WO2014039951A1 - Compositions pharmaceutiques entérales - Google Patents

Compositions pharmaceutiques entérales Download PDF

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Publication number
WO2014039951A1
WO2014039951A1 PCT/US2013/058721 US2013058721W WO2014039951A1 WO 2014039951 A1 WO2014039951 A1 WO 2014039951A1 US 2013058721 W US2013058721 W US 2013058721W WO 2014039951 A1 WO2014039951 A1 WO 2014039951A1
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WIPO (PCT)
Prior art keywords
apc
medicament
segment
dosage form
length
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PCT/US2013/058721
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English (en)
Inventor
Alex AYCINENA
Riccardo Panicucci
Vijay SETHURAMAN
Lipa Shah
Bo Zhou
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Novartis Ag
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Publication of WO2014039951A1 publication Critical patent/WO2014039951A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets

Definitions

  • Enteral pharmaceuticals such as pills, tablets and suppositories are typically
  • discrete dosage forms each of which contains a specific amount of active ingredient that is determined by the manufacturer.
  • Administering a smaller or larger amount of the active ingredient requires a user to combine multiple dosage forms for doses larger than the fixed dosage selected by the manufacturer, or splitting one discrete dosage form into smaller pieces to provide smaller doses; or combining these methods to make up non-integral increased dosages.
  • Combining two or more discrete dosage units limits the accessible dosages to integral multiples of the amount of active ingredient in a single unit, while splitting discrete dosage units to provide a lower dose can be wasteful and does not provide precise control of the amount of the active ingredient(s).
  • discrete dosage forms like conventional pills and capsules are not well suited to allow a user to provide a precisely selected dosage.
  • An active ingredient could be provided to end users as a powder or small pieces from which a customized dosage could be produced, but precise dosing would then require a doctor, pharmacist or patient to accurately weigh the material, which is impractical for most end users.
  • Liquid formulations of active ingredients allow the user to adjust dosage, but accurately measuring a dose of a liquid can be difficult, and some of the liquid is generally wasted; moreover, limitations of solubility and/or stability prevent some drugs from being formulated in liquid form.
  • manipulation of the bulk pharmaceutical in liquid or powder form may allow contamination.
  • conventional pharmaceutical dosage forms do not provide a convenient way to prepare a customized unit dosage for a specific patient or situation that is usable with most drugs, including experimental ones where toxicity profile, efficacy, stability and solubility are not well established.
  • Certain pharmaceuticals have been formulated as thin films that can be ingested. See, e.g., Siddiqui, et al., Advances in Biol. Res. 5(6), 291 -303 (201 1 ); Chaturvedi, et al.,
  • Adjustment of the dosage of such films could be achieved by cutting a sample with known concentration to a desired size, but storage and administration remain problematic, and the available films are specifically designed for rapid dissolution in the mouth, which is not suitable for many drugs and is particularly contra-indicated for APCs with unpleasant tastes.
  • Another known pharmaceutical composition uses a rigid, generally planar material having a pharmaceutical agent contained therein, and uses the structure of the rigid support or carrier to control the location of release of the pharmaceutical agent. See e.g., US Patent No. 6,685,962; WO2007/083309; WO 2003/105,812; WO2007/000070.
  • a rigid drug-containing strip of material is folded and compressed, and placed inside a capsule for ingestion. When the capsule dissolves in the stomach, the drug-containing material springs back to an extended shape.
  • the relatively rigid elongated shape of the strip of material is intended to retain the material containing the active ingredient in the recipient's stomach.
  • these rigid materials reside in the stomach for an extended period of time, which may be undesirable; and the rigid materials may not be suitable for suppositories or for patients with stomach problems.
  • the present invention provides new pharmaceutical compositions and methods that address such needs, and are especially useful for drugs not known to be suitable for liquid formulation and ones where at least a brief delay in dissolution is desirable during administration.
  • the present invention provides pharmaceutical compositions that permit easy adjustment of the amount of active ingredient in an enterally delivered dosage form: the amount of active ingredient in a dosage form can be customized by an end user such as a doctor, pharmacist or patient, rather than being dictated by the manufacturer. They permit clinicians, physicians and pharmacists to select a customized dosage for a specific patient or purpose, and to prepare dosage forms with the customized dosage quickly and easily from a bulk material containing the particular active ingredient.
  • the pharmaceutical compositions of the invention are prepared from a bulk drug- containing medicament that comprises an Active Pharmaceutical Component (APC) and a polymeric carrier.
  • the medicament is a solid material often similar in texture to fast- dissolving films used to deliver active ingredients by dissolving in the mouth.
  • the APC contains at least one active ingredient (drug), and can be evenly distributed along or within the bulk polymeric carrier material, or it can be distributed in portions that are regularly spaced along the bulk material.
  • the amount of active ingredient or APC in a portion of the bulk material can readily be determined from optical or similar measurements of the material without need for weighing the bulk material or portions thereof.
  • the bulk material may be a fast-dissolving thin film that can be rolled up for storage, and can be unrolled and cut into segments for use, where the length of a segment determines the amount of active ingredient or APC contained in the segment.
  • the cross-sectional shape of the bulk material is typically constant or regular enough so that the amount of APC in a segment can easily be determined from the length of the segment with sufficient accuracy for pharmaceutical dosing.
  • the bulk medicament is in the form of a long strip up to about 2 cm wide and about 0.01 to 2 mm thick, with a rectangular cross-section and comprises up to about 30% by weight APC in or on a polymeric carrier.
  • the polymeric carrier comprises at least 50% of the weight of the medicament, typically at least 70% of the weight.
  • the polymeric carrier is a supple film, similar in texture to fast-dissolving films known for use to deliver active ingredients by rapidly dissolving in the mouth during ingest.
  • the amount of APC is preferably low enough so it does not significantly affect the stability, integrity or pliability of the polymeric carrier.
  • the medicament may be provided in an elongated bulk form such as a strip, ribbon, tube, film, or wire shaped polymeric carrier, where the active pharmaceutical component (APC) is carried in or on the polymeric carrier.
  • the APC may be distributed in or on the bulk carrier in a known fashion that depends upon the length of a segment of bulk medicament, so that a user can determine a suitable dosage and then cut a segment of the bulk material of suitable length to provide the specific customized dose, or cut a plurality of lengths, the sum of which provides the specific customized dose.
  • the user can prepare from this segment a convenient enterally-administrable dosage form by enclosing the segment with a protective layer or shell such as a capsule that keeps the dosage form from prematurely dissolving during administration.
  • the dosage forms of the invention thus contain an amount of active ingredient that is custom-selected by an end user, rather than being predetermined by the manufacturer, and dissolve after
  • the pharmaceutical compositions of the invention comprise a segment of a bulk drug- containing carrier that is substantially enclosed by a protective layer of pharmaceutically acceptable material that controls timing and location of dissolution of the medicament, and is typically designed to dissolve in the stomach relatively quickly after ingestion, for example.
  • the bulk drug-containing medicament can be manufactured as a composition that is easily handled and distributed to users.
  • the bulk medicament may contain a known amount of APC per unit of length so that the length of a segment of the elongated drug-containing material may be directly proportional to the amount of active ingredient it contains.
  • the APC can be evenly distributed along the length of the bulk medicament, or it can be distributed in portions at fixed, well defined intervals along the bulk medicament.
  • the bulk medicament may be readily cut into segments to provide customized unit dosage amounts of the active ingredient: a desired amount of the active ingredient required for a particular dosage form can be obtained by cutting a segment from the bulk material.
  • a unit dosage of the pharmaceutical compositions of the invention typically contains a segment of the bulk material, comprising a segment of a drug-containing medicament in the form of a fast-dissolving film that contains the APC and can be largely or entirely enclosed in a protective layer to provide an enteral dosage form of the invention.
  • the segment of elongated medicament is at least substantially, typically entirely, contained inside a protective layer of pharmaceutically acceptable material that protects the segment and APC during ingestion and facilitates handling of the potentially fragile medicament.
  • the protective layer of pharmaceutically acceptable material prevents the segment of medicament from dissolving during administration, such as in the mouth of the subject when the composition is ingested.
  • the protective layer dissolves in the body after administration (e.g., in the stomach upon oral administration, or in the colon upon suppository delivery), exposing the segment of medicament in the Gl tract so the APC can be released from the material and absorbed into the subject's body.
  • the segment of medicament typically dissolves quickly once the protective layer is breached or dissolved.
  • the medicament is a thin film drug composition such as the fast-dissolving orally administered films known in the art (see Siddiqui and Chaturvedi) that contains an APC of interest, and the protective layer or coating material surrounding it is a pharmaceutical-grade hard or soft capsule.
  • a segment of the medicament containing a desired amount of APC is cut from bulk material, either manually or by a suitable device that measures and cuts the medicament. Once a segment of the thin film of appropriate length is cut, the segment is rolled, folded, compressed or otherwise formed into a shape that will fit inside the pharmaceutical capsule.
