WO2008065144A2 - Préparations galéniques de composés organiques - Google Patents

Préparations galéniques de composés organiques Download PDF

Info

Publication number
WO2008065144A2
WO2008065144A2 PCT/EP2007/062960 EP2007062960W WO2008065144A2 WO 2008065144 A2 WO2008065144 A2 WO 2008065144A2 EP 2007062960 W EP2007062960 W EP 2007062960W WO 2008065144 A2 WO2008065144 A2 WO 2008065144A2
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
pth
form according
delivery
excipient
Prior art date
Application number
PCT/EP2007/062960
Other languages
English (en)
Other versions
WO2008065144A3 (fr
Inventor
Begona Carreno-Gomez
Original Assignee
Novartis Ag
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 Novartis Ag filed Critical Novartis Ag
Publication of WO2008065144A2 publication Critical patent/WO2008065144A2/fr
Publication of WO2008065144A3 publication Critical patent/WO2008065144A3/fr

Links

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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • 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
    • A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a dosage form for transmucosal delivery of parathyroid hormone (PTH).
  • the mammalian parathyroid hormones e.g. human (hPTH), bovine (bPTH) and porcine (pPTH) are single polypeptide chains of 84 amino acid residues having molecular weights of approximately 9500.
  • the present invention relates to PTH fragments incorporating at least the first 28 N-terminal amino acid residues (PTH (1 - 28)) up to and including the first 41 N-terminal amino acid residues (PTH (1 -41 )).
  • the present invention also relates to the use of these hormones and fragments thereof as medicaments.
  • the instant invention is directed to a pharmaceutical composition for transmucosal delivery comprising a therapeutically effective amount of a PTH fragment, said PTH fragment selected from PTH (1 -28) to PTH (1 -41 ).
  • a PTH fragment selected from PTH (1 -28) to PTH (1 -41 ).
  • the PTH is human parathyroid hormone, hPTH.
  • the PTH fragments can be of any parathyroid hormone, particularly mammalian parathyroid hormone, e.g.
  • hPTH human
  • bovine bovine
  • porcine pPTH and particularly hPTH and will incorporate at least the first 28 N-terminal residues (PTH (1 -28)) up to and including the first 41 N-terminal residues (PTH (1 -41 )) and include without limitation PTH (1 -28), PTH (1 -31 ), PTH (1 -34), PTH (1 -37), PTH (1 -38) and PTH (1 -41 ).
  • Human parathyroid hormone (1 -34) is particularly preferred. These parathyroid hormone fragments are commercially available or can be obtained recombinantly or by peptide synthesis.
  • the invention is directed to a method for transmucosal delivery of an effective dose of PTH comprising orally administering to a patient in need of PTH a pharmaceutical composition comprising a therapeutically effective amount of a PTH fragment, said PTH fragment selected from PTH (1 -28) to PTH (1 -41 ).
  • the invention is also directed to a method of stimulating new bone formation comprising orally administering to a patient in need of new bone formation a pharmaceutical composition comprising a therapeutically effective amount of a PTH fragment, said PTH fragment selected from PTH (1 -28) to PTH (1 -41 ).
  • the invention is directed to a method of treatment or prevention of osteoporosis comprising orally administering to a patient in need of said treatment or prevention a pharmaceutical composition comprising a therapeutically effective amount of a PTH fragment, said PTH fragment selected from PTH (1 -28) to PTH (1 -41 ).
  • oral administration of such pharmaceutical agents as tablets or capsules has certain advantages over parenteral administration such as i.v. or i.m. Diseases requiring treatment with painful injectable formulations are considered to be more serious than those conditions which can be treated with oral dosage forms.
  • parenteral formulations have to be administered in most cases by a physician or paramedical personnel.
  • PTH is difficult to formulate and heretofore it is not trivial to prepare oral formulations in the form of tablets in a reliable and robust way.
  • a galenic formulation comprising PTH, or a pharmaceutically acceptable salt thereof, a high amount is normally needed of the drug substance (DS) with properties that make the formulation of tablets difficult.
  • DS drug substance
  • the bioavailability of the therapeutic agent may be reduced by the action of so-called “efflux pump” proteins which actively eject foreign substances from the cell to give rise, for example, to the multidrug resistance effect.
  • These drug efflux proteins principally comprise MDR (multidrug resistance protein) and MRP (multidrug resistance associated protein) type transporters.
  • MDR multidrug resistance protein
  • MRP multidrug resistance associated protein
  • Some of the best studied efflux proteins include P-glycoprotein (Pgp or MDR1 ) and MRP2.
  • the present invention relates to a dosage form for transmucosal administration of PTH, or a pharmaceutically acceptable salt thereof, comprising a therapeutically effective amount of PTH, or a pharmaceutically acceptable salt thereof and an excipient for transmucosal delivery, wherein the active ingredient is present in an amount of 0.001 to 80% based on the total weight of the dosage form.
  • the bioavailability of PTH may be improved by changing the absorption site from oral to transmucosal, such as buccal, nasal, ocular or vaginal, absorption sites.
