets, Volume 1 second edition, H A Lieberman, L Lachman and J B Schwartz (eds) Marcel Dekkker, 1989, New York and G C Cole & J Hogan in Pharmaceutical coating technology, Taylor & Francis, London, 1995 which are herein included by reference.
  • the quantity of the aprepitant required in each component of each formulation can be determined by the skilled worker from the information provided in this invention. Firstly the target pharmacokinetic profile for the formulation is selected in line with the objects of the present invention. Then, from knowledge of the therapeutic window as defined herein, the mean rate of elimination of the aprepitant in the body, and the release profile of the aprepitant from each component, it is a matter of routine experimentation to establish the necessary quantity of aprepitant in each component in light of the information provided here. Information on particular preferred dosages overall and in the first and controlled-release fractions is nonetheless also provided herein.
  • any form of aprepitant may in principle be employed in the first fraction and in the controlled-release fraction.
  • a range of forms of aprepitant are known to the skilled person.
  • the aprepitant in the first fraction is: aprepitant free base, a pharmaceutically acceptable salt of aprepitant, a prodrug of aprepitant, or a co-crystal of aprepitant
  • the aprepitant in the controlled-release fraction is: aprepitant free base, a pharmaceutically acceptable salt of aprepitant, a prodrug of aprepitant, or a co-crystal of aprepitant.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may both be: aprepitant free base, a pharmaceutically acceptable salt of aprepitant, a prodrug of aprepitant, or a co-crystal of aprepitant.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may both be: aprepitant free base.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may both be: a pharmaceutically acceptable salt of aprepitant.
  • the pharmaceutically acceptable salt of aprepitant in the first fraction may be the same salt as, or a different salt from, the pharmaceutically acceptable salt of aprepitant in the controlled-release fraction.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may both be: a prodrug of aprepitant. Typically, they are both the same prodrug, which is typically fosaprepitant.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may both be: a co-crystal of aprepitant. They may be the same cocrystal or different cocrystals of aprepitant.
  • the aprepitant in the first fraction and the aprepitant in the controlled-release fraction may, on the other hand, be different ones of: aprepitant free base, a pharmaceutically acceptable salt of aprepitant, a prodrug of aprepitant, and a co-crystal of aprepitant.
  • the aprepitant in the first fraction may be aprepitant free base
  • the aprepitant in the controlled-release fraction may be a pharmaceutically acceptable salt of aprepitant, a prodrug of aprepitant or a co-crystal of aprepitant.
  • the aprepitant in the controlled-release fraction may for instance be a pharmaceutically acceptable salt of aprepitant.
  • the aprepitant in the first fraction may, on the other hand, be a pharmaceutically acceptable salt of aprepitant, and the aprepitant in the controlled-release fraction may be aprepitant free base .
  • the aprepitant in the first fraction may be a pharmaceutically acceptable salt of aprepitant
  • the aprepitant in the controlled-release fraction may be a prodrug of aprepitant, or for instance a co-crystal of aprepitant.
  • the aprepitant in the first fraction may be a prodrug of aprepitant
  • the aprepitant in the controlled-release fraction may be aprepitant free base
  • the aprepitant in the first fraction may be a cocrystal of aprepitant
  • the aprepitant in the controlled-release fraction may be aprepitant free base
  • the prodrug of aprepitant in these embodiments may be fosaprepitant.
  • the aprepitant in the first fraction and the aprepitant in the controlled- release fraction are aprepitant free base.
  • all the aprepitant in the first fraction and the aprepitant in the controlled- release fraction are aprepitant free base.
  • composition of the invention is aprepitant free base.
  • This patent application covers a raft of new products which could form a virtual pharmaceutical company of late stage pipeline projects which can be developed and approved and launched with license from the innovator or at patent expiry.
  • Such products are termed Value Added Generics and are improved versions of aprepitant which can be launched without license from Merck at patent expiry of the base patent or alternatively, they can be launched earlier with a license from Merck.
  • Aprepitant is currently marketed as the free base in numerous countries including the USA and the European Union.