  • one, some, or all, of the segments that are cut are cut to be a shape capable of fitting within a pharmaceutical capsule, or one, some, or all of the segments might require forming as described above.
  • The, or each, segment is inserted into the capsule, which is then closed or capped to provide a dosage form having a customized amount of active ingredient. Additional embodiments of the pharmaceutical compositions and methods and devices for their preparation are described herein.
  • Processing the bulk medicament to form unit dosages for enteral administration can readily be automated, so customized dosages can be produced as capsules or other discrete dosage forms from the bulk drug-containing medicament by an end user such as a doctor, pharmacist, clinician, or patient, rather than by the manufacturer of the bulk material. Accordingly, methods and devices for mechanizing the preparation of the pharmaceutical compositions described herein are also aspects of the invention.
  • the pharmaceutical compositions of the invention are especially advantageous where a dosage of a drug must be precisely tailored for a given individual or application, as they provide an easy way to measure and deliver any desired amount of the active ingredient by cutting a suitable length of a bulk medicament.
  • the bulk material is typically provided as an elongated strip of flexible, preferably supple, material, which can easily be cut to a desired length and rolled or folded into a compact shape suitable for insertion into a capsule or otherwise being coated with or surrounded by protective material.
  • These dosage forms are advantageous because the medicament can be produced as a bulk, distributable product without the need for the manufacturer to specify a specific amount of APC for a unit dosage, since customized unit dosages can be created by a doctor or pharmacist or even a patient once an ideal dosage has been selected.
  • compositions and methods permit evaluation of the handling properties and stability of the bulk material, as well as manufacturing of the bulk material in large quantities, even before a fixed amount of active ingredient per unit dosage has been determined, such as before a final decision is made on a unit dosage amount during clinical trials, thereby accelerating the drug development process.
  • Figure 1 depicts an embodiment of the invention wherein a roll of a thin film medicament (1 ) is measured and cut to a desired length, and then rolled up and inserted into an empty two-piece gelatin capsule that is then assembled into a finished dosage form (5).
  • Figure 2 depicts an example of a dosage form of the invention prepared from a strip of packets filled with APC and rolled up for insertion into a gelatin capsule.
  • Figure 3 depicts a diagram of a device for preparing the dosage forms of the invention.
  • Figure 4 depicts the dissolution rate for Compound A alone, Compound A in a thin film, and the thin film enclosed in a gelatin capsule.
  • Figure 5 shows dissolution rates for films with 10% and 25% loading of Compound A.
  • Figure 6 shows rate of compound A release from low-dosage films.
  • the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In preferred embodiments, the subject is a human.
  • primates e.g., humans, male or female
  • the subject is a primate.
  • the subject is a human.
  • treat refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or
  • treat refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both.
  • treat refers to preventing or delaying the onset or development or progression of the disease or disorder.
  • a subject is "in need of a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • 'Active pharmaceutical component,' or APC refers to a medicinal material, which comprises at least one pharmaceutically active ingredient, or drug.
  • the active ingredient frequently comprises a low-molecular weight drug but can also comprise a biologic; the drug or biologic is intended to provide one or more medical benefits to a consumer.
  • the APC can consist of, or consist essentially of, the active drug itself, or the APC can be an active ingredient formulated with one or more pharmaceutically acceptable excipients.
  • the APC can be introduced into the medicaments of the invention as a pure unformulated active ingredient, or it can be admixed with other
  • the APC can be a solid or a liquid or gum at room temperature, and solid APC can be crystalline or amorphous.
  • the term 'dosage form' refers to an individual unit containing an amount of an active pharmaceutical ingredient that corresponds to a single dose of the APC or active ingredient, or to an integral fraction of a single dose such as half, a third, or a quarter of a dose, where two, three or four of such dosage forms can be taken together to provide a single dose.
  • Typical dosage forms include capsules, pills, suppositories, and the like.
  • the dosage form is a capsule, particularly a gelatin capsule, in which a segment of a pharmaceutical composition comprising an APC in or on a fast-dissolving film suitable for pharmaceutical use. The segment contains a single dosage of the APC that has been selected for a particular patient or use, and the desired dosage is used to determine the length of the segment.
  • a 'Dose' refers to an amount of an APC intended to be administered at one time.
  • a dose can be contained in one dosage form, or it can be contained in two, three, four, or more than four dosage forms.
  • a 'typical' or 'normal' dose as used herein refers to an amount of APC that would deliver a dose considered suitable for an average recipient to take at one time.
  • the dosage forms of the invention provide methods and compositions that allow the actual dose in a single dosage form to be adjusted or customized for a particular individual or purpose, such as to allow the amount being administered in a drug trial to change without reformulating the APC, or to allow a treating physician to adjust the amount of drug administered in view of a particular patient's age, gender, ethnicity, body weight, or sensitivity to the active ingredient.
  • 'Fast dissolving' takes its ordinary meaning in the field, as it is utilized in literature related to orally administered thin film medications such as those described in Siddiqui and Chaturvedi, cited above.
  • 'Medicament' is used herein to describe a thin film or similar flexible polymeric carrier to which at least one APC has been added.
  • the medicament is typically an elongated strip of APC-containing polymeric carrier that can be cut into segments for use in making unit dosage forms of the invention.
  • the bulk medicament is in the form of an elongated strip that resembles a roll of ribbon material, and segments are cut from the strip of bulk material much as pieces of ribbon are cut from a roll of ribbon.
  • the pharmaceutical compositions of the invention comprise medicament comprising a drug-containing polymeric material, and a protective layer that surrounds the medicament and prevents it from dissolving or releasing the active ingredient prematurely. While the protective layer may dissolve relatively quickly, it at least protects the medicament from beginning to dissolve rapidly in the mouth during oral administration, for example.
  • the medicament is typically a segment of an elongated strip of material containing a known amount of active ingredient per unit of length, so that the amount of APC in a segment of the elongated drug-containing material can easily be calculated from the length of the segment.
  • the APC need not be evenly distributed along the length of the polymeric carrier; it can be applied in bands across the strip, for example, or portions of the APC can be sandwiched between layers of polymeric carrier material in pouches or packets formed of two strips of polymeric carrier, or a folded, sealed, single strip: in these embodiments, the amount of APC per band or packet may limit the dosage in a dosage form to integral multiples of the amount per band or packet, but by making that amount per band or packet small relative to the normal dose (e.g., less than a third or less than a quarter of the normal lowest dose), fine tuning of the dosage can readily be achieved.
  • a segment, or segments, of the medicament containing the desired amount of APC is encased within a protective layer of pharmaceutically acceptable material, which at least substantially encompasses the segment of medicament.
  • the protective layer does not substantially dissolve during administration, such as while an oral unit dosage is being swallowed, and covers enough of the drug-containing material to prevent significant dissolution of the material or APC it contains during administration.
  • the protective layer completely encloses the drug-containing medicament.
  • the protective layer shields the mouth from exposure to high concentrations of the active ingredient during oral administration, for example, and protects the subject from the potentially objectionable taste of the medicament.
  • the medicament comprises a fast-dissolving polymeric material
  • the protective layer prevents it from dissolving prematurely in the mouth.
  • the protective layer readily dissolves in the stomach after ingestion to release the medicament, thus exposing the active ingredient for dissolution and absorption.
  • the protective layer dissolves fairly rapidly after administration, releasing the medicament within minutes; however, such rapid dissolution is not necessary, and the protective layer and/or the polymeric carrier can be selected to release the APC more slowly when desired.
  • the medicament typically dissolves either immediately or within a few minutes once it is exposed, or within an hour or two after administration, to release the APC.
  • the protective layer provides convenient handling and insertion of a suppository dosage form to allow placement without losing APC during insertion.
  • the surrounding protective layer can be a pre-formed empty capsule or shell into which the segment of medicament is inserted, or it can be a layer of material applied to the bulk medicament, or to the segment or formed segment thereof, by dipping or spraying, or it can be simply wrapped around the formed segment of medicament.
  • the protective layer is provided as an open container such as an unfilled capsule designed for pharmaceutical use, and the container is capped or sealed after the medicament is inside. Suitable materials for this protective layer are known in the art, including those materials typically used for making hard or soft pharmaceutical capsules. These pharmaceutical capsules may be hard or soft capsules, and they include hard and soft gelatin capsules as well as various types of hypromellose or HPMC capsules.
  • One embodiment of the invention utilizes a bulk drug-containing medicament fabricated as a continuous, flexible polymeric material having a consistent amount of active pharmaceutical component (APC) per unit of length.
  • the drug-containing material is typically a supple solid that may have a rubber, gum or gel texture; preferably it has sufficient linear cohesion to remain substantially intact during handling (measuring and cutting) as described herein. If needed, linear cohesion and improved handling properties may be achieved by supporting the medicament on a flexible, preferably supple, substrate or carrier such as waxed paper, Mylar, and the like. When the medicament is supported on a substrate, the medicament is separated from the substrate before a protective layer of coating material is applied to the segment or the bulk medicament.
