WO2020121027A1 - Compositions d'alprazolam amorphe avec activité anxiolytique, avec éthylcellulose et crospovidone, et procédés correspondants - Google Patents

Compositions d'alprazolam amorphe avec activité anxiolytique, avec éthylcellulose et crospovidone, et procédés correspondants Download PDF

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Publication number
WO2020121027A1
WO2020121027A1 PCT/IB2018/059911 IB2018059911W WO2020121027A1 WO 2020121027 A1 WO2020121027 A1 WO 2020121027A1 IB 2018059911 W IB2018059911 W IB 2018059911W WO 2020121027 A1 WO2020121027 A1 WO 2020121027A1
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Prior art keywords
alprazolam
tablets
premix
suspension
composition
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English (en)
Spanish (es)
Inventor
Mario Atilio Los
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Laboratorios Bago SA
Eastbrand Holding GmbH
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Laboratorios Bago SA
Eastbrand Holding GmbH
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Priority to PCT/IB2018/059911 priority Critical patent/WO2020121027A1/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
    • A61K9/0012—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to a process for the production of a granule in common use formed from a specific premix containing the active ingredient alprazolam previously dissolved and subsequently distributed homogeneously to the mostly amorphous physical state throughout the mass of excipients and, where the granulate is optionally compressed or fractionated and packed as a powder to prepare suspensions.
  • Pharmaceutical compositions containing the granulate and processes for preparing the premix, granules and pharmaceutical compositions are also described.
  • alprazolam contained in the composition is mostly in an amorphous physical state. In this sense, in general, when in the present description and claims reference is made to "amorphous alprazolam” or “mostly amorphous alprazolam” it should be understood that it refers to an alprazolam that has less than 10% in crystalline state.
  • composition is presented indistinctly in the form of orally disintegrating scored tablets (ODT) made by simple compression of the granules, or in powder form to form the suspension for administration to the patient with water or another drink.
  • ODT orally disintegrating scored tablets
  • the product is made by simple fractionation and conditioning of said commonly used granules.
  • the scored tablets have an in vitro disintegration time of less than 20 seconds and preferably less than 15 seconds according to the test described in USP 37. In the oral cavity, disintegration begins before 5 seconds and is complete before 8 seconds.
  • the tablets do not require the use of water for administration.
  • they can also be administered in the form of a suspension with a pleasant taste, after breaking up into a small volume of water.
  • the dissolution rate of alprazolam containing the composition In addition to the significant disintegration rate, the dissolution rate of alprazolam containing the composition. Thus, for example, compared to commercial products used as benchmarks, the dissolution rate of alprazolam was greater than 70% after 30 seconds, according to the dissolution test described in USP 37, in buffer medium at pH 6.0. Novel feature not previously described, which contributes to initiating the oropharyngeal absorption of alprazolam before swallowing the suspension formed by the tablets with saliva in the oral cavity
  • composition in the form of powder to form a suspension with water determines the immediate availability of the alprazolam it contains when entering the oral cavity
  • the absence of nuisance particles in the oral cavity from the composition and its pleasant taste contribute to patient acceptability.
  • the acceptability of the composition is greater and more prominent in geriatric, pediatric or neurological situations that determine swallowing problems.
  • composition due to the unexpected disintegration speed together with the remarkable dissolution speed of the active ingredient it contains presents a faster therapeutic effect than traditional oral tablets containing alprazolam.
  • the composition also has convenient flexibility due to its easy dosage fractionation during administration.
  • Tablets for oral use are the most preferred dosage form among all dosage forms available for human use.
  • oral tablets frequently present administration difficulties associated with inconveniences during swallowing the tablet. Such swallowing difficulty is even observed in patients who do not have feeding problems and is a consequence of the size of the tablet, surface or taste.
  • ODT Oral Disintegration Tablets
  • ODT tablets The disintegration of ODT tablets is fast. In contact with saliva they disintegrate forming a suspension that can be easily ingested by the patient.
  • these pharmaceutical forms for oral use can improve the absorption of the active ingredient they contain and offer greater bioavailability than conventional tablets and capsules.
  • ODT tablets also called “orodispersible”
  • Pregastric or oropharyngeal absorption involves absorption through the sublingual and buccal mucosa.