  • a first step in solving this problem is finding variants of the product i.e. rapidity maintenance which possess physical and chemical characteristics which are conclusive to addressing one or more of the problems associated with aprepitant such as rapidity of action duration of effect and sustenance within the therapeutic window for prolonged periods of time from dose to dose.
  • Aprepitant is commercially available as the free base and is the obvious choice as a starting material. Few alternative salts of aprepitant have been disclosed in the art however none have been tested for rapidity or duration of effect or for any tendency to be within the therapeutic window from dose to dose. It has been surprisingly found that one class of salts lends itself to forming superior adduct with aprepitant and which adducts possess superior properties
  • a further aspect provides aprepitant adapted in a multi component dosage form such a tablet said dosage form being adapted in a first way to provide rapid release of aprepitant into the bloodstream (e.g. via the first, rapid release fraction as defined herein) said dosage form being adapted in a second way (e.g.
  • a controlled-release fraction as defined herein
  • the dosage form being adapted in a third way (e.g. via the same or another controlled-release fraction as defined herein) to provide a modified or delayed release format of the aprepitant product which lasts from dose to dose.
  • each component is dependent on the choice of formulation but in general the choice of each component will be made so that the amount of active ingredient in each component delivers the right amount of drug product to ensure rapidity longevity from dose to dose and maintenance of dose within the therapeutic window.
  • the total amount of the active ingredient in aprepitant in a formulation is at least 20mg and usually 50 to 150mg.
  • a Multi component tablet is preferred
  • Product line extenders of the present invention are designed to give a new product with superior biological profiles over the existing aprepitant product in terms of efficacy, safety and or side effect profile.
  • Emend® The active ingredient in Emend® is aprepitant.
  • This compound has two basic centres i.e., amine functions and is therefore capable of forming of salts with acids.
  • suitable acids which form an aspect of the present invention include common mineral acids such as hydrochloric, hydrobromic and sulfuric acids, small organic acids such tartaric acid (tartrate) and maleic acid, and more exotic salts including strontium.
  • Emend® product deficiencies Emend® is deficient because it has low bioavailability i.e., around 60 per cent. It also has a short half-life of 9 to 13 hours.
  • Emend® also has a number of serious side effects which are described below.
  • Emend i.e. aprepitant
  • the active ingredient in Emend is prepared from readily available starting material using procedures known in the art.
  • New product line extenders address the following technical issues.
  • the product should have a fast onset of action in order for the active ingredient to have a biological effect at the earliest possible opportunity.
  • This patent describes various inventions to enable this to occur.
  • Emend Some products such as Emend have limited possibilities for a long acting product due to its half-life and other problems.
  • the present invention addresses these issues and provides a product with a long duration of action, preventing issues such as nocturnal deficit from becoming an issue.
  • An optimal profile for all pharmaceutical products is dose to dose maintenance within the therapeutic window, thus addressing the issues of rapidity, longevity and preventing a bolus blip of high concentration of active ingredient which may cause serious side effects.
  • the present invention provides technical solutions to this issue.
  • Combinations of two or more from rapidity, longevity and dose to dose maintenance within the therapeutic window are preferred. Addressing two or preferably all three issues results in a superior product. This is a highly preferred aspect of this invention.
  • product line extenders include those which are adapted for oral route of administration such as tablet or capsule and non-oral routes of administration such as patches, depots or suppositories.
  • Product line extenders which address the issues above can be made using techniques known in the art and specifically described in well-known texts such as Remington, the seminal text book on Pharmaceutical science. These include but are not limited to PLE's which address rapidity, longevity and dose to dose maintenance within the therapeutic window.
  • the pharmaceutical composition of the invention which comprises a first fraction comprising aprepitant, and a controlled-re lease fraction comprising aprepitant, may be used for the treatment or prevention of any condition or disorder which is treatable using aprepitant.
  • the pharmaceutical composition of the invention provides for maintenance of the aprepitant in the therapeutic window from dose to dose, i.e. throughout the dosing interval, for such conditions and disorders such that an improved treatment for such conditions and disorders, with increased efficacy, reduced side effects, or both, is obtained compared to prior art formulations.
  • Conditions and disorders which are treatable using aprepitant, and for which improved treatments can therefore be provided by the present invention include: nausea, vomiting, travel sickness, pain, depression and anxiety.