  • the medicament is typically provided as a strip, strand, or ribbon, of material that contains a consistent amount of active ingredient per unit length in or on a polymeric carrier, so that the dosage in a segment of the medicament is proportional to the length of the segment.
  • the material is flexible and supple (not brittle or rigid), so a segment of the medicament can be configured into any desired shape without breaking, and so it is able to move through the gastrointestinal system freely, which might be hindered if the material were relatively rigid.
  • the medicament is preferably supple, meaning it flexes freely in all directions with little resistance, and has little or no tendency to revert to any particular shape when released.
  • Fast-dissolving films such as those known in the art for oral administration (see Siddiqui, Chaturvedi, and Kunte, for example) are suitable embodiments of this supple medicament, but the material need not be fast-dissolving as long as it is not rigid enough to affect mobility within the Gl system or to risk causing physical damage to internal tissues such as the lining of the intestines.
  • APC manufactured in bulk form, having a known amount of APC per unit of length (e.g., mg APC / cm of length varies no more than about +/-10%, no more than +1-5%, or no more than 2%, along the length of the bulk material).
  • a desired amount of APC for a custom unit dosage to be prepared can be calculated from the known amount of APC per unit length, and the desired amount of APC can be obtained by cutting a segment of the proper length to provide the desired amount of APC.
  • the APC is not substantially evenly distributed along the length of the carrier, but is instead
  • the desired amount of APC can be obtained by cutting a segment including the desired number of APC containing portions. Cuts are preferably made through regions containing no APC in these embodiments.
  • the bulk drug-containing material can be wrapped onto a spool or hub like a roll of tape, optionally supported by a backing material that does not stretch along its length, such as waxed paper, Mylar or foil, for convenient handling.
  • the drug-containing material can be sandwiched between two layers of such backing or support material.
  • the drug-containing material is contained in a dispensing cartridge or container for protection and convenient dispensing.
  • Suitable materials for a medicament that comprises a matrix containing the APC distributed evenly throughout the polymeric carrier include those known in the art for making thin film drug delivery compositions, particularly fast-dissolving thin films. See, e.g., Siddiqui and Chaturvedi.
  • the matrix typically includes at least one pharmaceutically- acceptable polymer that is wettable (hydrophilic) and possesses sufficient tensile strength for handling. Modified starches (e.g., Insta Pure Cote), cellulose materials such as microcrystalline celluloses (e.g., AvicelTM), methylated cellulose such as Methocel K4M, and water-soluble resins such as PolyoxTM (e.g., PolyoxTM N80, PolyoxTM N10) can be used.
  • Modified starches e.g., Insta Pure Cote
  • cellulose materials such as microcrystalline celluloses (e.g., AvicelTM), methylated cellulose such as Methocel K4M
  • water-soluble resins
  • Cellulose hydroxypropyl cellulose (e.g., KlucelTM), hydroxypropyl methyl cellulose (HPME), starch, pullulan, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone K-90, polyethylene glycol, polysorbate 80, gelatin, pectin, sodium or calcium alginate, polyvinyl alcohol, maltodextrins, Eudragit RD10, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polymerized rosin, and polyacrylic acid are also suitable as components of this matrix.
  • hydroxypropyl cellulose e.g., KlucelTM
  • HPME hydroxypropyl methyl cellulose
  • pullulan carboxymethyl cellulose
  • sodium carboxymethyl cellulose sodium carboxymethyl cellulose
  • polyvinyl pyrrolidone K-90 polyethylene glycol
  • polysorbate 80 gelatin
  • pectin sodium or calcium al
  • At least one plasticizer is included in the matrix to maintain the flexibility or suppleness of the material; examples include glycerin or glycerol, propylene glycol, low molecular weight polyethylene glycols, sorbitol, maltodextrin, phthalates such as dimethyl, diethyl, dibutyl and dioctyl phthalate, citrate esters such as tributyl, triethyl, and acetyl citrate, as well as triacetin and castor oil are suitable plasticizers.
  • Additives to provide desired flavors can be added as well.
  • Surfactants can be added to promote rapid dissolution; examples of suitable surfactants include polaxamers, sodium lauryl sulfate, benzalkonium chloride, TweenTM, and the like.
  • loading of the APC in the material is less than about 50% by weight, typically less than about 30% by weight, and preferably less than about 25% by weight.
  • the APC can be in a liquid form or in the form of a particulate material, provided it is properly distributed along the length of the elongated drug-containing material so that the amount of APC per unit of length is readily determined from the length of the segment of medicament, e.g. it varies by no more than about 10% from the average value.
  • Methods for forming medicaments of the invention into convenient forms such as films are known in the art, and include solvent casting, semisolid casting, hot melt extrusion, solid dispersion extrusion, and rolling methods.
  • enterally-administerable active pharmaceutical ingredient can be delivered by compositions and methods such as those described herein, some active pharmaceutical ingredients are better suited than others to these methods and compositions.
  • the APC should be compatible with a suitable polymeric carrier, and selection of a polymeric carrier should be made with due consideration to miscibility and compatibility between carrier and APC. If an APC is not compatible with polymeric carriers approved for pharmaceutical use, it may be better to use a different delivery method for that APC.
  • selection of a solvent for preparing the film can be important, because it affects the crystallinity of the active ingredient in the final film: a solvent that dissolves the active ingredient tends to produce a film wherein the active is amorphous, while use of a solvent that does not dissolve the active ingredient well tends to cause the active ingredient to be more crystalline.
  • the selection of the polymeric carrier can be used to promote even distribution of the APC within the film.
  • a high molecular weight polymeric carrier reduces migration of the active ingredient within the film, thus reducing the tendency to migrate and potentially crystallize or otherwise change form. This can be beneficial, especially for very low dose actives, where the dose to be delivered in a segment of the medicament is less than 10 mg, and particularly where the dose is less than 1 mg.
  • the physical properties of the medicament are important in the handling and storage of these medicaments and
  • compositions, and putting too much APC into a medicament may reduce its suitability.
  • the APC and polymeric carrier are not compatible, the physical properties of the APC (crystallinity, hygroscopicity) or its stability for storage may be changed by the polymeric carrier in ways that reduce the usefulness of the compositions and methods described herein. Selection of a suitable polymeric carrier may overcome such problems, but because of such issues, not all carrier / APC combinations are equally useful, and a user may need to test several carriers to find one suitable for a particular APC.
  • Methods useful for determining the compatibility of a particular carrier with a particular APC include Raman spectroscopy and microscopy, e.g., polarized light microscopy: these and similar methods can be used to measure APC stability, crystallinity, and aggregation.
  • more than 50% of the weight of the medicament and preferably at least about 70% of the weight of the medicament should be the polymeric carrier plus plasticizers in order to ensure that the amount of APC does not adversely affect the physical and handling properties of the carrier. Also, if more than 30% of the medicament is active ingredient, it is more prone to change form or aggregate.
  • the loading limitations may make it impractical to use the compositions and methods described herein, simply because the amount of medicament required to deliver a large dosage of APC may deter use.
  • the compositions and methods are especially useful for lower-dosage APCs, where a typical unit dosage contains up to about 100 mg, and particularly for APCs where a typical unit dosage contains 10 mg of APC or less.
  • the medicaments of the invention are treated to prevent dissolution in the mouth, generally by being substantially enclosed in or encapsulated by a protective layer of pharmaceutically acceptable material that does not dissolve rapidly during administration, but does dissolve relatively quickly in the Gl tract.
  • a protective layer of pharmaceutically acceptable material that does not dissolve rapidly during administration, but does dissolve relatively quickly in the Gl tract.
  • shell materials such as those used in hard or soft pharmaceutical capsules (e.g., gel caps) are an example of a material that provides suitable dissolution properties for use in the compositions of the invention.
  • a strip of a medicament can be coated with a protective layer before it is cut to length, in which case only the ends where a segment is cut would be exposed during administration; but more typically, a segment is cut from the strip of medicament, and the segment is enveloped in a protective layer.
  • a segment of a supple medicament can be cut to a suitable length to provide a desired unit dosage, and the segment can be rolled up, compressed, or folded into a formed shape, such as a shape like a capsule or tablet suitable for ingestion, or a capsule shape suitable for a suppository.
  • the formed segment can then be inserted into a capsule or similar pre-formed container suitable for delivery, or it can be coated by spraying or dipping with a material that will form a protective layer around the formed segment.
  • a segment of the medicament is formed to fit into a gelatin capsule, and the formed segment is then inserted into a gelatin capsule, which is then closed or sealed for administration.
  • a segment of the medicament is adapted to be ingested, and to deliver a desired dosage of an active ingredient that is intended to be released in the stomach or lower Gl tract rather than in the mouth.
  • Figure 1 depicts an embodiment of the invention wherein a roll of a thin film medicament (1 ) is measured and cut to a segment having a desired length (2), and then rolled up (3) and inserted into an empty two-piece gelatin capsule that is then assembled for use as a dosage form of the invention (5).