  • the active ingredient fraction of the pharmaceutical composition absorbed by this route prevents the enterohepatic passage and contributes to achieving the presence of the active ingredient in blood in less time than absorption through the gastrointestinal tract, generating a faster therapeutic effect.
  • ODT rapidly disintegrating tablets
  • the difference in the release rate of the active ingredient in rapidly disintegrating tablets (ODT) has been up to five times greater than the release rate in conventional tablets. This is highlighted for clonazepam Shirsand SB and colab. (Indian J. Pharm. Sci. 2009; 71, 567-572).
  • the tablets are obtained by direct compression from crystals of the active ingredient coated to taste masking and micro granules containing disintegrating agents with high swelling capacity.
  • sugars that is made by granulation and where the sugars with little plastic characteristics (mannitol, lactose, glucose, sucrose or erythritol) but more soluble are covered by another sugar with greater plasticity (maltose, sorbitol, trehalose).
  • the active ingredient is added during granulation or at a later stage.
  • microparticles of polymers airborne, methacrylic, methylcellulose, ethylcellulose resins
  • mannitol and oxide of magnesium to facilitate the release of the active ingredient from the polymer.
  • the pressure applied during compression is generally low to avoid the breakdown of the microparticles that worsens the flavor of the product.
  • the tablets have very little hardness and are packed in an aluminum blister using a special filling machine.
  • the tablets obtained have a high degree of porosity and dissolve rapidly in contact with saliva.
  • the active ingredients should preferably be insoluble, with a small particle size of less than 50 microns to avoid sedimentation during lyophilization.
  • the active ingredient is in suspension with other substances (gelatin, dextrans, etc.) and the suspension they form must be stable throughout the process. 1 Freeze drying of soluble active ingredients is not simple. In some cases it requires the incorporation of ion exchange resins and particular technical considerations. e The tablets made by lyophilization are characterized by their brittleness that requires specific conditioning conditions to avoid breakage. ⁇ Avoid contact with moisture as much as possible.
  • FLASH DOSE Method known as FLASH DOSE. It is based on the previous formation of a matrix of threads of interlaced sugars called "Floss", generally of sucrose, dextrose, fructose, or lactose by rapid heating and subjected to a centrifugal force that generates a physical appearance similar to the so-called cotton candy.
  • Floss generally of sucrose, dextrose, fructose, or lactose by rapid heating and subjected to a centrifugal force that generates a physical appearance similar to the so-called cotton candy.
  • sucrose the heating temperature is mentioned to be between 82 and 130 ° C.
  • the active ingredient and excipients are incorporated into these fibers and the obtained mixture is finally compressed.
  • the fat-soluble active ingredients are preferably for your application and when they use water-soluble active ingredients, special operating conditions are necessary.
  • the fragility of the tablets obtained and the taste masking of the active ingredient are other aspects that each technology tends to solve in a particular way.
  • ODT orally disintegrating tablets
  • the technology for making ODT tablets that can be defined as “optimal or ideal” must include, among others, the following characteristics:
  • Oral disintegration tablets located in the oral cavity have the advantage of forming a suspension with saliva.
  • the drug they contain is partially or completely dispersed or dissolved and can be partially absorbed through the sublingual, buccal, pharyngeal or esophageal mucosa.
  • the fraction absorbed through the aforementioned mucosa does not undergo enterohepatic circulation; also not likely classical enzymatic or chemical degradations of conventional oral tablets containing the same active ingredient and where the active ingredient is absorbed exclusively through the gastrointestinal tract. Consequently, it determines that the bioavailability of the active ingredient in ODT tablets is eventually greater than that observed from conventional oral tablets. This is also highlighted by several authors. Among them: Priyanka Nagar et al. In Journal of Applied Pharmaceutical Science 01 (04), 2011, 35-45.
  • the disintegration time of ODT tablets in the oral cavity and the frequency of swallowing of the suspension formed by the particles with the saliva that is produced automatically and little controlled by the will, obviously compete with each other and negatively affect the level absorption of the active ingredient through the sublingual and oropharyngeal mucosa.