  • the present invention provides a pharmaceutical composition of the invention, for use in a method for treatment of the human or animal body by therapy.
  • the invention further provides a pharmaceutical composition of the invention, for use in a method for the treatment or prevention of a condition selected from nausea, vomiting, travel sickness, pain, depression and anxiety.
  • the invention further provides a pharmaceutical composition of the invention, for use in a method for preventing nausea or vomiting caused by surgery.
  • the method may be for preventing post-operative nausea or vomiting.
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for treating or preventing cyclic vomiting syndrome.
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for preventing nausea or vomiting caused by chemotherapy.
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for preventing nausea or vomiting caused by administration of one or more chemotherapeutic agents.
  • the method typically in this embodiment comprises administering (i) the composition and (ii) the one or more chemotherapeutic agents, to a subject in need thereof.
  • (i) the composition, and (ii) the one or more chemotherapeutic agents are typically administered to the subject separately, simultaneously, concomitantly or sequentially.
  • the one or more chemotherapeutic agents may be selected from known
  • chemotherapeutic agents and known combinations of chemotherapeutic agents.
  • the one or more chemotherapeutic agents may be selected from:
  • Abiraterone Acetate Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin- stabilized Nanoparticle Formulation), ABVD (i.e. a combination of Doxorubicin
  • ABVE i.e. a combination of Doxorubicin Hydrochloride, Bleomycin, Vincristine Sulfate and Etoposide
  • ABVE-PC i.e. a combination of Doxorubicin Hydrochloride, Bleomycin, Vincristine Sulfate, Etoposide, Prednisone and Cyclophosphamide
  • AC i.e. a combination of Doxorubicin Hydrochloride and Cyclophosphamide
  • AC-T i.e. a combination of Doxorubicin
  • Aminolevulinic Acid Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium), Arimidex (Anastrozole), Aromasin (Exemestane), Arranon (Nelarabine), Arsenic Trioxide, Arzerra (Ofatumumab), Asparaginase Erwinia chrysanthemi, Atezolizumab, Avastin (Bevacizumab), Axitinib, Azacitidine, BEACOPP (i.e. a combination of Bleomycin, Etoposide, Doxorubicin Hydrochloride, Cyclophosphamide, Vincristine Sulfate (Oncovin), Procarbazine
  • BEP i.e. a combination of Bleomycin, Etoposide and Cisplatin (Platinol)
  • BEP i.e. a combination of Bleomycin, Etoposide and Cisplatin (Platinol)
  • Bevacizumab Bexarotene
  • Bexxar Tositumomab and Iodine I 131
  • Tositumomab Bicalutamide, BiCNU (Carmustine), Bleomycin, Blinatumomab, Blincyto (Blinatumomab), Bortezomib, Bosulif (Bosutinib), Bosutinib, Brentuximab Vedotin, BuMel, Busulfan, Busulfex (Busulfan), Cabazitaxel, Cabometyx (Cabozantinib-S-Malate),
  • Cabozantinib-S-Malate i.e. a combination of Cyclophosphamide, Doxorubicin Hydrochloride (Adriamycin) and Fluorouracil), Campath (Alemtuzumab), Camptosar (Irinotecan Hydrochloride), Capecitabine, CAPOX (a combination of Capecitabine and Oxaliplatin), Carac (Fluorouracil—Topical), Carboplatin, CARBOPLATIN-TAXOL (a combination of Carboplatin and Paclitaxel), Carfilzomib, Carmubris (Carmustine),
  • Cyclophosphamide Methotrexate and Fluorouracil
  • Cobimetinib Cobimetinib
  • Cometriq Cabozantinib-S- Malate
  • COPDAC a combination of Cyclophosphamide, Vincristine Sulfate (Oncovin), Prednisone and dacarbazine
  • COPP a combination of Cyclophosphamide, Vincristine Sulfate (Oncovin), Procarbazine Hydrochloride and Prednisone
  • COPP-ABV a combination of Cyclophosphamide, Vincristine Sulfate, Procarbazine Hydrochloride, Prednisone