  • the APC may not be admixed into the polymeric carrier; rather, it can be disposed on the polymeric carrier, or sandwiched between layers of the carrier or between a layer of a carrier and a supporting layer (substrate).
  • the APC may be applied to a surface of the polymeric carrier or substrate in an even layer, or in other convenient ways such as in bands across the width of a strip of polymeric carrier or substrate.
  • the amount of APC may be directly related to the length of the segment of polymeric carrier in order to simplify handling, i.e., in order for the amount of APC to be readily determined from the length of the segment cut from the bulk material; however, in these embodiments the APC may be divided into portions positioned at regular intervals along the carrier or substrate.
  • the amount of APC can be determined by counting the number of bands or dots, etc. of APC applied to the polymeric carrier or substrate.
  • the medicament is again substantially surrounded by a protective layer that prevents it from dissolving prematurely during administration.
  • This protective layer can be provided by a capsule into which the medicament is inserted.
  • the APC is contained in packets or pouches of ingestible material that may be provided in the form of a band or strip of connected packets for convenience.
  • the length of the band or strip is related to the amount of APC it contains in a predictable way, so that a desired amount of APC can be obtained by cutting the band to the appropriate length to have a particular number of packets, or alternatively by counting out the correct number of packets to provide the desired customized dose of APC.
  • the packets are formed to be separated from each other by seams that are transverse to the length of the band of bulk material, so that a user can cut across the band at one of these seams and avoid cutting open any of the packets of APC.
  • the carrier may include preformed weaknesses such as thinned regions, such as score lines, a line of perforations or other suitable weakness facilitating tearing of the strip along the preformed weaknesses.
  • FIG. 2 depicts an example of this where a strip of pouches (2) having an open edge (3) are formed from an ingestible thin-film material (1 ). A seam between the pouches (4) is free of APC and provides a convenient place to cut the strip between pouches.
  • the pouches are then filled with APC (6) and sealed to form filled packets, and a segment of suitable length to provide a desired dosage (7), three filled packets (8) in this example, is cut with a cutting device (5), cutting along a seam between packets.
  • the segment of three filled packets is then rolled up (9) and placed inside a two-piece gelatin capsule (10) to provide a completed dosage form of the invention (1 1 ).
  • Figure 2B shows an edge view of the filled packets on a roll of medicament of this embodiment (1 ).
  • these packets are formed on a thin film or on a substrate of materials such as those discussed above.
  • the packets are formed at least in part of fast-dissolving thin film material for rapid release of the APC once the medicament is exposed inside the body.
  • the packets are formed from two films or from a thin film and a substrate material; Figure 2 illustrates one embodiment of these packets.
  • the packets typically each contain the same amount of APC, which is typically a fraction (e.g., half, or a third, or a fourth, or a fifth, or a smaller fraction) of a typical or minimal dose of the particular APC.
  • the accessible dosages using these embodiments are limited to integral multiples of the amount of APC per packet; thus advantageously the amount of APC per packet is a small fraction (e.g., 25% or less) of an average dose of the APC.
  • the APC can be introduced into the packets either before or after they are formed.
  • the APC is often introduced as a powder.
  • the powder contains at least one excipient, such as a dissolution agent, in addition to the drug being delivered.
  • compositions of the invention can be used to deliver any active pharmaceutical ingredient. They are particularly useful for APC's that are intended to be administered orally for release in the stomach, and for APCs that can be administered as suppositories. They are applicable to APCs that have unpleasant taste, since the APC is not exposed to the oral cavity during oral administration, and they are suitable for use with solid APCs that exhibit low solubility.
  • the APC is or comprises a low molecular weight drug, e.g., an organic compound having a molecular weight up to about 1500, or up to about 1200.
  • suitable classes of active drugs for use in the APC include cancer drugs like Afinator®, osteoporosis drugs including bis-phosphonates such as Zometa®, analgesics, antibacterials like tobramycin, hypolipidemics such as various statins, cardiovascular drugs, generic drugs like acetaminophen, diclofenac, levothyroxine etc., and experimental or developmental drugs, particularly those where the anticipated normal dose per administration is less than about 500 mg and preferably less than 250 mg.
  • the APC is a biologic medicinal agent such as a therapeutic antibody or polypeptide.
  • the methods and compositions of the invention are particularly useful for drugs during the development stage, when no final decision has been made on dosage, and the ability to prepare the bulk medicament without defining a precise dosage is particularly important.
  • This pharmaceutical compositions of the invention can be used to deliver any desired amount of active ingredient that can be formulated into a flexible drug-containing material to be inserted into a capsule or other protective layer of suitable size and shape for administration to a subject to be treated.
  • the amount of APC in a single dosage form can be customized for a specific purpose without having to weigh out the drug-containing material, since the length of the segment determines the amount of APC delivered in a dosage. It is typically most useful when the desired amount of APC in a single unit dosage form is less than a gram, desirably less than 0.5 grams, and frequently less than about 200 mg. Dosage amounts up to about 150 mg are preferred for making the dosage forms of the invention. However, larger dosage amounts can readily be provided by making two or more discrete dosage forms of the pharmaceutical compositions described herein that, when taken together, provide the desired total dosage.
  • the protective layer is a capsule selected to provide suitable dissolution characteristics following ingestion or insertion;
  • suitable capsules for both oral and suppository delivery are well known in the art, and include known hard and soft shell capsule materials, such as gelatin, collagen, carrageenans, and modified starch or cellulose materials. Methods for producing unfilled capsules of these materials, and for filling and closing them, are well known in the art. Any suitable size of capsule can be used, and typically capsules from size 0 to size 5 are suitable for use in the methods described herein when the composition is to be delivered orally, while larger capsules may be used for APCs to be delivered as suppositories.
  • the segment of the medicament for a dosage form can be shaped into any desired shape and coated by dipping or spraying or wrapping it with a suitable protective layer of material that will not substantially dissolve during administration, but will dissolve at a suitable rate enterally after administration. After enteral administration, the protective layer dissolves or degrades to expose the drug-containing material for uptake of the APC.
  • the invention provides a process for making the pharmaceutical compositions and dosage forms of the invention.
  • the methods comprise providing at least one segment of a medicament, wherein the segment contains a known amount of an active pharmaceutical ingredient that is related to the length of the segment, and surrounding the segment with a protective layer of pharmaceutically acceptable material to prevent it from dissolving prematurely during administration.
  • the segment is cut to a length that provides an amount of APC corresponding to a desired dosage amount for a single dosage form.
  • the segment is typically cut from a bulk supply of elongated medicament (which is often formed as a ribbon or tape) that is preferably supple.
  • the bulk elongated medicament has a known loading of APC per unit length; often the APC is distributed in a constant amount per unit length along the polymeric carrier, but optionally it may be distributed in portions at known and preferably constant intervals along the length of the polymeric carrier.
  • the cross-sectional shape of the carrier is typically consistent along the length of the elongated material.
  • the cross-sectional shape can be round, forming a cylinder like a wire, or it can be square or rectangular, such as a tape or film, or it can be of any other convenient cross-sectional shape.
  • the cross-sectional shape of the elongated bulk medicament is rectangular and the band or strip of medicament is referred to as a film or a thin film.
  • the bulk medicament may be supported on a carrier for mechanical stability and to simplify handling and automated processing, especially if the medicament in its elongated form can easily be stretched enough to affect its drug loading/length ratio.
  • the process provides a way for an end user, such as a clinician, doctor, pharmacist or patient, to use a bulk medicament to produce discrete dosage forms containing customized amounts of APC.
  • the process wastes little or none of the APC, permits a user to select a specific amount of APC for each discrete dosage unit, and can readily be automated to produce a supply of customized dosage units for a particular patient, for example.
  • a desired amount of active pharmaceutical component (APC) for a particular purpose is provided by cutting the bulk elongated medicament into segments having the appropriate length to deliver a desired amount of APC.
  • the bulk medicament can be cut to a desired length at any stage prior to administration.
  • the bulk medicament is an elongated, flexible solid such as a strip that can be cut to a desired length by an end user just prior to dispensing to a patient, e.g., by a pharmacist or doctor.
  • the strip of medicament is cut to length by a doctor or clinician or pharmacist, and it may be further treated or modified prior to administration to a patient.
  • the medicament may be cut into multiple segments of identical length containing a specific dosage selected for a particular patient or use. These segments can then be coated or encapsulated with a protective layer as described herein for delivery or administration to a patient.
  • Segments can be cut just prior to administration or delivery to a consumer, e.g., by a doctor administering the drug or by a pharmacist filling a prescription, so each segment can be cut to a length chosen to provide a customized amount of APC for a particular patient or purpose. It is also understood that a segment of desired length can, without departing from this description, consist of two or more sub-segments, provided the total length of the sub- segments equals the desired length of the segment of interest.
  • segment of desired length can be produced by providing two or more sub-segments that can be combined together to produce the desired dosage amount for a desired unit dosage.
  • segments of suitable length from medicaments containing the separate APCs can be cut and can be combined into a single protective layer, e.g., a single capsule.