  • this route does not have the disadvantages such as hepatic first pass metabolism and enzymatic degradation within the Gl tract, that prohibit or hinder the oral administration of certain classes of drugs.
  • Transmucosal routes of drug delivery i.e., the mucosal linings of the nasal, rectal, vaginal, ocular, and oral cavity
  • These advantages include possible bypass of first pass effect, avoidance of presystemic elimination within the Gl tract and a better enzymatic flora for drug absorption.
  • the dosage form is a delivery system for transmucosal delivery using the oral mucosal cavity and buccal delivery.
  • delivery of drugs is classified into three categories: (i) sublingual delivery, which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth, (ii) buccal delivery, which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa), and (iii) local delivery, which is drug delivery into the oral cavity.
  • sublingual delivery which is systemic delivery of drugs through the mucosal membranes lining the floor of the mouth
  • buccal delivery which is drug administration through the mucosal membranes lining the cheeks (buccal mucosa)
  • local delivery which is drug delivery into the oral cavity.
  • buccal and sublingual delivery is the most preferred .
  • the dosage form is a delivery system for transmucosal delivery using the nasal cavity (nasal delivery).
  • Preferred examples for delivery by the transmucosal route are sprays, lozenges, capsules, such as soft bite capsules, tablets, such as rapidly disintegrating tablets, in particular lyophilized disintegrating tablets, effervescent oral dosage forms, chewing gums, such as natural gums, thin films, patches, such as bioerodible patches, powders or drops.
  • sprays suitable for the present invention are disclosed, e.g. WO05/032520, WO05/030167, WO05/032517 and WO05/032518.
  • Exemplary sprays may be aerosol sprays or pump sprays.
  • the mucosal membranes are typically coated with fine droplets of spray containing the active compound.
  • a spray may preferably contain PTH in an amount of 0.001 to 60%, more preferably 0.01 to 50 %, most preferably 0.05 to 40%, of the total composition.
  • a solvent is present as an excipient.
  • the solvent can be a non-polar or polar solvent or a mixture of these solvent.
  • the solvent is typically present in an amount of 10 to 99.99%, more preferably 20 to 99.8%, most preferably 30 to 99 %, of total composition. If the spray is a propellant-free spray, such as a pump spray, then the solvent may make up the remaining amount present in addition to PTH.
  • the non-polar solvent is a non-polar hydrocarbon, preferably a C e hydrocarbon of a linear or branched configuration, fatty acid esters, and triglycerides, such as miglyol.
  • the solvent must dissolve the active compound and be miscible with the propellant, i.e., solvent and propellant must form a single phase at a temperature of 0-40 9 C a pressure range of between 1 -3 atm.
  • Suitable non-polar solvents include non-polar hydrocarbons, such as C 7 toC 18 linear or branched hydrocarbons, fatty acid esters, such as C 2 toC 24 fatty acid C 2 -C 6 esters, C 2 to C 6 alkanoyl esters, and the triglycerides of the corresponding acids, such as miglyol.
  • polar solvents there may be used low molecular weight polyethyleneglycols (PEG) of 400-1000 Mw (preferably 400- 600), low molecular weight (C 2 -C 8 ) mono and polyols and alcohols of C 7 -Ci 8 linear or branch chain hydrocarbons, glycerin may also be present and water may also be used in the sprays.
  • the solvent must dissolve the active compound. If a propellant is present, the solvent must be miscible with the propellant, i.e., solvent and propellant must form a single phase at a temperature of 0-40 °C a pressure range of between 1 -3 atm.
  • the spray may contain further excipients, e.g. an aerosol spray may contain a propellant.
  • the propellant may be present preferably in an amount of 5 to 80%, more preferably 10 to 70 %, of the total composition.
  • the propellant is a non-Freon material, preferably a C 3 to C 8 hydrocarbon of a linear or branched configuration.
  • the propellant should be substantially non-aqueous.
  • the propellant produces a pressure in the aerosol container such that under expected normal; usage it will produce sufficient pressure to expel the solvent from the container when the valve is activated but not excessive pressure such as to damage the container or valve seals.
  • propellants for the non polar sprays propane, N-butane, iso- butane, N pentane, iso-pentane, and neo-pentane, and mixtures thereof may be used. It is permissible for the propellant to have a water content of no more than 0. 2%, typically 0.1 -0.2%. All percentages herein are by weight unless otherwise indicated. It is also preferable that the propellant be synthetically produced to minimize the presence of contaminants which are harmful to the active compounds. These contaminants include oxidizing agents, reducing agents, Lewis acids or bases, and water. The concentration of each of these should be less than 0.1 %, except that water may be as high as 0.2%.
  • a flavoring agent if necessary or desired may be added.
  • the flavoring agent if present, is preferably employed in an amount of 0.05 to 15 %, more preferably 0.1 to 10%, most preferably 0.5 to 8%, of the total composition.
  • the preferred flavoring agents are synthetic or natural oil of peppermint, oil of spearmint, citrus oil, fruit flavors, sweeteners (sugars, aspartame, saccharin, etc.), and combinations thereof.
  • the flavoring agent may also include a taste mask.
  • taste mask as used herein means an agent that can hide or minimize an undesirable flavor such as a bitter or sour flavor.