  • Doxorubicin Hydrochloride Bleomycin and Vinblastine Sulfate), Cosmegen (Dactinomycin), Cotellic (Cobimetinib), Crizotinib, CVP (a combination of Cyclophosphamide, Vincristine Sulfate and Prednisone), Cyclophosphamide, Cyfos (Ifosfamide), Cyramza (Ramucirumab), Cytarabine, Cytarabine Liposome, Cytosar-U (Cytarabine), Cytoxan (Cyclophosphamide), Dabrafenib, dacarbazine, Dacogen (Decitabine), Dactinomycin, Daratumumab, Darzalex (Daratumumab), Dasatinib, Daunorubicin Hydrochloride, Decitabine, Defibrotide Sodium, Defitelio (Defibrotide Sodium), Degarelix, Denileukin Diftito
  • Fluorouracil Topical, Flutamide, Folex (Methotrexate), Folex PFS (Methotrexate), FOLFIRI (a combination of Leucovorin Calcium (Folinic Acid), Fluorouracil and Irinotecan Hydrochloride), a combination of 5 -fluorouracil, oxaliplatin and folinic acid (as used in FOXFIRE), FOLFIRI-BEVACIZUMAB (a combination of Leucovorin Calcium,
  • FOLFIRI-CETUXIMAB a combination of Leucovorin Calcium, Fluorouracil, Irinotecan Hydrochloride and Cetuximab
  • FOLFIRINOX a combination of Leucovorin Calcium, Fluorouracil, Irinotecan
  • Fluorouracil and Oxaliplatin Fluorouracil and Oxaliplatin
  • Folotyn Pralatrexate
  • FU-LV a combination of Fluorouracil and Leucovorin Calcium
  • Fulvestrant Gardasil (Recombinant HPV Quadrivalent Vaccine), Gardasil 9 (Recombinant HPV Nonavalent Vaccine), Gazyva (Obinutuzumab), Gefitinib, Gemcitabine Hydrochloride, Gemcitabine-Cisplatin combination, Gemcitabine-Oxaliplatin combination, Gemtuzumab, Ozogamicin, Gemzar (Gemcitabine Hydrochloride), Gilotrif (Afatinib Dimaleate), Gleevec (Imatinib Mesylate), Gliadel (Carmustine Implant), Gliadel wafer (Carmustine Implant), Glucarpidase, Goserelin Acetate, Halaven (Eribulin Mesylate), Herceptin (Trastu
  • Hydrochloride Hydrea (Hydroxyurea), Hydroxyurea, Hyper-CVAD (a combination of Cyclophosphamide, Vincristine Sulfate, Doxorubicin Hydrochloride (Adriamycin) and Dexamethasone), Ibrance (Palbociclib), Ibritumomab Tiuxetan, Ibrutinib, ICE (a combination of Ifosfamide, Carboplatin and Etoposide), Iclusig (Ponatinib Hydrochloride), Idamycin (Idarubicin Hydrochloride), Idarubicin Hydrochloride, Idelalisib, Ifex (Ifosfamide),
  • Mitoxantrone Hydrochloride Mitozytrex (Mitomycin C), MOPP (a combination of
  • Nanoparticle Formulation Navelbine (Vinorelbine Tartrate), Necitumumab, Nelarabine, Neosar (Cyclophosphamide), Netupitant and Palonosetron Hydrochloride, Neupogen
  • PAD a combination of Bortezomib (PS-341), Doxorubicin Hydrochloride (Adriamycin) and Dexamethasone
  • Palbociclib Palifermin, Palonosetron Hydrochloride, Palonosetron Hydrochloride and Netupitant, Pamidronate Disodium
  • Prednisone R-CVP (a combination of Rituximab, Cyclophosphamide, Vincristine Sulfate and Prednisone), Recombinant Human Papillomavirus (HPV) Bivalent Vaccine, Recombinant Human Papillomavirus (HPV) Nonavalent Vaccine, Recombinant Human Papillomavirus (HPV) Quadrivalent Vaccine, Recombinant Interferon Alfa-2b, Regorafenib, R-EPOCH (a combination of Rituximab, Etoposide, Prednisone, Vincristine Sulfate, Cyclophosphamide and Doxorubicin Hydrochloride), Revlimid (Lenalidomide), Rheumatrex (Methotrexate), Rituxan (Rituximab), Rituximab, Rolapitant Hydrochloride, Romidepsin, Romiplostim, Rubidomycin (Daunor
  • Trisenox Arsenic Trioxide
  • Tykerb Lapatinib Ditosylate
  • Unituxin Unituximab
  • Uridine Triacetate VAC (a combination of Vincristine Sulfate, Dactinomycin (Actinomycin-D) and Cyclophosphamide), Vandetanib
  • VAMP Vincristine Sulfate
  • Doxorubicin Hydrochloride (Adriamycin), Methotrexate and Prednisone), Varubi (Rolapitant Hydrochloride), Vectibix (Panitumumab), VelP (a combination of Vinblastine Sulfate (Velban), Ifosfamide and Cisplatin (Platinol)), Velban (Vinblastine Sulfate), Velcade (Bortezomib), Velsar (Vinblastine Sulfate), Vemurafenib, Venclexta (Venetoclax),
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for the treatment or prevention of travel sickness.