  • the elongated medicament is covered with or encapsulated in a protective layer such as a shell of a pharmaceutically acceptable material that can be ingested.
  • a protective layer such as a shell of a pharmaceutically acceptable material that can be ingested.
  • the shell or protective layer can be applied to the medicament prior to having it cut to a desired length, in which case the protected segment can be administered directly, or the segment and protective layer can be formed into a shape more convenient for administration, e.g., by being rolled into a cylindrical shape.
  • the segment can first be formed into a suitable shape for administration before the protective layer is applied to the segment (or this can be done using sub-segments that combine to provide a segment of desired length).
  • the protective layer is a pharmaceutical capsule such as a gelatin capsule, and a segment of the medicament of appropriate length is formed and inserted into the capsule for administration to a subject.
  • the invention thus provides devices for producing the dosage forms of the invention.
  • the devices are often configured to receive a bulk supply of an elongated medicament, optionally in a form resembling a roll of tape or ribbon.
  • the devices will contain the bulk medicament in a form readily dispensed and easily measured, and optionally include a cutting system to cut segments of desired length from the bulk material, and/or a loading system adapted to put the segment of drug-containing material inside or substantially inside a protective layer of pharmaceutically acceptable coating material.
  • a device useful for preparation of the compositions described herein comprises a holder for the bulk medicament or a holder for a supply of empty capsules, or both, and one or more additional components for making the dosage forms of the invention. See Figure 3 for a diagram depicting an example of such a device.
  • the bulk medicament may be formed as a roll, for example (1 ), and may be contained in a cartridge or on a spool or other suitable holder (2); in the example, the holder has a window (7) that permits a user to see the bulk roll of medicament.
  • the bulk medicament may, as discussed above, be supported on a substrate.
  • the substrate may be notched, perforated, or marked at regular intervals to assist in handling and to help with automation of one or more of the steps required to process the bulk medicament to form unit dosage forms as described herein, e.g., the substrate may be marked to facilitate unrolling it from a spool, positioning it in the device, dispensing it, identifying the drug and/or loading of the medicament, or measuring the length of a portion of the medicament or a segment thereof.
  • the device can also be configured to separate the substrate from the medicament, typically after a segment of medicament has been measured and cut to a desired length.
  • the device comprises a feeding mechanism (4) that permits dispensing, or optionally mechanically assists with dispensing, a segment of medicament from the bulk medicament in the holder.
  • the feeding mechanism may comprise one or more rollers to align the bulk material, and optionally an electric motor to smoothly advance the material at a controlled rate suitable for dispensing.
  • the device includes a physical, electronic or optical measuring system (5) configured to measure the length of a segment of the medicament as or after it is dispensed, typically before it is cut, or to permit a user to measure the length of a segment in preparation for cutting it to a desired length.
  • the measuring system can be as simple as a gradations or a ruler applied to a surface of the device for use in measuring a segment.
  • the measuring system may be an optical, electronic or mechanical measuring device.
  • the measuring system is configured to measure the length of a segment as it passes through an opening that allows the segment to exit from the holder, and once a segment of the desired length has passed though the opening, feeding of the bulk material may be stopped for the user to cut the segment from the bulk material; or the device may be configured with a cutting system (6), optionally positioned at the opening, which can be used to cut the segment at the desired length once that length has been dispensed.
  • the device also includes a cutting system (6) positioned to cut a segment of the medicament having a desired length, typically while using the measuring system to determine the length of the segment.
  • a cutting system (6) positioned to cut a segment of the medicament having a desired length, typically while using the measuring system to determine the length of the segment.
  • the device is configured to cut a segment of the medicament having a desired length (and thus containing a desired amount of APC), and also to substantially surround the segment with a protective layer of pharmaceutically acceptable material, although these steps can be performed by separate devices.
  • the bulk supply of the medicament is formed as a film or band, and is optionally supported on a substrate that provides stability for the film and prevents significant elongation that would stretch the film and change its consistent amount of APC per unit length.
  • the bulk medicament is contained in a cartridge that is optionally encoded or marked with information about the identity of the APC and the amount of APC per unit length in the bulk material. Alternatively, this information may be encoded in or on a substrate on which the elongated medicament is supported.
  • the device is configured to automatically detect information from the cartridge or the substrate about the identity and amount of APC.
  • the device typically comprises a holder (1 ) configured to receive a bulk supply of the medicament, which may be provided in a cartridge or other package. It also typically comprises a feeding mechanism (4) that is configured to advance a portion of the bulk medicament so that it extends outward from the bulk supply. Preferably, the portion of the medicament that extends away from the bulk supply is positioned to be accessible to the cutting assembly or system, so the device or the user can use the cutting system to cut a segment of the medicament from the bulk supply.
  • the device further comprises a measuring system (5) that can measure the length of the segment before it is cut from the bulk medicament.
  • the feeding system is operatively linked to the measuring system so that the measuring system provides information about the length of the segment as it is advanced by the feeding system and before it is cut; an electronic controller (7) is optionally included for this purpose.
  • the feeding system can adjust the position of the material relative to the cutting system so that the action of the cutting system causes a segment to be cut to the desired length.
  • the feeding system and measuring system are controlled by an electronic controller (7), so a user can program the device to dispense and/or cut a segment of a desired length.
  • the electronic controller is further programmed with information about the amount of APC per unit length in the bulk material in its holder, so that a user can input a desired amount of APC per unit dosage, and the feeding system and measuring system work in concert to cut a segment from the bulk medicament that contains the desired amount of APC, based on measuring the length of the segment before it is cut from the bulk material.
  • the device optionally comprises a shaping module (8) that forms the segment of medicament into a desired shape.
  • This module can be part of the device comprising the cutting and measuring systems, or it may be contained in a separate device.
  • the shaping module is configured to roll or fold the segment into a formed segment of a size and shape suitable to fit inside a pharmaceutical-grade capsule or other container. In other embodiments, the shaping module simply compresses the segment into a formed segment having a suitable size and shape.
  • the device includes a holder (9) for parts of pharmaceutical capsules, e.g., halves of a two-piece hard gelatin capsule.
  • the device also optionally comprises an encapsulation module (10) that surrounds the formed segment with a protective layer of pharmaceutically-acceptable material.
  • the encapsulation module applies a protective layer by spraying, dipping or wrapping it onto the formed segment.
  • the encapsulation module provides this protective layer by placing the formed segment into a capsule or other container, such as a pharmaceutical gelatin capsule.
  • the encapsulation module also seals or caps the capsule or container.
  • the device typically includes a holder (9) for a supply of empty capsules or capsule components to facilitate encapsulation.
  • the device further includes a marking device such as a printer, and applies information to the finished dosage form (1 1 ) to allow a user to determine the identity and/or amount of APC in the finished dosage form, or it may apply a computer- readable code such as a bar code to the dosage form to simplify further automated handling of the finished product.
  • the marking device utilizes an ingestible ink.
  • the device optionally includes a quality control module that provides information to verify the identity of the APC in the medicament, either before or after cutting it into one or more segments.
  • the quality control module may detect optical properties of the medicament, such as optical signatures characteristic of the APC (e.g., UV, IR, Raman absorptions) or readily detected signatures such as fluorescent markers added to the medicament or the polymeric carrier for identity verification.
  • the polymeric carrier comprises or consists of a fast-dissolving material such as a fast-dissolving film.
  • the film typically is formed into a strip having a thickness of about 0.1 to 1 mm or more, and a width of about 2-20 mm, though other dimensions may be used, e.g. a thickness of 80-120 micrometers
  • the film preferably has suitable cohesive strength to be handled by a mechanized apparatus, and may be carried on a supporting surface, if desired, to make mechanical processing easier.
  • the film has a homogeneous composition, and a consistent cross-sectional area and shape, so that it will contain a consistent amount of Al per unit length, preferably within a variation of less than +/- 10%.
  • the film can thus be cut into segments that contain a predictable amount of Al, based on the length of the segment.
  • Each segment can be shaped if desired; for example, a segment of a film can be rolled up, folded over, or compressed into any desired shape.
  • the segment can be treated to prevent immediate dissolution in the mouth, as by coating or enclosing it with a protective layer, or by inserting it into a container that provides a protective layer.
  • the protective layer is a pharmaceutically acceptable material that will not substantially dissolve in the mouth during ingestion by a subject, but which will dissolve readily in the stomach after ingestion. Commonly, it will dissolve within minutes in the stomach, releasing the drug-containing medicament.
  • the film may be a fast-dissolving composition, or it may be a timed-release or slow dissolving material.
  • the polymeric carrier is typically prepared as two separate strips and then formed into pouches of suitable size. The two strips may be the same or different in composition; at least one of the two strips is preferably a fast-dissolving film.
  • the APC is typically a solid, often a finely divided powder.
  • the APC may be placed onto a first strip and the second strip pressed onto the first to form pouches around the APC, or the two strips may be formed into pouches and the APC added to the pouches, which are then sealed.
