WO2003092661A1 - Administration multiplhasique par l'absorption transmucosale d'anorexiants et de medicaments de reduction de l'etat de manque - Google Patents

Administration multiplhasique par l'absorption transmucosale d'anorexiants et de medicaments de reduction de l'etat de manque Download PDF

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Publication number
WO2003092661A1
WO2003092661A1 PCT/US2003/013101 US0313101W WO03092661A1 WO 2003092661 A1 WO2003092661 A1 WO 2003092661A1 US 0313101 W US0313101 W US 0313101W WO 03092661 A1 WO03092661 A1 WO 03092661A1
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WIPO (PCT)
Prior art keywords
active
composition
buffer
minutes
release
Prior art date
Application number
PCT/US2003/013101
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English (en)
Inventor
John M. Pinney
Edward J. Cone
Original Assignee
Npd Llc
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Npd Llc filed Critical Npd Llc
Priority to AU2003231156A priority Critical patent/AU2003231156A1/en
Publication of WO2003092661A1 publication Critical patent/WO2003092661A1/fr

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Classifications

    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the present invention concerns a composition for oral administration of an active for appetite suppression.
  • the composition comprises a carrier, an active or medicament for appetite suppression, and a buffer.
  • the carrier may be a gum, a lozenge, a candy or a tablet suitable for administration in an oral cavity.
  • the buffer is water-soluble, and facilitates bi-phasic release of the active for transmucosal absorption.
  • a method of delivering the active for appetite suppression in a bi-phasic manner is also provided.
  • Delivery systems containing medicaments, or actives, for oral administration are sometimes administered through a carrier, such as a chewing gum matrix, a lozenge, a tablet or a candy.
  • a carrier such as a chewing gum matrix, a lozenge, a tablet or a candy.
  • Formulations permit release of the active over time as the product is masticated or manipulated in the mouth.
  • the action of saliva further facilitates release of the active, which may then be absorbed by the mucous membranes lining the mouth, throat, larynx and esophagus.
  • a problem with many delivery system formulations is that they fail to deliver an adequate dosage of active in the appropriate manner over the entire dosing interval. This results in insufficient active being absorbed into the bloodstream for effective therapeutic or pharmacological actions. There are many reasons for inadequate dosing. Many formulations release the active slowly over time in a more or less continuous fashion. Other formulations may retain a significant portion of the active during the prescribed dosing period, resulting in inadequate dosing of the patient. Further, the carrier chosen to contain and subsequently release the active may not perform optimally. For example, a gum prepared from a gum base may be difficult to chew or be unusually hard, thereby damaging the teeth and gums.
  • the amount of active absorbed is partially related to the chewing or manipulation rate of the gum or lozenge, and the time the saliva is held in the mouth.
  • these variables are significant only at the extremes of rapid versus slow manipulation, and frequent versus infrequent swallowing. Outside of such extremes, these variables have relatively little impact on active absorption. For example, it generally takes approximately 10 to 30 minutes to achieve adequate blood levels of an active for appetite suppression, regardless of how a user chews or manipulates the carrier. A delay of 10 minutes or more in the release and absorption of the active, however, may be excessively long for someone who is trying to reduce food cravings. Thus, a product that delivers the appetite suppressant active too slowly may be ineffective. Many products simply fail to deliver an adequate dosing of the medication within a few minutes of administration.
  • the final product should be easy to administer and have highly suitable organoleptic properties that enhance its use.
  • the product should also contain a demonstrably reliable buffer system for maintaining a proper pH inside the mouth to permit optimal absorption of the active.
  • the present invention relates to gums, lozenges, candies, and tablets; and more particularly, to chewing gum, lozenge, candy and tablet compositions that contain orally administered medications that are released in the oral cavity for appetite suppression and food craving reductions.
  • the medications, or actives, contained in the gums, lozenges, and candies can be delivered in a multi-phase release mode.
  • the compositions also contain buffer systems that facilitate oral absorption. A rapid initial release is followed by slower release of medicament, thus creating a bi-phasic release. The initial release counters a craving, while the sustained release prevents further occurrence of the craving.