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for the treatment or prevention of pain.
  • the invention also provides a pharmaceutical composition of the invention, for use in a method for the treatment or prevention of depression or anxiety.
  • the controlled-release fraction in the pharmaceutical composition of the invention is usually adapted to ensure maintenance of the aprepitant within the therapeutic window from dose to dose, or at least for a certain, preferably high, proportion of the time during the dosing interval.
  • the method for the treatment or prophylaxis of the condition in question typically comprises administering the composition to a subject in need thereof once every dosing interval, and thereby ensuring maintenance of the aprepitant within the therapeutic window throughout each dosing interval.
  • the dosing interval i.e. the interval of time between administration of consecutive doses of a drug
  • the method for the treatment or prophylaxis of the condition comprises administering the composition to a subject in need thereof once every 24 hours, and thereby ensuring maintenance of the aprepitant within the therapeutic window throughout each 24 hours.
  • the method for the treatment or prophylaxis of the condition comprises administering the pharmaceutical composition of the invention to a subject in need thereof, and thereby releasing the aprepitant from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to the subject.
  • all of the aprepitant is released from the controlled-release fraction over the defined period.
  • x is at least 3, so that it takes at least 3 hours for all of the aprepitant to be released from the controlled-release fraction. It will be appreciated that aprepitant has a relatively long half life so will generally remain in the bloodstream for hours after all of the aprepitant has been released from the controlled-release fraction.
  • x may be at least 4, or, for instance, at least 6, so that it takes at least 4 hours, or at least 6 hours, for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 4 to 24, so that it takes from 4 to 24 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be from 4 to 16, or from 6 to 14. Often, x is at least 6, so that it takes at least 6 hours for all of the aprepitant to be released from the controlled-release fraction, x may for instance be at least 8, for example at least 12, at least 14, or at least 20. x may for instance be from 6 to 24, or from 8 to 24, or for instance from 12 to 16, or from 14 to 20, or from 15 to 24.
  • the method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the aprepitant within the therapeutic window for y % of the time during each dosing interval.
  • the dosing interval may be defined as, say, z hours beginning with administration of the composition to a subject.
  • z is generally 24, i.e. the dosing interval is 24 hours. Accordingly, z is typically from 20 to 28, for instance about 24. Often, z is 24.
  • other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and z may therefore have other values.
  • z may for instance be 6, 8 or 12, or even 48.
  • z may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, z is 24.
  • y is at least 50, such that the aprepitant is maintained within the therapeutic window for at least 50% of the time during the dosing interval. It is of course preferred, however, that y is greater than 50. Preferably, for instance, y is at least 60, and more preferably at least 70, for instance at least 75. Typically, y is at least 80, for instance at least 85. Often, y is at least 90, and is preferably at least 95. y may for instance be 100, such that the aprepitant is maintained within the therapeutic window throughout the dosing interval, i.e. from dose to dose. Typically, z is 24 and y is at least 50.