  • each pouch contains the same amount of APC, and the amount of APC per pouch is often a fraction (e.g., less than half) of the amount of APC that is anticipated to be used as a single dose.
  • two or more pouches are typically used, although a single pouch can be used if the amount of APC in the pouch provides a suitable amount of APC.
  • One example of methods and materials for forming such methods is described in US2006/0073190, where a strip of edible fast dissolving thin film is used to contain flavored materials in packets, and some of the films used form self-sealing packets.
  • a segment of the strip of pouches described above can be cut, preferably along a seam between two adjacent pouches so that cutting does not open any of the pouches, for use in making a dosage form of the invention.
  • the length of the segment or the number of pouches it contains can be used to measure the amount of APC contained in the segment.
  • the segment for a single dosage form is selected to provide a predetermined amount of the APC that is needed for the dosage form being prepared.
  • the pouches are then substantially enclosed with a protective layer as discussed above; for example, the pouches may be placed inside a pharmaceutical grade capsule.
  • the invention provides a method to treat a subject with a dosage form containing a customized amount of an APC, comprising preparing a dosage form as described above to contain an amount of APC selected for treating the particular subject.
  • the bulk medicament dosage form is cut into a segment of a suitable length to provide the amount of the active ingredient needed for the particular subject.
  • the segment of the medicament is then encapsulated, such as in a gelatin capsule, for administration, or is otherwise treated to prevent the composition from dissolving rapidly in the mouth when it is ingested. It is then delivered to or administered to a subject in need of the specific APC dose provided by the customized dosage form.
  • the dosage form contains a medicament that comprises an active ingredient and polymeric carrier suitably combined to form an elongated band or strip of bulk medicament that is flexible and cohesive.
  • the composition is formed into a film having a thickness between 0.1 and 1 mm or 2 mm, and a width of about 2 to 20 mm, with a consistent rectangular cross-section along its length.
  • the composition is homogenous enough so that the length of a segment of the bulk drug- containing material determines the amount of active ingredient present in the segment. Therefore, a desired unit dosage can be obtained by measuring a segment of the material having the correct length.
  • the bulk medicament is cut to provide a segment having a suitable length to contain a desired dosage of the active ingredient.
  • This segment is then rolled or coiled up to a roughly cylindrical shape, or it may be folded or compressed to a suitable shape, and is then inserted into a capsule, such as a gelatin capsule of standard pharmaceutical size and composition.
  • a capsule such as a gelatin capsule of standard pharmaceutical size and composition.
  • the capsule is then ready for administration to a subject in need of the selected dosage of the active ingredient.
  • the bulk drug-containing medicament for use in the methods and compositions described herein can be any formulation having suitable physical properties: it is typically a non-rigid solid material, and is often formed into a thin film suitable for cutting to desired lengths.
  • Known formulations designed for ingestion as fast-dissolving thin films can be used. See e.g. Siddiqui, et al. and Chaturvedi, et al., infra.
  • other compositions that may dissolve more slowly can be used, typically in the form of a supple material that is readily processed mechanically, optionally supported on a substrate.
  • the bulk drug-containing material is formulated to dissolve rapidly in the stomach environment, thus it may be formulated to dissolve more rapidly at lower pH such as at pH below about 6 rather than at neutral or basic pH such as that typically found in the mouth (about pH 7.4).
  • the medicament in these homogeneous films may contain any concentration of APC that provides suitable physical properties.
  • the concentration in the medicament is such that a length of between 5 mm and 200 mm is sufficient to provide a sufficient amount of APC for a single typical dose, although where appropriate, a longer or shorter strip of film can be used for a single dose; and optionally a single dose can be produced by combining two or more of the dosage forms described herein, where the combined dosage forms contain the total dose to be administered.
  • the dosage forms of the invention can contain more than one active ingredient, which may be admixed in a single APC, or may be in two or more APCs.
  • a second APC can be blended homogeneously with the first APC, or the second APC can be
  • the second APC can be contained in a second layer and applied atop the film containing the first APC, or the second APC can be contained in a second band that may be produced separately, or may be parallel with and produced along with the medicament film containing the first APC.
  • the latter arrangements allows the user to adjust the ratio of first and second APCs by adjusting the thickness of the second layer relative to the thickness of the layer containing the first APC, or by adjusting the width of the second band relative to the width of the band of film containing the first APC.
  • the dosage forms of the invention can include agents for masking taste of the active ingredient or other components, coloring agents, agents to accelerate dissolution, and the like, such as those often found in fast-dissolving films designed to dissolve in the mouth.
  • agents for masking taste of the active ingredient or other components such as those often found in fast-dissolving films designed to dissolve in the mouth.
  • coloring agents, agents to accelerate dissolution, and the like such as those often found in fast-dissolving films designed to dissolve in the mouth.
  • additives are not required for the present invention, where the
  • the dosage forms of the invention are free of added flavorings and taste-masking agents, and optionally also free of coloring agents and/or additives included to accelerate dissolution or adhesion to mucosa.
  • the dosage forms of the invention can be used to deliver any type of active ingredient.
  • Solids can be blended into the composition regardless of their solubility properties, as they do not have to be dissolved for incorporation into the film or into the packets of the dosage forms described herein. It may be beneficial to grind solids into very fine particles.
  • Amorphous solids and oils can be incorporated as well, with appropriate adjustments to the composition of the carrier as needed in view of the physical state and properties of the APC.
  • the APC may contain, in addition to the active drug itself, pharmaceutically acceptable excipients such as antiadherents (e.g., magnesium stearate), binders, coatings, disintegrants (e.g., crospovidone), coloring agents, flavoring agents, fillers, lubricants, glidants, and/or preservatives.
  • the APC is a powder that may be an unformulated active drug compound.
  • the powder comprises an active drug compound admixed with at least one excipient; in some embodiments, the excipient is a dispersant or disintegrant.
  • the polymeric carrier used for the medicaments of the invention can be any ingestible, pharmaceutically acceptable material suitable for use in film-like pharmaceutical formulations, including those used for fast-dissolving oral formulations, see e.g. Siddiqui, et al. and Chaturvedi, et al. (infra).
  • a fast-dissolving carrier is not always required: it may be advantageous for certain applications because it would minimize the effect of the carrier's dissolution profile on the rate of release of the APC.
  • the carrier itself can be used to modulate the rate of release of the APC, and it may be a slower dissolving matrix; thus the carriers usable for the present invention include but are not limited to those found suitable for use in thin film medicaments designed to rapidly dissolve in the mouth.
  • the carrier for the pharmaceutical compositions of the invention will typically include at least one water-soluble or hydrophilic polymer providing a solid or semi-solid matrix, which may be a natural polymer such as cellulose, starch, pullulan, gelatin, pectin, xanthan and other gums; a synthetic polymer (or copolymer) such as polyetheylene glycol (PEG), polyvinyl alcohol, or polyvinyl pyrrolidinone (PVP); or a modified natural polymer such as hydroxypropylmethyl cellulose, carboxymethyl cellulose, sorbitan monoleate and the like.
  • a natural polymer such as cellulose, starch, pullulan, gelatin, pectin, xanthan and other gums
  • a synthetic polymer such as polyetheylene glycol (PEG), polyvinyl alcohol, or polyvinyl pyrrolidinone (PVP)
  • PEG polyetheylene glycol
  • PVP polyvinyl pyrrolidinone
  • suitable polymers for use in the carrier for the present invention include: cellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, starch, pullulan, gelatin, pectin, sodium or calcium alginate, polyvinyl pyrrolidone, polyethylene glycol, polysorbates such as polysorbate 80, polyvinyl alcohol, maltodextrins, eudragit RD10, Xanthan gum, Tragancanth gum Guar gum, Acacia gum, Arabic gum, gum of Moringa Oleifera, carageenans, polyacrylic acid, and polymerized rosins. For optimal properties, mixtures of these are often used.
  • the carrier for the pharmaceutical compositions may also contain one or more
  • plasticizers which are typically hydrophilic compounds or lower molecular-weight polymers that promote physical flexibility (fluidity) of the carrier and minimize brittleness.
  • Suitable plasticizers are known in the art, and can be selected readily by the skilled person with reference to known pharmaceutical carriers— see, e.g., Chaturvedi, et al., discussed above, and US2005/02081 10.
  • Examples include lower-molecular weight PEG, PVA or PVP; glycerin, propylene glycol and similar low-molecular weight polyhydric alcohols; phthalates; citrate esters; phosphate esters; adipate esters; sebacate esters; tartrate esters; glycol and glycerol esters; and esters or ethers of PEG, sugars, fatty acids, sorbitan, and the like.
  • Specific examples include triethyl citrate, tributyl citrate, PEG having a molecular weight of about 300-600, dibutyl phthalate and dioctyl phthalate.
  • Other materials may be added to the carrier to further optimize its physical properties and dissolution rate, including various monosaccharides and disaccharides, sugar alcohols such as mannitol or sorbitol, maltodextrins, cyclodextrins, methylcellulose, carboxymethyl cellulose, hydroxymethyl cellulose, and the like.