  • the buffer system is released simultaneously with the medicament, thereby facilitating transmucosal and buccal absorption of the active(s).
  • the invention thus delivers, first, rapidly an initial pharmacologically effective dose of medicine and, second, a prolonged pharmacologically sufficient dose for longer-term relief of symptoms.
  • a composition for oral administration of an active for appetite suppression comprises a carrier, an active or medicament for appetite suppression, and a buffer.
  • the carrier may be a gum, a lozenge, a candy or a tablet suitable for administration in an oral cavity.
  • the buffer is water-soluble, and facilitates bi-phasic release of the active for transmucosal absorption.
  • a method of delivering a medicament for appetite suppression in a bi-phasic manner is also provided.
  • a carrier suitable for oral administration is provided having an active for appetite suppression, as well as a buffer.
  • a first, rapid pharmacologically effective dose of the active is released in an oral cavity for a first period of time.
  • a second, prolonged pharmacologically sufficient dose of the active is thereafter released in the oral cavity for a second period of time longer than the first period of time.
  • Figure 1 is a graph showing a bi-phasic release of an active over a period of time according to an exemplary embodiment of the present invention.
  • a transmucosal delivery system composition comprises a carrier suitable for oral administration.
  • the carrier is preferably one of a chewing gum, lozenge, candy, and tablet, all of which are suitable for oral administration to a human.
  • a buffer is dispersed within the carrier. There is sufficient buffer to achieve a predetermined pH within the oral cavity of a user.
  • a suitable buffer for basic active ingredients is potassium carbonate, although calcium and sodium based buffers may also be used.
  • Preferably the buffer and the active are uniformly distributed within the carrier.
  • an active is also dispersed within the carrier, at least a portion of the active being unionized at the predetermined pH for transmucosal absorption within the oral cavity.
  • the active is a medicament for appetite suppression, preferably selected from the group of central nervous system stimulants including d-amphetamine, 1- amphetamine, mixtures of d- and 1-amphetamine, ephedrine, pseudoephedrine, d- methamphetamine, 1-methamphetamine, mixtures of d- and 1-methamphetamine, phenylpropanolamine, propylhexadrine, related phenylethylamine derivatives, phentermine, phendimetrazine, and sibutramine. It should be understood that other actives may be provided for relief from other symptoms, cravings, conditions, or provide like therapeutic effect.
  • the composition of the present invention is a multi-phasic delivery system for medicament in gums, lozenges, candies, and tablets, and a method for making those delivery systems.
  • the delivery is multi-phasic because the active is delivered at different dosing rates, via different forms of the active ingredient, or other than at a constant rate.
  • the invention thus delivers, first, rapidly an initial pharmacologically effective dose of medicine over a relatively short period of time and, second, a pharmacologically sufficient sustained dose for longer-term relief of symptoms, conditions or provision of therapeutic effect over a sustained period of time.
  • FIG. 1 An exemplary embodiment of the release profile of the delivery system of the present invention is best shown in Figure 1.
  • the percentage by weight of active released of the total active in the composition is compared to time.
  • a first, rapid dose Dl of active is released within a predetermined period of time.
  • the predetermined time within which the first dose Dl is provided may vary.
  • the amount of active released in the first dose Dl may also vary as desired.
  • the rate of release of active may vary.
  • a second, sustained dose D2 is thereafter provided, which releases the remaining active over a desired period of time.
  • the period of time over which the second dose D2 is provided may also vary.
  • the percentage by weight of active released of the total active in the composition may also vary.
  • the primary route for delivery of the active is by the transmucosal route (sublingual, buccal, pharyngeal), although some minor amounts of active may be ingested during manipulation of the carrier (for example, chewing gum or sucking and wetting lozenges).
  • the disclosed delivery system delivers the medicament into the oral cavity for subsequent abso ⁇ tion into the bloodstream in a highly efficacious manner.
  • the speed of release of active ingredients is particularly important because a slow release rate would result in an insufficient amount being absorbed into the bloodstream for relief of symptoms, conditions or cravings, whereas an extremely rapid release rate could result in unpleasant tastes and potential undesirable side effects from the active ingredient(s). In addition, an extremely rapid release rate could overwhelm the abso ⁇ tion process and result in swallowing of significant amounts of active ingredient(s), possibly producing gastric distress.