  • a representative taste mask is a combination of vanillin, ethyl vanillin, malted, iso-amyl acetate, ethyl oxyhydrate, anisic aldehyde, and propylene glycol (commercially available as "PFC 9885 Bitter Mask” from Pharmaceutical Flavor Clinic of Camden, NJ).
  • a taste mask in combination with a flavoring agent is particularly advantageous when the active compound is an alkaloid since alkaloids often have a bitter taste.
  • soft bite capsules suitable for the present invention are disclosed, e.g. WO99/016417.
  • the mucosal membranes are typically coated with a solution or paste of the capsule containing the active compound.
  • the composition of the soft bite capsules with respect to the amounts and types of excipients is similar to the above-described spray.
  • the capsule should contain not more than 10% water.
  • other liquid components may be used instead of the above low molecular weight solvents. These include soya oil, corn oil, other vegetable oils.
  • rapidly disintegrating tablets suitable for the present invention are disclosed, e.g. in US patents US5976577, US6413549, US6680071 and US6509040.
  • rapidly disintegrating means that the solid dosage form will disintegrate in water at 37.degree. C. in 60 seconds or less.
  • the forms usually disintegrate in about 5-20 seconds, more usually 5 to 10 seconds or less, when tested by the following procedure which is analogous to the Disintegration Test for Tablets, B. P. 1973 which is described in British patent number 1548022..
  • a rapidly disintegrating tablet may preferably contain PTH in an amount of 0.1 to 98%, more preferably 1 to 90 %, most preferably 10 to 60%, of the total composition.
  • the rapidly disintegrating tablet may contain a carrier material for PTH.
  • the carrier material allows to form structure which will lead to the rapid disintegration of the table.
  • the carrier material which forms a network or matrix containing PTH may be any water-soluble or water-dispersible material that is pharmaceutically acceptable, inert to the pharmaceutically active substance and which is capable of forming a rapidly disintegrating network, i.e. disintegrates within 10 seconds or less in the mouth.
  • the preferred carrier material for use in the present invention is gelatin, usually pharmaceutical grade gelatin.
  • carrier material substances may be used as the carrier material are, for example, hydrolyzed dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, corn-syrup solids, pectin, carrageenan, agar, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, conjac flower, rice flower, wheat gluten, sodium starch glycolate, soy fiber protein, potato protein, papain, horseradish peroxidase, glycine and mannitol. Most preferably, gelatin is used.
  • the tablets may contain a coating on the PTH particles.
  • the coating on the particles is a polymer or lipid material and serves to prevent loss of the pharmaceutical agent during processing, as well as delaying release of the pharmaceutically active substance beyond the point of disintegration of the form in the mouth. Any suitable polymer or lipid or combination can be used as the coating material.
  • suitable polymers include cellulose and derivatives such as ethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, cellulose acetate, cellulose acetate phthalate, hydroxypropylmethylcellulosephthalate, acrylic derivatives, such as polymethacrylates, polyglycolic-polylactic acid, polyvinylalcohol, gelatin, collagen and polyethyleneglycol.
  • suitable lipid materials include waxes such as beeswax and lanolin, stearic acid and derivatives such as glycerol esters, fixed oils, fats, phospholipids, and glycolipids
  • An agent may be added to the suspension when forming the rapidly disintegrating tablet which gives increased structural integrity to the matrix.
  • the structure-forming agent is typically a polyhydric alcohol, for example mannitol or sorbitol.
  • the structure-forming agent is normally added to the suspension in an amount of about 1 -5% by weight, for example about 2-4% by weight.
  • Preferred is a lyophilized rapidly disintegrating tablet.
  • effervescent tablets suitable for the present invention are disclosed, e.g. in WO00/57858.
  • An effervescent tablet may preferably contain PTH in an amount of 0.1 to 98%, more preferably 1 to 90 %, most preferably 10 to 60%, of the total composition.
  • the effervescent tablets should include as an excipient an effervescent.
  • the effervescent is present in an amount o effective to aid in penetration of the drug across the oral mucosa.
  • the effervescent is provided in an amount of between about 5% and about 95% by weight, based on the weight of the finished tablet, and more preferably in an amount of between about 30% and about 80% by weight. It is particularly preferred that sufficient effervescent material be provided such that the evolved gas is more than about 5 cm 3 but less than about 30 cm 3 , upon exposure of the tablet to an aqueous environment.
  • effervescent includes compounds which evolve gas.
  • the preferred effervescent agents evolve gas by means of a chemical reaction which takes place upon exposure of the effervescent agent (an effervescent couple) to water and/or to saliva in the mouth. This reaction is most often the result of the reaction of a soluble acid source and a source of carbon dioxide such as an alkaline carbonate or bicarbonate. The reaction of these two general compounds produces carbon dioxide gas upon contact with water or saliva.