  • Surfactants may also be added to modify the dissolution properties of the carrier and its loading capacity.
  • a dosage form for enteral administration comprising:
  • the medicament comprises at least one active pharmaceutical component (APC) carried in or on a polymeric carrier; and
  • APC active pharmaceutical component
  • the protective layer prevents the medicament from dissolving prior to reaching the stomach or intestine during enteral administration.
  • the segment is non-rigid.
  • the medicament is a strip of an edible thin film or a strip of packets or pouches made at least partially of an edible thin film; preferably, the thin film is an edible, pharmaceutically suitable polymer-containing material that dissolves when contacted with an aqueous material such as bodily fluids like saliva.
  • the carrier for an approved pharmaceutical fast-dissolving film product Preferably it is a pharmaceutically acceptable supple film that is compatible with the APC to be delivered.
  • the medicament is an elongated material such as a strip of film that contains a known amount of APC per unit of length, and this known amount is used to select the length of the segment for a particular dosage form.
  • the total desired dose of APC for a dosage form can be contained in a single segment or in two or more segments.
  • the protective layer can surround one segment, or more than one segment, for a single dosage form.
  • the medicament comprises at least one active pharmaceutical component dispersed in a polymeric carrier comprising a hydrophilic polymer or mixture of two or more hydrophilic polymers.
  • the polymeric carrier is a fast-dissolving thin film having an active pharmaceutical agent, either alone or formulated as an APC, evenly distributed within the film. 7.
  • an active pharmaceutical agent either alone or formulated as an APC, evenly distributed within the film. 7.
  • the amount of APC in a segment of the medicament is directly proportional to the length of the segment.
  • the pouch may be formed between two layers of a quick- dissolving thin film, or it may be formed by one layer of such thin film and a second layer of other edible film material.
  • pouches are formed using a quick-dissolving thin film and a portion of APC equal to a fraction (half, one quarter, one third, one fourth, or a smaller fraction) of a single normal dose is placed inside the pouch, which is then sealed.
  • a segment of the medicament containing one, two, three, four or more than four pouches can then be cut from a bulk supply (strip) of medicament to provide APC for use in one dosage form.
  • Each pouch contains a known amount of APC, which may be a pure active ingredient or a formulated APC material, and the number of pouches used to make one dosage form determines the dose of active ingredient or of APC in the dosage form.
  • a method to prepare a dosage form for enteral administration containing a customized dose of an APC comprising:
  • APC active pharmaceutical component
  • a device for preparing a dosage form of a medicament that comprises at least one active pharmaceutical component (APC) carried in or on a strip of polymeric carrier, wherein the amount of APC in a segment of the medicament is determined by the length of the segment, and wherein medicament is substantially enclosed within a protective layer that prevents the drug-containing material from dissolving during administration,
  • APC active pharmaceutical component
  • the device comprises a holder for a supply of bulk medicament and/or a supply of empty pharmaceutical capsules, and at least one of the following:
  • a measuring system configured to measure the length of a segment
  • a shaping module that forms a segment or two or more segments of medicament into a formed segment that will fit into a pharmaceutical capsule
  • a loading module that places a formed segment of medicament into an empty pharmaceutical capsule.
  • compositions of the present invention can deliver an APC in unit dosages from less than 1 mg to about 1000 mg of active ingredient(s), but due to the loading limitations of some materials, combined with practical limitations on the physical size of dosage forms that can be easily administered to a typical human patient, the upper limit on the amount of APC per dosage form (e.g., per capsule) is often about 500 mg, or in some embodiments 250 mg.
  • the compositions and methods described herein are used for oral delivery of APCs, and are intended to deliver a unit dosage up to about 200 mg or up to about 150 mg of active ingredient per encapsulated dosage form when intended for oral administration. Selection of a dosage for a specific patient is within the level of skill of a treating physician and depends on factors such as the size, age, condition and gender of the patient, the indication being treated, and of course the particular active ingredient to be administered.
  • the methods of the invention can be practiced with any suitable polymeric carrier and APC; many components for suitable ingestible polymeric carriers are known in the art.
  • the polymeric carrier is a quick-dissolving thin film such as those known in the art for oral delivery of active ingredients.
  • the film-former components were stirred together in water with an overhead stirrer. Once the Methocels were completely dissolved, acetone was added to reduce the viscosity and all other ingredients were added to obtain a uniform solution that was white in color with no visible solids. The solution was sonicated for 30 mins and then left unstirred overnight to get rid of any air/bubbles in the solution. The solution was then cast into film on a paper substrate using a hand film-caster with a knife gap of 200 ⁇ . The cast film was then dried in a vacuum oven at 40°C and l OOmbar Hg for 2hrs. Component Quantity' 1 ' Function Ref. standard
  • Titanium Dioxide 3328 1 .15% Pigment USP/Ph. Eur.
  • Sample A Strip rolled up lengthwise and encapsulated in Size 3 gelatin Capsule
  • Sample B Prepared as Sample A, but rubbed with dry talc powder prior to encapsulation
  • Sample C Strip rolled up (no talc, no capsule used)
  • Each of the three samples was placed in a standard capsule-disintegration apparatus (37°C water) for testing.
  • Sample A Capsule breaks within 5min. Rolled strip forms a plug which disintegrates/dissolves in 15-20min
  • Sample B Capsule breaks within 5min. Rolled strip forms a plug which disintegrates/dissolves in 15-20min (similar observations to Sample A)
  • sample C the unencapsulated rolled-up film, dissolves in 5 minutes, so layers of the film would begin dissolving right away in the mouth; the unprotected film would likely not be a suitable delivery system for the APC, because it would not deliver the entire dosage to the stomach.
  • the encapsulated films dissolved in a suitable amount of time after capsule breakage exposed them to liquid media. Addition of talc may improve handling properties of the film, and has little effect on dissolution characteristics.
  • the drug load for the example used here ( ⁇ 90mg / capsule) is on the order of many marketed products; for higher doses, a higher concentration or larger capsule can be used. For doses over about 200 mg, it is anticipated that two or more capsules would be advantageous. Dose adjustments using this method could be easily achieved by selecting a suitable length for the segment or strip of bulk material inserted into the capsule.
  • compositions of the invention include:
  • Each of these recipes can be varied by changing the relative amounts of the components, and suitability for use in the medicaments of the invention can be readily determined by one of skill in the art.
  • the amount of APC in Recipe 3 can be increased or decreased while keeping the other ingredients in the same relative amounts in order to adjust loading of APC into the composition.
  • Dissolution rates can be measured using any method known in the art. For example, the following method can be used.
  • a rigid basket-rack assembly supporting six cylindrical glass tubes, 77.5 ⁇ 2.5 mm long, 21.5 mm in internal diameter and with a wall thickness of about 2 mm.
  • the tubes are held vertically by two superimposed transparent plastic plates, 90mm in diameter and 6mm thick perforated by six holes having the same diameter as the tubes.
  • the holes are equidistant from the centre of the plate and are equally spaced from one another.
  • Attached to the under side of the lower plate is a piece of woven gauze made from stainless steel wire 635 mm in diameter and having nominal mesh apertures of 2.00 mm.
  • the upper plate is covered with a stainless steel disc perforated by six holes, each about 22 mm in diameter, which fits over the tubes and holds them between the plastic plates. The holes coincide with those of the upper plastic plate and the upper open ends of the glass tubes.
  • the plates are held rigidly in position and 77.5 mm apart by vertical metal rods at the periphery and a metal rod is also fixed to the centre of the upper plate to enable the assembly to be attached to a mechanical device capable of raising and lowering it smoothly at a constant frequency of between 28 and 32 cycles per minute through a distance of 50 to 60 mm.
  • the design of the basket-rack assembly may be somewhat different provided specifications for the glass tubes and the screen mesh size are unchanged.
  • a cylindrical disc for each tube each 20.7 ⁇ 0.15 mm thick in diameter and 9.5 ⁇ 0.15 mm thick, made of transparent plastic with a relative density of 1.18 to 1 .20, and pierced with five holes, each 2 mm in diameter, one in the centre and the other four spaced equally on a circle of radius 6mm from the centre of the disc.
  • Four equally-spaced grooves are cut in the Lateral surface of the disc in such a way that at the upper surface of the disc they are 9.5mm wide and 2.55mm deep and at the lower surface 1.6 mm square.
  • the disc is inserted into the tube above any capsule or tablet that tends to float.
  • the assembly is suspended in the liquid medium, typically water or neutral buffer solution, in a suitable vessel, preferably a 1000-ml beaker.
  • a suitable vessel preferably a 1000-ml beaker.
  • the volume of liquid is such that the wire mesh at its highest point is at least 25mm below the surface of the liquid, and at its lower point is at least 25mm above the bottom of the beaker.
  • One tablet or capsule is placed into each tube and add a disc to each tube where the dosage form to be tested floats in the test solution. Suspend the assembly in the beaker containing the specified liquid and operate the apparatus, monitoring the operating time until the dosage form has dissolved. Dissolution is deemed complete when any solid particles have become small enough that they are no longer retained by the mesh at the bottom of the tube, even though some solid may remain in the apparatus, or when the only solids remaining in the tube are residues of the capsule or protective layer.