  • a preferred release profile of appetite suppressant active from the carrier is in the range of 10-60% percent by weight ("PBW") of the total content of active within the first 10 minutes of placement into the oral cavity, more preferably at least about 25% PBW of the total content of active within the first 5 minutes.
  • the initial rapid release of active is followed by slower release of the remaining active over an additional period of 10-60 minutes, preferably at least about 20 minutes, that the delivery system remains in the mouth.
  • the overall release pattern provided by this formulation is considered a form of sustained release delivery system, wherein a continued release of active over a sustained period of time keeps the active concentration in the bloodstream at or near a pharmacologically effective concentration.
  • sustained release assures relief from cravings or other discomforts.
  • the two doses help to prevent a relapse, a situation frequently encountered where cravings, etc. are environmentally induced.
  • the pattern of release of buffer chemicals likewise is important to the invention, because of the need to control oral pH.
  • Many active ingredient components of medicaments that may be inco ⁇ orated into the delivery system are sensitive to pH conditions.
  • Medicaments that contain basic nitrogen moieties in their structure may demonstrate a pKa in the range of 3 to 11.
  • acidic pH conditions in the mouth pH 6.0 to pH 7.0
  • many of the useful compounds would be highly ionized and would not be efficiently absorbed into the bloodstream by the transmucosal route.
  • Buffer chemicals such as alkali carbonates rapidly elevate the pH of saliva in the mouth, and provide favorable pH conditions for efficient abso ⁇ tion of active ingredients.
  • Buffering agents are those compounds that assist in release and conversion of an active from an ionized state ("ionized active") to an unionized state (“unionized active”). Passage of actives across the mucous membranes inside the mouth to the bloodstream is due primarily to passive diffusion of unionized active. Upon release from the carrier into the mouth, some active ingredients will be highly ionized as a result of pH characteristics or oral fluids, while others will be primarily neutral or unionized. The unionized form of active is absorbed through the oral mucosa. As the buffer is also released, and dissolves in the mouth with the active, the pH in the oral cavity may be controlled.
  • the buffer material should be released in sufficient amounts with the release of the active to create a basic or alkaline pH environment inside the mouth, thereby unionizing the active and facilitating effective delivery of the active. Consequently, conversion of the active from ionized to unionized in mouth saliva is an important step in providing adequate blood levels of the appetite suppressant active.
  • Buffer compounds assist with this conversion by raising the pH and thereby facilitating abso ⁇ tion of the medicament.
  • use of potassium carbonate buffer in the delivery vehicle alters the mouth pH conditions to approximately 7-10 and provides a suitable environment for efficient abso ⁇ tion of most active ingredients containing basic nitrogen groups. Any one or combination of nontoxic potassium, sodium, calcium, magnesium or aluminum salts may be used to elevate mouth pH conditions.
  • the buffer preferably comprises about 0.1 to 10% of the total delivery system composition, and desirably will be within the range of about 0.5 to 5% thereof.
  • Table 1 demonstrates the dose of various appetite suppressant actives suitable for abso ⁇ tion through the buccal mucosa within the first 5 minutes after oral administration when oral pH is raised to 9, as well as the percentage of each active that would be absorbed.
  • the relatively long half-lives of the medicaments listed in Table 1 provide sustained symptom relief for several hours after the product has been removed from the mouth or completely dissolved.
  • compositions may desirably deliver about 60% of their active content within 10 minutes of oral manipulation, and up to about 90%>, more preferably 100%>, of their active content within about 50 minutes, more desirably within about 30 minutes. In this way, a prolonged loaded concentration of the appetite
  • the buffer be chosen so as to yield a pH in excess of at least about 7.5 inside the mouth, and even more desirably in excess of about 8.0, or even greater than about 8.5.
  • a pH level of at least about 9.0 is particularly preferred inside the mouth after about 10 minutes, more preferably after about 5 minutes from the onset of mastication or manipulation. Even more desirable is a pH of at least about 9.0 after about 3 minutes, and especially after about 1 minute.