  • Such water- activated materials must be kept in a generally anhydrous state and with little or no absorbed moisture or in a stable hydrated form, since exposure to water will prematurely disintegrate the tablet.
  • the acid sources may be any which are safe for human consumption and may generally include food acids, acid and hydrite antacids such as, for example: citric, tartaric, amalic, fumeric, adipic, and succinics.
  • Carbonate sources include dry solid carbonate and bicarbonate salt such as, preferably, sodium bicarbonate, sodium carbonate, potassium bicarbonate and potassium carbonate, magnesium carbonate and the like. Reactants which evolve oxygen or other gasses and which are safe for human consumption are also included.
  • the effervescent agent(s) used in the present invention is not always based upon a reaction which forms carbon dioxide.
  • the effervescent includes two mutually reactive components, such as an acid source and a carbonate source, it is preferred that both components react completely. Therefore, an equivalent ratio of components which provides for equal equivalents is preferred. For example, if the acid used is diprotic, then either twice the amount of a mono- reactive carbonate base, or an equal amount of a di-reactive base should be used for complete neutralization to be realized. However in other embodiments of the present invention, the amount of either acid or carbonate source may exceed the amount of the other component. This may be useful to enhance taste and/or performance of a tablet containing an overage of either component. In this case, it is acceptable that the additional amount of either component may remain unreacted.
  • the present dosage forms may also include in amounts additional to that required for effervescence a pH adjusting substance.
  • a pH adjusting substance For drugs that are weakly acidic or weakly basic, the pH of the aqueous environment can influence the relative concentrations of the ionized and unionized forms of the drug present in solution according to the Henderson-Hasselbach equation.
  • the pH solutions in which an effervescent couple has dissolved is slightly acidic due to the evolution of carbon dioxide.
  • the pH of the local environment e.g., saliva in immediate contact with the tablet and any drug that may have dissolved from it, may be adjusted by incorporating in the tablet a pH adjusting substances which permit the relative portions of the ionized and unionized forms of the drug to be controlled.
  • the present dosage forms can be optimized for each specific drug. If the unionized drug is known or suspected to be absorbed through the cell membrane (transcellular absorption) it would be preferable to alter the pH of the local environment (within the limits tolerable to the subject) to a level that
  • Suitable pH adjusting substance for use in the present invention include any weak acid or weak base in amounts additional to that required for the effervescence or, preferably, any buffer system that is not harmful to the oral mucosa.
  • Suitable pH adjusting substance for use in the present invention include, but are not limited to, any of the acids or bases previously mentioned as effervescent compounds, disodium hydrogen phosphate, sodium dihydrogen phosphate and the equivalent potassium salt.
  • a dosage form according to the present invention may also include suitable non-effervescent disintegration agents.
  • suitable non-effervescent disintegration agents include: microcrystalline, cellulose, croscarmelose sodium, - WO 00/57858 PCT/USOO/075677 crospovidone, starches, corn starch, potato starch and modified starches thereof, sweeteners, clays, such as bentonite, alginates, gums such as agar, guar, locust bean, karaya, pecitin and tragacanth.
  • Disintegrants may comprise up to about 20 weight percent and preferably between about 2 and about 10% of the total weight of the composition.
  • the dosage forms may also include glidants, lubricants, binders ' sweeteners, flavoring and coloring components. Any conventional sweetener or flavoring component may be used. Combinations of sweeteners, flavoring components, or sweeteners and flavoring components may likewise be used.
  • binders which can be used include acacia, tragacanth, gelatin, starch, cellulose materials such as methyl cellulose and sodium carboxy methyl cellulose, alginic acids and salts thereof, magnesium aluminum silicate, polyethylene glycol, guar gum, polysaccharide acids, bentonites, sugars, invert sugars and the like. Binders may be used in an amount of up to 60 weight percent and preferably about 10 to about 40 weight percent of the total composition.
  • Coloring agents may include titanium dioxide, and dyes suitable for food such as those known as F.D.&. dyes and natural coloring agents such as grape skin extract, beet red powder, beta-carotene, annato, carmine, turmeric, paprika, etc.
  • the amount of coloring used may range from about 0.1 to about 3.5 weight percent of the total composition.
  • Flavors incorporated in the composition may be chosen from synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plants, leaves, flowers, fruits and so forth and combinations thereof.
  • cinnamon oil may include cinnamon oil, oil of wintergreen, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
  • flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth.
  • Flavors which have been - WO 00/57858 PCT/USOO/07567 8 found to be particularly useful include commercially available orange, grape, cherry and bubble gum flavors and mixtures thereof.