  • z is 24 and y is at least 60, and more preferably at least 70, for instance at least 75. Typically, z is 24 and y is at least 80, for instance at least 85. Often, z is 24 and y is at least 90, and is preferably at least 95. In some cases, z is 24 and y is 100.
  • the method for the treatment or prophylaxis of the condition may comprise administering the pharmaceutical composition of the invention to a subject in need thereof once every dosing interval, and thereby maintaining the aprepitant at or above a drug plasma level, 1, in the subject for q % of the time during each dosing interval.
  • the dosing interval may in this case be defined as t hours beginning with
  • the pharmaceutical composition is often a unit dosage form suitable for once daily (OD) dosing.
  • t is generally 24, i.e. the dosing interval is 24 hours. Accordingly, t is typically from 20 to 28, for instance about 24. Often, t is 24.
  • other dosing frequencies may of course be employed, depending on the drug, patient and condition being treated, and t may therefore have other values.
  • t may for instance be 6, 8 or 12, or even 48.
  • t may be from 6 to 48, but is typically from 12 to 36, for instance from 20 to 28. Often, t is 24.
  • q is at least 40, such that the aprepitant is maintained at or above the drug plasma level, 1, for at least 40% of the time during the dosing interval. It is of course preferred, however, that q is greater than 40. Preferably, for instance, q is at least 45, and more preferably at least 50, for instance at least 60. Typically, q is at least 65, for instance at least 70. Often, q is at least 75. Typically, q is at least 80, for instance at least 85. Often, q is at least 90, and is preferably at least 95. q may for instance be 100, such that the aprepitant is maintained at or above the drug plasma level, 1, throughout the dosing interval, i.e. from dose to dose.
  • t is 24 and q is at least 45. More preferably, t is 24 and q is at least 50, and more preferably at least 60, for instance at least 65, at least 70, or for instance at least 75. Typically, t is 24 and q is at least 80, for instance at least 85. Often, t is 24 and q is at least 90, and is preferably at least 95. In some cases, t is 24 and q is 100.
  • the drug plasma level, 1, may be any drug plasma level within the therapeutic window. Alternatively, it may be an IC50, i.e. a plasma concentration required for obtaining 50% of a maximum therapeutic effect in vivo.
  • 1 is the plasma concentration (IC50) required for obtaining 50% of a maximum therapeutic effect in vivo.
  • the maximum therapeutic effect in vivo is typically the maximum therapeutic effect in vivo that is obtainable by aprepitant when treating the condition in question.
  • the method generally comprises administering a therapeutically effective amount of the pharmaceutical composition of the invention to the subject.
  • the subject is generally a human or animal. Usually the subject is a human or mammal. The subject is typically human, i.e. a human patient.
  • the pharmaceutical composition of the invention is typically an oral dosage form and is typically therefore administered orally.
  • the pharmaceutical composition is typically therefore for use in a method as defined herein, wherein the method comprises administering the composition to a subject in need thereof orally.
  • the method for the treatment or prophylaxis of the condition comprises administering the composition to a subject in need thereof orally.
  • This may comprise placing the composition in the mouth for a period of time long enough to allow the first fraction - or a rapid release fraction within the first fraction, or a disintegrating portion of the first fraction - to dissolve completely, or to disperse completely, in the buccal fluid.
  • the first fraction itself, or a rapid release fraction within the first fraction, or a disintegrating portion of the first fraction may be a component that is suitable for sublingual administration - i.e. a component that dissolves completely, or disperses completely, in the buccal fluid.
  • administering the composition to the subject orally typically comprises placing the composition in the mouth for a period of time during which the first fraction - or a rapid release fraction within the first fraction, or a disintegrating portion of the first fraction - dissolves or disperses in the buccal fluid.
  • the oral administration may be sublingual administration. Therefore, administering the composition to the subject orally may comprise placing the composition under the tongue, or placing the composition between the cheek and gum.
  • administering the composition to the subject orally typically comprises placing the composition under the tongue, or placing the composition between the cheek and gum, for a period of time during which the first component - or a rapid release fraction within the first fraction, or a disintegrating portion of the first fraction - completely dissolves or disperses in the buccal fluid.