  • the buffer system is preferably optimized in conjunction with the other components of the formulation so that it does not result in excessive release of active inside the mouth, which may overwhelm the user.
  • the quantity and type of buffer materials furthermore should not cause unpleasant organoleptic side effects, such as irritation, coughing or choking, etc.
  • the carrier of a composition containing medicament may be a chewing gum.
  • One benefit of using chewing gum as the carrier is the potential for lower abuse liability of formulations containing potentially abusable drugs as the active (e.g., amphetamine, methamphetamine). Specifically, substantial effort would be required to remove the active from the gum matrix for intravenous administration or abuse of the product. This benefit also would be applicable to lozenge formulations, though to a slightly lesser degree.
  • the gum matrix is preferably comprised of a chewing gum base having hydrophobic and relatively hydrophilic components, a water soluble portion that preferably includes sweeteners and an active(s), fillers that may be insoluble or partially water soluble, and water insoluble flavorants and colorants.
  • water-soluble buffer chemicals are added to control the pH conditions in the mouth.
  • One or more gum base materials that are at least partially hydrophilic in nature are especially desirable. It is even more preferred that the material have significant hydrophilic characteristics.
  • polyvinyl acetate is particularly preferred.
  • low to medium weight polyvinyl acetate such as polyvinyl acetate having a molecular weight (MW) of about 12,000 to 45,000.
  • MW molecular weight
  • the amount of polyvinyl acetate (PVA) in the gum base is maximized, and the quantity of non-PVA polymers such as butadiene- styrene, butylene-based polymers and copolymers is preferably minimized.
  • the gum base matrix may comprise from about 40 to 90%> by weight of the total composition of the invention, preferably less than about 70%> by weight, more preferably about 50 to 60% by weight of the total composition.
  • the gum base matrix may additionally contain other ingredients well known in the art and selected from the group consisting of plasticizers and softeners to help reduce the viscosity of the gum base to a desirable consistency and to improve the overall texture and bite. These compounds are also noted for their emulsifying properties. As non- limiting examples, compounds such as lecithin, mono- and diglycerides, lanolin, stearic
  • plasticizers and softeners are desirable as part of the formulation because in addition to softening the primary gum base polymeric compound, they also seem to facilitate release of the active upon mastication. When added, the plasticizers and softeners will comprise from about 0.1 to 20% of the gum base matrix formulation, and more desirably will be within the range of about 5-15%) thereof.
  • the gum base matrix may also comprise both natural and synthetic hydrophobic elastomers and rubbers, natural and synthetic resins, fats, oils, waxes, and inorganic fillers.
  • the elastomers and resins may be selected from the many gum base materials known in the art including naturally-derived products such as chicle, julutong, and gutta percha and synthetic materials such as butyl rubber, polyisobutylene, isobutylene, butadiene-styrene copolymers, polyethylene, polyvinylesters such as polyvinyl acetate, and mixtures of any of the foregoing.
  • Other materials which may be included as part of the gum base matrix include elastomer solvents.
  • rosin and resin material typically utilized in the confectionery chewing gum industry.
  • examples include methyl, glycerol, and pentaerythritol esters of rosins or modified rosins, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof.
  • More specific examples include pentaerythritol ester of partially hydrogenated wood rosin, pentaerythritol ester of wood rosin, glycerol ester of wood rosin, glycerol ester of partially dimerized rosin, glycerol ester of polymerized rosin, glycerol ester of tall oil rosin, glycerol ester of wood rosin and partially hydrogenated wood rosin and partially
  • Elastomer solvents can comprise from about zero to 75% of the gum base. It is preferable, however, to minimize or even eliminate the quantity of rosin/resin in the gum base. It is especially desirable not to exceed about 10%> by weight of the gum base matrix with rosin/resin compound(s).
  • Filler material may be selected to enhance the chewability of the final chewing gum composition. In at least some embodiments, certain filler material may also enhance the release and abso ⁇ tion of nicotine and other tobacco alkaloids.
  • Desirable filler materials will therefore include calcium carbonate, magnesium silicate (talc), as well as dicalcium phosphate, and any mixtures thereof. Particularly preferred may be dicalcium phosphate.
  • Other metallic mineral salts may also be utilized as filler material, as for example alumina, aluminum hydroxide, and aluminum silicates, provided they possess the characteristics heretofore set forth.