  • the amount of flavoring may depend on a number of factors, including the organoleptic effect desired. Flavors may be present in an amount ranging from about 0.05 to about 3 percent by weight based upon the weight of the composition.
  • Particularly preferred flavors are the grape and cherry flavors and citrus flavors such as orange.
  • One aspect of the invention provides an effervescent solid, oral tablet dosage form suitable for sublingual, buccal, and gingival administration.
  • Excipient fillers can be used to facilitate tableting.
  • the filler desirably will also assist in the rapid dissolution of the dosage form in the mouth.
  • suitable fillers include: mannitol, dextrose, lactose, sucrose, and calcium carbonate.
  • thin films and patches suitable for the present invention are disclosed, e.g. in US5192802 (bioadhesive gels), US45518721 (denture adhesive pastes), US5,800,832 and 6,159, 498 and US 6585997 (bioerodible films) as well as in Amir H Shojaei et al., J Pharm Pharmaceut Sci (www.ualberta.ca/ ⁇ csps) 1 (1 ):15-30, 1998 (comprehensive review on buccal patches, including references cited therein).
  • a thin film or patch may preferably contain PTH in an amount of 0.001 to 50%, more preferably 0.002 to 30 %, most preferably 0.005 to 20%, of the total composition.
  • Thin films and patches are devices that are applied to mucosal surfaces and provide protection of the application site while delivering pharmaceuticals to treat specific diseases or disorders.
  • the device causes minimum discomfort, is easy to use and provides an effective residence time that can be tailored to deliver therapeutics over different time intervals.
  • the device comprises a mucoadhesive multi-layered film disc that is water- soluble and bioerodable.
  • the device comprises a multi-layered film having an adhesive layer and a coated backing layer containing PTH in either or both layers.
  • the film may be cut or fabricated into any desired shape, such as a disc, square, oval, parallelepiped, etc., that provides convenience for use in application and/or treatment.
  • the adhesive layer of the device is water soluble and the backing layer is bioerodible.
  • the adhesive layer preferably comprises a film-forming polymer such as hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or hydroxyethylmethyl cellulose, alone or in combination, and a bioadhesive polymer such as polyacrylic acid, polyvinyl pyrrolidone, or sodium carboxymethyl cellulose, alone or in combination.
  • the non- adhesive backing layer is preferably a precast film alone or in combination with other layers.
  • the precast film is preferably comprised of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylmethyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, ethylene oxide-propylene oxide co-polymers, or other water soluble film-forming polymer, alone or in combination thereof.
  • the precast film may also include plasticizers or other excipients required to enhance the film forming properties of the polymer.
  • the non-adhesive backing layer is further modified to render it water erodible instead of water soluble.
  • water erodible means a material or substance that does not dissolve in in water or bodily fluids in total, however will disintegrate and completely break apart upon exposure to water or bodily fluids. This is accomplished by coating the backing layer film with a more hydrophobic polymer selected from a group of Eudragit® and/or ethyl cellulose and methyl cellulose polymers that are approved by the FDA for use in pharmaceutical applications. Other hydrophobic polymers known to those skilled in the art may also be used. The type and amount of hydrophobic polymer used will provide a wide and controlled range of Residence Times for the layered disk device.
  • the modified, precast backing layer eliminates the need to use a rigid support material such as a polyethylene film or other non-porous material as the casting surface on which both the adhesive layer and backing layer are produced.
  • This casting surface is no longer an integral component of the layered device, which from a safety and production point of view, is extremely desirable.
  • the mucoadhesive erodible multi layered device comprises preferably a first water soluble adhesive layer to be placed in contact with a mucosal surface and second water erodible non- adhesive backing layer that controls residence time of the device. Residence time, the time for which device in placed on the target mucosal surface will remain substantially intact).
  • the first layer preferably comprises at least one water soluble film forming element in combination with at least one mucoadhesive polymer.
  • the second water erodible non adhesive backing layer preferably comprises a precast film containing at least one of hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, polyethylene oxide, and ethylene oxide-propylene oxide co- polymer.
  • This layer is coated with at least one hydrophobic polymer alone or in combination with at least one hydrophilic polymer, such that the layer is bioerodible.
  • the first water-soluble adhesive layer comprises at least one water-soluble film-forming polymer selected from the group consisting of hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, and hydroxyethyl methylcellulose, in combination with at least one mucoadhesive polymer selected from the group consisting of polyacrylic acid, polyvinyl pyrrolidone, and sodium carboxymethyl cellulose.
  • the second water erodible non-adhesive backing layer may act as a casing and support surface on which the adhesive layer is prepared.