  • the period of time is usually less than or equal to 120 seconds. It may for instance be less than or equal to 90 seconds, for example less than or equal to 60 seconds.
  • the period of time is usually at least 1 second, for instance at least 15 seconds, because it must be sufficiently long enough for the first component to dissolve or disperse in the buccal fluid. In some embodiments, the period of time is at least 30 seconds. Thus, the period of time may for instance be from 15 seconds to 120 seconds, for example from 15 seconds to 90 seconds, for instance from 15 seconds to 60 seconds, or for example from 30 seconds to 60 seconds.
  • the method typically further comprises swallowing the composition after the period of time has elapsed. This ensures that any remaining part of the first fraction of the composition (e.g. in cases where not all of the first fraction is a rapid release fraction), as well as the controlled-release fraction of the composition, which typically comprises a core adapted for prolonged release of aprepitant, is swallowed.
  • the prolonged release and any additional maintenance dose can the be effected such that the aprepitant may be delivered from dose to dose.
  • the method typically therefore further comprises swallowing the composition after the period of time has elapsed, and optionally thereby releasing the aprepitant from the controlled-release fraction in vivo over a period of x hours from the time of administration of the composition to the subject wherein x may be as further defined herein.
  • the method may comprise administering the composition to a subject in need thereof, e.g. by the subject swallowing the composition, and thereby releasing the aprepitant from the first fraction in vivo within a period of 60 minutes from the time of administration of the composition to a subject, preferably within 30 minutes from the time of administration, more preferably within 10 minutes from the time of administration, within 5 minutes from the time of administration, or within 2 minutes from the time of administration, for instance within a period from the time of administration of from 15 seconds to 120 seconds, for example from 15 seconds to 90 seconds, for instance from 15 seconds to 60 seconds, or for example from 30 seconds to 60 seconds.
  • the method may comprise administering the composition to a subject in need thereof, e.g. by the subject swallowing the composition, and thereby releasing at least 50% of the aprepitant from the first fraction in vivo within 10 minutes of the time of administration of the composition to a subject, preferably within 5 minutes from the time of administration, more preferably within 2 minutes from the time of administration, or within 30 seconds from the time of administration.
  • composition of the invention will generally be an oral dosage form as further defined herein.
  • the invention further provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in the treatment or prevention of a condition selected from nausea, vomiting, travel sickness, pain, depression and anxiety.
  • a condition selected from nausea, vomiting, travel sickness, pain, depression and anxiety.
  • the treatment or prophylaxis of said condition may be as further defined anywhere herein.
  • the invention also provides a method for the treatment or prevention of a condition selected from nausea, vomiting, travel sickness, pain, depression and anxiety, which method comprises administering a pharmaceutical composition of the invention to a subject in need thereof.
  • a condition selected from nausea, vomiting, travel sickness, pain, depression and anxiety comprises administering a pharmaceutical composition of the invention to a subject in need thereof.
  • the method may be as further defined anywhere herein.
  • the invention additionally provides a combination product comprising (i) a pharmaceutical composition of the invention, and (ii) one or more chemotherapeutic agents.
  • the combination product of the invention comprises (i) a first
  • composition which is the pharmaceutical composition of the invention, and (ii) one or more further pharmaceutical compositions which comprise the one or more chemotherapeutic agents.
  • the one or more chemotherapeutic agents may be as further defined hereinbefore.
  • the invention also provides a combination product of the invention for use in a method for (a) treating cancer with the one or more chemotherapeutic agents and (b) preventing nausea or vomiting caused by the one or more chemotherapeutic agents.
  • the method comprises administering the one or more chemotherapeutic agents to a subject in need thereof and, separately, simultaneously, concomitantly or sequentially, administering the pharmaceutical composition of the invention to the subject.
  • Formulations for sustained release of aprepitant are produced as described below.
  • the sustained release formulations in this Example may be employed as the controlled-release fraction in the compositions of the invention.
  • Sustained release formulation 1 (20% Methocel in lactose filler; 40 mg aprepitant free base):
  • Method of manufacture the components in the table above were blended and then compressed to a hardness of approximately lOkp.