  • Filler material will typically comprise about 0.1 to 30%> of the gum base matrix, and more preferably will be within the range of about 10 to 20%> thereof.
  • BHT butylated hydroxy toluene
  • Such ingredients are well known in the art and are selected to adjust the gum base consistency to a desirable consistency for overall gum texture and chewability.
  • the gum base be constructed to provide an initial soft chew that continues to be relatively soft-chewing throughout 30 to 45 minutes of
  • the characteristics of a soft-chewing gum base facilitate the ability of the individual chewer to exert control over the amount and speed of release of active ingredient(s) during the chewing period.
  • An additional desirable feature of the gum base is the ability to release reliably a portion of the active ingredient(s) during the early stages of chewing.
  • the gum base allows release of 10-60%> of the initial dose of active ingredient(s) within the first 10 minutes of chewing.
  • the composition in all its embodiments can be soft and pliable inside the mouth, both upon initial chew and after prolonged mastication.
  • the formulation be substantially non-liquid as well. That is, the formulation of the invention is substantially 0%> liquid.
  • chewing gum formulations comprise three major components. These are gum base, solids and liquids. By excluding substantially all liquid from the formulation, incompatibility problems between the various components, and the concomitant problems of instability (especially of the active materials), migration and interaction among the actives, flavors, sweeteners and buffers, etc, can often be avoided.
  • the bulk sweeteners may constitute about 20-80%) by weight of the chewing gum and are preferably sugarless sweeteners. Such ingredients are well known in the art and are selected to impart improved palatability to the chewing gum and to aid in masking the bitter or unpleasant taste of some actives and/or dietary supplements.
  • flavorants may be used in the chewing gum within the range of 0.1 - 10% by weight, preferably between about 0.5-4%> by weight of the chewing gum.
  • the flavoring agents may include natural and synthetic agents and all such combinations thereof.
  • Colorants may include food and pharmaceutical grade coloring agents.
  • the chewing gum composition of the invention include, for example, various centerfill configurations.
  • the gum base matrix will at least partially surround a centerfill.
  • the centerfill will contain one or more of the active substances.
  • the centerfill may be a liquid or semi- liquid material and preferably will be low fat or fat free.
  • the centerfill may contain one or more sweeteners and/or flavorants as heretofore described.
  • a combination of saccharide material, flavoring, polyol and edible gel material is one example of a centerfill.
  • One or more of the active ingredient(s) and/or the sweeteners and flavorants, etc. may be encapsulated as previously set forth, and then inco ⁇ orated into the centerfill.
  • the centerfill embodiment may be particularly desirable wherein immediate release of the active is particularly desired (i.e. less than 1 minute). Encapsulating the active(s) in this embodiment may help to taste-mask those actives which provide an undesirable organoleptic sensation. Other than the centerfill portion, it is preferred that the formulation ingredients of this embodiment be substantially liquid- free, or about 0%> liquid.
  • the carrier may be a lozenge or candy.
  • lozenges and candies may be used as the multi-phasic drug delivery vehicle for medicament and buffer chemicals.
  • Lozenges and candies are flavored dosage delivery systems for medicament(s) and dietary supplements that are held in the mouth, wetted with saliva and sucked until dissolution occurs in a multi-phasic manner.
  • lozenges and candies have a base composed of a mixture of sugar and other carbohydrate bulking agents.
  • Non-fermentable sugars such as sorbitol, mannitol, xylitol, isomalt and
  • the carrier may be a tablet. Tablets are dosage delivery systems for medicament that is placed in the mouth or under the tongue for multi-phasic dissolution of the active and abso ⁇ tion through epithelial tissues.
  • a general discussion of tablet forms may be found in H.A. Lieberman, Pharmaceutical Dosage Forms, Volume 1 : Tablets (1989), Marcel Dekker, Inc., New York, N.Y. at Medicated Confections, pages 719-582, which disclosure is inco ⁇ orated herein by reference.
  • the carrier may be a tablet. Tablets are dosage delivery systems for medicament that is placed in the mouth or under the tongue for multi-phasic dissolution of the active and abso ⁇ tion through epithelial tissues.
  • a general discussion of tablet forms may be found in H.A. Lieberman, Pharmaceutical Dosage Forms, Volume 1 : Tablets (1989), Marcel Dekker, Inc., New York, N.Y. at Medicated Confections, pages 75-418, which disclosure is inco ⁇ orated herein