  • This second layer preferably comprises a premade film of hydroxypropyl methylcullulose in combination with a coating consisting of at least one hydrophobic polymer selected from the family of Eudragit polymers, ethyl cellulose and methylcellulose alone or in combination with at least hydrophilic polymer selected from the group consisting of polyvinyl pyrrolidone, hydroxypropylmethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose and polyvinylalcohol.
  • the mucoadhesive bioerodible multilayered device o has a second water erodible non- adhesive backing layer that comprises a pre-made film of hydroxypropyl methylcullulose and a coating of a hydrophobic and hydrophilic polymer mixture at a ratio of 0.5:1 to 18:1 .
  • a more preferred ratio is 1 :0 to 10:1 .
  • the non-adhesive backing layer of the device of the present invention preferably comprises a precast film of hydroxypropyl methylcellulose with a coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1 :0 to 10:1.
  • This coating contains at least one of propylene glycol, polyethylene glycol or glycerine as a plasticizer to improve flexibility.
  • a preferred non-adhesive backing layer of the device of the present invention comprises a premade film of hydroxypropyl methylcellulose and a coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1 :0 to 10:1.
  • a preferred coating mixture contains at least one of hyaluronic acid and an alpha hydroxyl acid as a humectant to improve softness or feel.
  • a preferred humectant is glycolic acid.
  • the mucoadhesive erodible multi layered device has an non-adhesive backing layer that comprises a precast film of hydroxypopyl methylcellulose and a coating mixture of hydrophobic and hydrophilic polymers at a ratio of 1 :0 to 10:1 .
  • a preferred coating mixture contains titanium dioxide, zinc oxide or zirconium silicate as an opacifier and one or less FD& Red, Yellow, Green or Blue as a coloring agent to help distinguish the backing layer from the mucoadhesive layer.
  • the backing layer of the present device comprises a premade film of hydroxypropyl methylcellulose, a coating comprising a mixture of hydrophobic and hydrophilic polymers at a ratio of 1 :0 to 10:1 , a plasticizer and a coloring agent or an opacifier whose combined total is less than about 4% by weight of the device.
  • the mucoadhesive, erodible multi-layered device further comprises PTH within said first or second layer.
  • PTH may be incorporated within the first or second layers of the device of the present invention. These layers may each independently comprise flavoring agent to mask the taste of any pharmecutical agent or simply to improve patient compliance.
  • the delivery systems in accordance with the present invention may be used in conjunction with permeation/absorption enhancers known in the art. Suitable examples include
  • Anionic surfactants e.g. sodium lauryl sulfate, sodium laureate
  • Nonionic surfactants e.g. Polysorbate-80
  • Bile salts e.g. Sodium glycodeoxycholate, Sodium glycocholate, Sodium taurodeoxycholate, Sodium taurocholate
  • absorption enhancers are fatty acids, bile salts and surfactants. Detail of their use and amounts are provided in MORISHITA M, BARICHELLO JM, TAKAYAMA K, CHIBA Y, TOKIWA S, NAGAI T: Pluronic F-127 gels incorporating highly purified unsaturated fatty acids for buccal delivery of insulin. Int. J. Pharm. (2001 ) 212:289- 293, and TSUTSUMI K, OBATA Y, NAGAI T, LOFTSSON T, TAKAYAMA K: Buccal absorption of ergotamine tartrate using the bioadhesive tablet system in guinea pigs. InLJ. Pharm. (2002) 238:161 -170.
  • Bile salts have been used extensively as penetration enhancers, and are believed to act by the extraction of lipids or proteins from the cell wall, membrane fluidisation and reverse membrane micellation without causing major damage to the buccal mucosa.
  • VEUILLEZ F KALIA YN, JACQUES Y, DESHUSSES J, BURI P: Factors and strategies for improving buccal absorption of peptides. Eur. J. Pharm. Biopharm. (2001 ) 51 :93-109.
  • Glyceryl monooleates were reported to enhance peptide absorption by a co-transport mechanism, see for more detail LEE J, KELLAWAY W: Buccal permeation of [D-Ala2 D- Leu5]enkephalin from liquid crystalline phases of glyceryl monooloeate. Int. J. Pharm. (2000) 195:3538.
  • the lipophilic skin-penetration enhancers octisalate, padimate (both used in sun screens) and laurocapram on the buccal absorption of various drugs in vitro have been described in e.g. NICLAZZO JA, REED BL, FINNIN BC: Modification of buccal delivery following pre-treatment with skin penetration enhancers. J. Pharm. Sci. (2004) 93(8):2054- 2063, and are equally applicable.
  • the dosage form in accordance with the present invention contains PTH in a therapeutically effective amount, preferably as mentioned above for the individual dosage forms.
  • effective amount or “therapeutically effective amount” refers to the amount of the active ingredient or agent which halts or reduces the progress of the condition being treated or which otherwise completely or partly cures or acts palliatively on the condition.
  • excipients mentioned above for the individual delivery systems can be selected and used by a person skilled in the art having regard to the particular desired properties of the dosage form for transmucosal administration by routine experimentation and without any undue burden.
  • the amount of PTH fragment to be administered is generally an amount effective to e.g. stimulate new bone formation i.e. a therapeutically effective amount.