  • a film was made by casting, using the composition described as Recipe 3 above, where the APC was a compound to be tested for hypolipidemic activity via oral administration.
  • APC loading was 10% by weight, and the film was 80 to 120 ⁇ (micrometers) in thickness.
  • the APC, compound A can be crystalline or amorphous: analysis of the film by Raman spectroscopy and polarized light microscopy showed that compound A was amorphous and was homogeneously distributed. The film disintegrated within about 5 minutes in water.
  • a sample of the thin film was rolled up and placed inside a gelatin capsule for dissolution testing.
  • Dissolution testing was done in a medium containing 0.5% sodium lauryl sulfate in 50 mM sodium phosphate buffer at pH 6.8 at 37°C.
  • Compound A has a solubility >0.5 mg/mL in this medium, and concentration at full dissolution in the sample of medium would be about 0.15 mg/mL.
  • Medium was stirred at 250 rpm.
  • Figure 4 shows the dissolution profile for the film alone, Compound A alone (CSF), and the film in a capsule. The film and the compound alone dissolve quickly; the film in capsule begins to dissolve at about 20 minutes, when the capsule has breached and dissolves more slowly than the film alone; however, dissolution is complete by 40 minutes.
  • Example 4 Film for low dose delivery.
  • Thin films were prepared from a mixture of Methocel K100 and Methocel K4M, with 16% glycerin as plasticizer, containing 0.5%, 2% or 4% of Compound B as the APC.
  • Compound B is a low-dose pharmaceutical compound: films contained either 0.01 mg or 0.10 mg of Compound B in a 1 .5 cm 2 film segment. By measuring the amount of Compound B released into solution, dissolution was completed within under 5 minutes for the 0.01 mg film and in under 30 minutes for the 0.1 mg film as shown in Figure 6.
  • Example 5 Diclofenac compositions.
  • Diclofenac was formulated with a hydroxypropyl methylcellulose (HPMC) suspension suitable for film formation at 30 % (wt/wt) loading. And cast on a paper substrate to dry at ambient temperature for several hours. The film was cut to provide segments 7 in. long and 0.75 in. wide, each weighing about 300 mg and containing about 90 mg diclofenac. Strip A was rolled up lengthwise and encapsulated in a size 3 gelatin capsule.
  • HPMC hydroxypropyl methylcellulose
  • Strip B was prepared similarly but was rubbed with dry talc powder before encapsulation.
  • Strip C was rolled up and left un-encapsulated.
  • the three strips were placed into disintegration testing apparatus, and immersed in 37°C water. Dissolution was monitored by visual observations.
  • Strip A capsule breaks within 5 minutes, leaving a rolled-up strip as a plug that dissolves in 15-20 minutes.
  • Strip B capsule breaks within 5 minutes, and the rolled up strip (plug) dissolved in 15-20 minutes— similar to Strip A.
  • Strip C the rolled-up strip dissolves within 5 minutes.
  • Example 6 Dissolution of thin film compared to non-film form of same composition.
  • Compound B (90 mg) was mixed with Methocel K4M (750 mg) and glycerin (150 mg).
  • a film was formed by dissolving this mixture in 30 mL water to provide a clear solution, then pouring the solution into a Teflon mold (7 cm x 10 cm) and allowing it to dry at room temperature.
  • the film was cut into segments containing 34 ⁇ 1 mg Compound B, rolled up and inserted into a gelatin capsule. The rolled segment had about 2 layers of film.
  • dissolution of Compound B from the thin film was complete by 60 minutes, while dissolution of Compound B from the dry mixture samples was still incomplete at 120 minutes.
  • dissolving the dry mixture into water and casting it as a thin film before encapsulation accelerated dissolution in an acidic medium when compared to the non-film version of the encapsulated dry mixture.

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Abstract

La présente invention concerne une composition pharmaceutique pour une administration entérale, qui comprend un médicament contenant un médicament souple allongé qui porte un composant pharmaceutique actif (APC) et une couche de protection d'une matière de revêtement pharmaceutiquement acceptable. La masse de médicament peut être coupée en segments contenant une quantité de médicament actif qui est déterminée par la longueur du segment ; la longueur du segment et, par conséquent, la dose précise de principe actif peuvent être choisies par un médecin ou un pharmacien. Le médicament ou ses segments sont traités pour retarder la dissolution pendant une administration entérale. Un segment de médicament peut, par exemple, être encapsulé pour fournir un dosage unitaire personnalisé d'APC pour un individu particulier ou un objectif particulier, sans devoir peser les matières. L'invention concerne des médicaments appropriés pour être utilisés dans ces formes posologiques, et des procédés et des dispositifs de fabrication de ces formes posologiques.
PCT/US2013/058721 2012-09-10 2013-09-09 Compositions pharmaceutiques entérales WO2014039951A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019069194A1 (fr) * 2017-10-02 2019-04-11 Novartis Ag Procédé de production d'un support pharmaceutique
WO2022060820A1 (fr) * 2020-09-16 2022-03-24 Eli Lilly And Company Dispositif d'administration de médicament par voie orale avec bande d'expansion

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003105812A1 (fr) 2002-06-18 2003-12-24 Euro-Celtique S.A. Systeme d'administration de medicaments contre la retention gastrique comprenant un polymere extrude hydratable
US6685962B2 (en) 1999-11-29 2004-02-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Gastroretentive controlled release pharmaceutical dosage forms
US20050175699A1 (en) * 2002-05-15 2005-08-11 Cuine-Backert Marie E. Multilamellar system for the administration of active agents by means of ingestion
US20050208110A1 (en) 2004-01-30 2005-09-22 Parminder Singh Rapidly dissolving film for delivery of an active agent
US20060073190A1 (en) 2004-09-30 2006-04-06 Carroll Thomas J Sealed, edible film strip packets and methods of making and using them
WO2007000070A1 (fr) 2005-06-29 2007-01-04 Swissqual License Ag Dispositif et procede destines a evaluer la qualite d'un telephone mobile ou d'un reseau de telephonie mobile
WO2007083309A2 (fr) 2006-01-18 2007-07-26 Intec Pharma Ltd. Procédé et appareil permettant de former des dispositifs d'administration pour la prise orale d'un agent
EP1920768A1 (fr) * 2006-11-10 2008-05-14 Abbott GmbH & Co. KG Forme de dosage solide comprenant un film avec un agent actif et méthode de production
WO2010064100A1 (fr) * 2008-12-04 2010-06-10 Intec Pharma Ltd. Système d’administration de médicament à rétention gastrique de baclofène

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6685962B2 (en) 1999-11-29 2004-02-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Gastroretentive controlled release pharmaceutical dosage forms
US20050175699A1 (en) * 2002-05-15 2005-08-11 Cuine-Backert Marie E. Multilamellar system for the administration of active agents by means of ingestion
WO2003105812A1 (fr) 2002-06-18 2003-12-24 Euro-Celtique S.A. Systeme d'administration de medicaments contre la retention gastrique comprenant un polymere extrude hydratable
US20050208110A1 (en) 2004-01-30 2005-09-22 Parminder Singh Rapidly dissolving film for delivery of an active agent
US20060073190A1 (en) 2004-09-30 2006-04-06 Carroll Thomas J Sealed, edible film strip packets and methods of making and using them
WO2007000070A1 (fr) 2005-06-29 2007-01-04 Swissqual License Ag Dispositif et procede destines a evaluer la qualite d'un telephone mobile ou d'un reseau de telephonie mobile
WO2007083309A2 (fr) 2006-01-18 2007-07-26 Intec Pharma Ltd. Procédé et appareil permettant de former des dispositifs d'administration pour la prise orale d'un agent
EP1920768A1 (fr) * 2006-11-10 2008-05-14 Abbott GmbH & Co. KG Forme de dosage solide comprenant un film avec un agent actif et méthode de production
WO2010064100A1 (fr) * 2008-12-04 2010-06-10 Intec Pharma Ltd. Système d’administration de médicament à rétention gastrique de baclofène

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHATURVEDI ET AL., CURRENT DRUG DELIVERV, vol. 8, 2011, pages 373 - 380
KUNTE, J. PHARM. BIOALLIED SCI., vol. 2, no. 4, October 2010 (2010-10-01), pages 325 - 28
SIDDIQUI ET AL., ADVANCES IN BIOL. RES., vol. 5, no. 6, 2011, pages 291 - 303

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019069194A1 (fr) * 2017-10-02 2019-04-11 Novartis Ag Procédé de production d'un support pharmaceutique
CN111182892A (zh) * 2017-10-02 2020-05-19 诺华股份有限公司 用于生产药物载体的方法
WO2022060820A1 (fr) * 2020-09-16 2022-03-24 Eli Lilly And Company Dispositif d'administration de médicament par voie orale avec bande d'expansion

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