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Abstract

La présente invention a trait à une composition pour l'administration orale d'un anorexiant actif. La composition comporte un support, un principe actif ou médicament de suppression d'appétit, et une solution tampon. Le support peut être une gomme, une pastille, un bonbon ou un comprimé apte à l'administration par la cavité buccale. La solution tampon est hydrosoluble et facilite la libération diphasique du principe actif pour l'absorption transmucosale. L'invention a trait également à un procédé d'administration diphasique du principe actif pour la suppression d'appétit.
PCT/US2003/013101 2002-04-30 2003-04-30 Administration multiplhasique par l'absorption transmucosale d'anorexiants et de medicaments de reduction de l'etat de manque WO2003092661A1 (fr)

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Application Number Priority Date Filing Date Title
AU2003231156A AU2003231156A1 (en) 2002-04-30 2003-04-30 Multi-phasic delivery via transmucosal absorption of appetite suppressants and craving reduction medicaments

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US37622202P 2002-04-30 2002-04-30
US60/376,222 2002-04-30

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071501A1 (fr) * 2003-02-10 2004-08-26 Shire Biochem Inc. Compositions enantiomeriques d'amphetamine pour traiter l'adhd

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5472711A (en) * 1992-07-30 1995-12-05 Edward Mendell Co., Inc. Agglomerated hydrophilic complexes with multi-phasic release characteristics
WO2001089476A1 (fr) * 2000-05-19 2001-11-29 Npd Llc Gommes a macher, pastilles, bonbons, tablettes, liquides et sprays destines a une administration efficace de medicaments et de supplements dietetiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5472711A (en) * 1992-07-30 1995-12-05 Edward Mendell Co., Inc. Agglomerated hydrophilic complexes with multi-phasic release characteristics
WO2001089476A1 (fr) * 2000-05-19 2001-11-29 Npd Llc Gommes a macher, pastilles, bonbons, tablettes, liquides et sprays destines a une administration efficace de medicaments et de supplements dietetiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE HCAPLUS [online] PINNEY ET AL.: "Chewing gums, lozenges, candies, tablets, liquids and sprays for efficient delivery of medications and dietary supplements", XP002968342, accession no. STN Database accession no. 2001:868177 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071501A1 (fr) * 2003-02-10 2004-08-26 Shire Biochem Inc. Compositions enantiomeriques d'amphetamine pour traiter l'adhd

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