  • Parathyroid hormones are indicated for preventing or treating all bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable, e.g. osteoporosis of various genesis (e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by corticoid-steroid therapy or inactivity), fractures, osteopathy, including acute and chronic states associated with skeletal demineralization, osteo-malacia, periodontal bone loss or bone loss due to arthritis or osteoarthritis or cancer (e.g. bone metastis) or for treating hypoparathyroidism.
  • osteoporosis of various genesis e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age or by corticoid-steroid therapy or inactivity
  • fractures e.g. juvenile, menopausal, post-menopausal, post-traumatic, caused by old age
  • Parathyroid hormones are particularly indicated for preventing or treating osteoporosis of various genesis.
  • the PTH may be employed as adjunct or adjuvant to other therapy, e.g. a therapy using a bone resorption inhibitor, for example as in osteoporosis therapy, in particular a therapy employing calcium, a calcitonin or an analogue or derivative thereof, e.g. salmon, eel or human calcitonin, a steroid hormone, e.g. an estrogen, a partial estrogen agonist or estrogen-gestagen combination, a SERM (Selective Estrogen Receptor Modulator) e.g.
  • a therapy using a bone resorption inhibitor for example as in osteoporosis therapy
  • raloxifene lasofoxifene, TSE-424, FC1271 , Tibolone (Livial ®), vitamin D or an analogue thereof or an activator of PTH release, or bisphosphonates, e.g. clodronic acid, etidronic acid, pamidronic acid, aledronic acid, ibandronic acid, zoledronic acid, risedronic acid or tiludronic acid and salts and hydrates thereof.
  • clodronic acid etidronic acid, pamidronic acid, aledronic acid, ibandronic acid, zoledronic acid, risedronic acid or tiludronic acid and salts and hydrates thereof.
  • dosages for the co-administered inhibitor will of course vary depending on the type of inhibitor drug employed, e.g. whether it is a steroid or a calcitonin, on the condition to be treated, whether it is a curative or preventive therapy, on the regimen and so forth.
  • the administered amount will necessarily vary with the age, size, sex and condition of the subject to be treated, the nature and severity of the disorder to be treated and the like. However, the amount can be less than that amount when a plurality of the compositions are to be administered, i.e., the total effective amount can be administered in cumulative dosage units.
  • the amount of PTH can also be more than the effective amount when the composition provides sustained release of the pharmacologically active agent.
  • the total amount of PTH to be used can be determined by methods known to those skilled in the art. However, in general, satisfactory results will be obtained systemically at daily dosages of from about 0.001 ⁇ g/kg to about 10 mg/kg animal body weight, preferably 1 ⁇ g/kg to about 6 ⁇ g/kg body weight.
  • the exact dose of the active agent and the particular formulation to be administered depend on a number of factors, e.g., the condition to be treated, the desired duration of the treatment and the rate of release of the active agent.
  • the amount of the active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect.
  • PTH 0.01 -5 0.05-3.5 0.075-1.75 polyethylene glycol 25-70 30-60 35-50 glycerin 25-70 30-60 35-50 flavors 0.1 -10 1 -8 3-6
  • a 300 gram batch of mucoadhesive coating solution was prepared using 268.2 grams of deionized water, 5.40 grams of hydroxyethyl cellulose, Natrosol 250 L NF (B F Goodrich), 4.0 g PTH, 7.81 grams Noveon AA1 , Polycarbophil (B F Goodrich), 13. 50 grams sodium carboxymethyl cellulose, 7LF PH (B F Goodrich), 0.96 grams sodium benzoate, NF(Spectrum Chemicals), and 0.95 grams propylene glycol, USP(Spectrum Chemicals).
  • a Lighnin® mixer with an A-100 propeller was used to effectively homogenize this viscous mucoadhesive coating suspension at a speed of 1000 rpm. The resulting percentage of film forming polymer was 1.8% and the mucoadhesive polymers was 7.1%.
  • This adhesive coating suspension was used as shown below.
  • a hydrophobic coating solution was prepared using stock solutions of both polyvinylpyrrolidone, 16% w/w of PVP, USP, one million molecular weight(BASF), dissolved in ethanol, USP, 190 proof(Spectrum Chemicals), and Eudragit® RS-100 NF(quaternary ammonium acrylate/methacrylate co-polymers) (Rohm GmbH), 48% w/w of polymer dissolved in ethanol, USP, 190 proof.
  • each solution from example 3 was applied to individual precast pieces of the backing film.
  • the films were then automatically dried in the oven portion of the lab coater, and a smooth, integral layer of deposited hydrophobic/water soluble polymer resulted.
  • Each coated film was removed and put back into the frame with the uncoated side of the backing layer facing up.
  • the adhesive coating suspension from example 1. was then used to coat each of the coated backing layer samples, using a 1.2 mm. setting on the doctor blade.
  • the films were dried as before, and a second coating and drying step using the adhesive layer was conducted.
  • the gelatin and mannitol were added to the water and heated to 40. degree. C. to dissolve before allowing to cool to 23. degree. C.
  • the mix was gradually added to the PTH powder with manual mixing until a fluid suspension was formed. The remainder of the solution was then added. Stirring was maintained in a thermostated water bath at 23. degree. C.
  • a 20 ml sample was transferred to a 20 ml glass vial and allowed to stand. A sample was also taken which was then frozen rapidly at -8O.degree. C. Freeze drying was then performed using a standard cycle.
  • Example 7 Effervescent tablet containing PTH