  • Table 1 Formulation details for sustained release core tablet (sustained release formulation 1)
  • Sustained release formulation 2 (30% Methocel in lactose filler; 40 mg aprepitant free base):
  • Method of manufacture the components in the table above were blended and then compressed to a hardness of approximately lOkp.
  • Table 2 Formulation details for sustained release core tablet (sustained release formulation 2)
  • a formulation for immediate release of aprepitant is produced as described below.
  • the immediate release formulation in this Example may be employed as the first fraction in the compositions of the invention.
  • Part 3 Final proposed manufacture combining the two formulations
  • the aprepitant sustained release core is made as described above in part 1 of this
  • Example using sustained release formulation 1 or 2.
  • the tooling is changed to 10 - 20mm Flat tooling.
  • the tablet die is filled with approximately 50% of the immediate release formulation 1 described in part 2 of this Example.
  • the aprepitant sustained release core is placed centrally into the pre-filled die.
  • Dissolution testing was performed on sustained release tablets having the sustained release formulations 1 and 2 above, and on immediate release tablets having the immediate release formulation 1 above. Dissolution conditions were as follows: USP 1 (basket), pH 6.8 phosphate buffer + 0.5% cetyl trimethylammonium bromide (CTAB), 900ml, 37°C, lOOrpm, samples analysed by HPLC. Formulation details
  • the sustained release formulations of Aprepitant shown in the following table were prepared in tablet form for dissolution testing.
  • the formulations were prepared as described above in part 1, where batch 17CF16-01-A has the above-described sustained release formulation 1 (20% Methocel in lactose filler; Table 1) and batch 17CF16-01-B has the above-described sustained release formulation 2 (30% Methocel in lactose filler; Table 2).
  • Batches 17CF16-01-A and 17CF16-01-B were each prepared in the form of tablets each weighing 300 mg in total and containing 40 mg Aprepitant.
  • Table 4 Formulation details of sustained release batches 17CF16-01-A and 17CF16-01-B
  • the immediate release formulation of Aprepitant shown in the following table was prepared in tablet form for dissolution testing.
  • the formulation was prepared as described above in part 2, where batch 17CF16-01-C has the above-described immediate release formulation 1 (Table 3).
  • Batch 17CF16-01-C was prepared in the form of tablets each weighing 500 mg in total and containing 40 mg Aprepitant.
  • Dissolution testing was performed on tablet batches 17CF16-01-A, 17CF16-01-B and 17CF16-01-C. The experiments were carried out three times (i.e. were repeated twice) giving three dissolution results per time point. The three results for each time point are shown in Tables 6 to 9 below together with the mean result. The results from Tables 6 to 9 are also plotted in Figures 1 to 4 respectively.
  • Table 6 Batch 17CF16-01-A - sustained release tablet (theoretical 40.0 mg/tablet aprepitant)
  • Table 7 Batch 17CF16-01-B - sustained release tablet (theoretical 40.0 mg/tablet aprepitant)
  • Table 8 Batch 17CF16-01-C - Immediate release tablet (theoretical 40.0 mg/tablet aprepitant) 500 mg nominal tablet weight) - 0 to 120 minute dissolution

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Abstract

L'invention concerne une composition pharmaceutique qui comprend: une première fraction comprenant de l'aprépitant; et une fraction à libération contrôlée comprenant de l'aprépitant.
PCT/GB2017/053864 2016-12-21 2017-12-21 Nouvelles formulations d'aprépitant Ceased WO2018115888A1 (fr)

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GBGB1621867.9A GB201621867D0 (en) 2016-12-21 2016-12-21 Novel formulations of aprepitant
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WO2022164985A1 (fr) * 2021-01-27 2022-08-04 Wellstat Therapeutics Corporation Formulation amorphe d'uridine triacétate
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WO2024144258A1 (fr) * 2022-12-28 2024-07-04 주식회사 삼양홀딩스 Composition pour comprimé à libération prolongée de ruxolitinib, et son procédé de préparation
CN119185243A (zh) * 2024-11-28 2024-12-27 山东齐都药业有限公司 福奈妥匹坦帕洛诺司琼口服掩味颗粒剂及其制备方法与应用

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