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Endocrinology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme posologique pour administration transmuqueuse comprenant une quantité thérapeutiquement efficace de PTH ou d'un sel pharmaceutiquement acceptable de ce dernier, ainsi qu'un excipient pour l'administration transmuqueuse, l'ingrédient actif étant présent en proportion comprise entre 0,001 et 80% en poids sur la base du poids total de la forme posologique.
PCT/EP2007/062960 2006-11-29 2007-11-28 Préparations galéniques de composés organiques WO2008065144A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP06125019.7 2006-11-29
EP06125019 2006-11-29

Publications (2)

Publication Number Publication Date
WO2008065144A2 true WO2008065144A2 (fr) 2008-06-05
WO2008065144A3 WO2008065144A3 (fr) 2009-03-19

Family

ID=37872188

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2007/062960 WO2008065144A2 (fr) 2006-11-29 2007-11-28 Préparations galéniques de composés organiques

Country Status (1)

Country Link
WO (1) WO2008065144A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125432A2 (fr) * 2008-04-11 2009-10-15 Lupin Limited Systèmes d'administration de médicament expansible alimentés par gaz
WO2013023841A1 (fr) * 2011-08-12 2013-02-21 Tesa Se Procédé de production et de contrôle de films orodispersibles
US10952959B2 (en) 2017-01-11 2021-03-23 Ferring B.V. Fast disintegrating pharmaceutical composition

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578567A (en) * 1990-09-20 1996-11-26 Sandoz Ltd. Nasal pharmaceutical composition
US20050276843A1 (en) * 2004-05-10 2005-12-15 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of parathyroid hormone
WO2006076692A1 (fr) * 2005-01-12 2006-07-20 Emisphere Technologies, Inc. Compositions pour l'administration orale de l'hormone parathyroide
US20060189533A1 (en) * 2004-05-10 2006-08-24 Nastech Pharmaceutical Company Inc. Stable pharmaceutical dosage forms of teriparatide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578567A (en) * 1990-09-20 1996-11-26 Sandoz Ltd. Nasal pharmaceutical composition
US20050276843A1 (en) * 2004-05-10 2005-12-15 Nastech Pharmaceutical Company Inc. Compositions and methods for enhanced mucosal delivery of parathyroid hormone
US20060189533A1 (en) * 2004-05-10 2006-08-24 Nastech Pharmaceutical Company Inc. Stable pharmaceutical dosage forms of teriparatide
WO2006076692A1 (fr) * 2005-01-12 2006-07-20 Emisphere Technologies, Inc. Compositions pour l'administration orale de l'hormone parathyroide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MORLEY PAUL: "DELIVERY OF PARATHYROID HORMONE FOR THE TREATMENT OF OSTEOPOROSIS" EXPERT OPINION ON DRUG DELIVERY, ASHLEY PUBLICATIONS, XX, vol. 2, no. 6, November 2005 (2005-11), pages 993-1002, XP008076969 ISSN: 1742-5247 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009125432A2 (fr) * 2008-04-11 2009-10-15 Lupin Limited Systèmes d'administration de médicament expansible alimentés par gaz
WO2009125432A3 (fr) * 2008-04-11 2010-03-25 Lupin Limited Systèmes d'administration de médicament expansible alimentés par gaz
WO2013023841A1 (fr) * 2011-08-12 2013-02-21 Tesa Se Procédé de production et de contrôle de films orodispersibles
US9539206B2 (en) 2011-08-12 2017-01-10 Tesa Se Method for producing and monitoring oral active ingredient films
US10952959B2 (en) 2017-01-11 2021-03-23 Ferring B.V. Fast disintegrating pharmaceutical composition

Also Published As

Publication number Publication date
WO2008065144A3 (fr) 2009-03-19

Similar Documents

Publication Publication Date Title
AU2007287549B2 (en) Galenic formulations of aliskiren
EP1652518B1 (fr) Composition pharmaceutique pour administration par voie sub-linguale
EP3067044B1 (fr) Dispositifs d'administration transmuqueuse avec absorption accrue
EP2029146B1 (fr) Procédés destinés à l'administration de formes posologiques solides d'éthinyl estradiol et de ses promédicaments présentant une biodisponibilité améliorée
KR20080084858A (ko) 구강 경점막 전달을 위한 생접착성 약물 제형
MX2007011440A (es) Tableta recubierta sublingual.
WO2007096906A2 (fr) Nouvelles compositions bucco-adhésives et procédé d'élaboration desdites compositions
EP4378527A2 (fr) Système thérapeutique transmucosal contenant de l'agomélatine
US20220401389A1 (en) Transmucosal therapeutic system containing agomelatine
WO2008065144A2 (fr) Préparations galéniques de composés organiques
WO2008133952A2 (fr) Méthodes de traitement par voie transmuqueuse chez des patients atteints de mucosite

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07847477

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07847477

Country of ref document: EP

Kind code of ref document: A2