  • Such FDA and EMEA recommendations on disintegration time are preferably limited to highlighting the advantages offered by ODT tablets over conventional oral tablets. This is; facilitate the swallowing of the suspension formed by the ODT tablets with the saliva of the oral cavity, optimize the administration in patients with dysphagia and also avoid the disintegration time in the stomach characteristic of oral tablets. Together, they promote patient acceptability and improve the bioavailability of the active ingredient compared to conventional oral tablets. They do not consider the practical importance of oropharyngeal absorption that only occurs for a short period of time before swallowing. But it has the advantage of minimizing the enterohepatic circulation of the active ingredient or its partial enzymatic or chemical degradation that frequently occurs when the active ingredient enters the gastrointestinal tract.
  • USP 37 describes disintegration and dissolution tests previously harmonized with the European Pharmacopoeia and the Japanese Pharmacopoeia.
  • Alphazolam Disintegration Tablets pages 1660-1661
  • the disintegration time must be 30 seconds and the dissolution time of the active ingredient they contain must be 10 minutes.
  • the 10-minute dissolution time mentioned in the USP does not expressly consider the possibility of absorption through the oropharyngeal mucosa.
  • the oropharyngeal absorption requires a higher dissolution rate, -as it refers to the fraction of the pharmaceutical composition that is absorbed in the short period of time between the entry of the composition into the oral cavity and the swallowing of the suspension that forms with saliva.
  • the active ingredient fraction with oropharyngeal absorption helps to initiate the therapeutic effect, minimize enterohepatic circulation, and the chemical or enzymatic degradation characteristic of the ingredient fraction that enters the gastrointestinal tract directly.
  • the USP defines a dissolution time of 10 minutes, a naturally long period of time for oropharyngeal absorption, since swallowing takes less time. But absolutely suitable for the active ingredient that after swallowing enters the gastrointestinal tract.
  • a disintegrating agent selected from cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, carboxymethyl hydroxypropyl starch, starch and mixtures of the foregoing;
  • a diluting agent selected from microcrystalline cellulose, lactose, sucralose, dextrose, sorbitol, mannitol and mixtures of the above; preferably a mixture of microcrystalline cellulose and lactose;
  • a lubricating agent selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, stearic acid and talc;
  • the ratio of alprazolam to ethylcellulose in the premix is in the range of 2.5: 1 to 5: 1;
  • the ratio of alprazolam to water-insoluble crospovidone is in the range of 0.06: 1 to 0.13: 1;
  • composition comprises:
  • each dosage unit comprises between 0.25 and 2.00 milligrams of alprazolam, and preferably each dosage unit comprises 0.25, 0.5, 1.0 or 2.0 milligrams of alprazolam.
  • the dissolution of the amorphous alprazolam present in the premix of the composition at the first minute is greater than 20 percent with respect to the dissolution of crystalline alprazolam present in a physical mixture with the same components, according to USP 35 test in buffer medium.
  • a preferred form of presentation of the composition is in the form of rapidly orally disintegrating tablets.
  • each tablet has a disintegration time of less than 20 seconds and preferably less than 15 seconds, measured by in vitro determination according to USP 37 in aqueous medium without disc and / or that the disintegration of the tablet located in the oral cavity begins. at 5 seconds and is total at 8 seconds. It is also advantageous if the suspension formed by the tablet with the saliva is free of nuisance particles or agglomerates and the suspension formed has a pleasant taste.
  • composition according to the invention is for oral administration to the patient by direct incorporation of the tablet into the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through the Type K-10 enteral probe. 8 or similar.
  • compositions are in the form of a powder for the extemporaneous preparation of a suspension.
  • administration of the previously formed suspension with water or other beverages is advantageously carried out by incorporation of the suspension in the oral cavity or by Type K-108 enteral tube or the like.
  • Another object of the invention is a process for preparing an amorphous alprazolam orally disintegrating composition, CHARACTERIZED BECAUSE it comprises preparing a premix according to the following sequence:
  • a disintegrating agent selected from cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, hydroxypropyl carboxymethyl starch, and starch and mixtures thereof; preferably crosslinked carboxymethyl cellulose;
  • a diluting agent selected from microcrystalline cellulose, lactose, sucralose, dextrose, sorbitol, mannitol and mixtures of the above, preferably a mixture of microcrystalline cellulose and lactose;
  • a flavor masking agent preferably Debitter
  • step c) incorporating the solution obtained in step a) onto the powder mixture obtained in step b) in a mixer;
  • -crospovidone insoluble in water preferably crospovidone CL grade
  • -flavoring agents preferably cherry essence and / or peppermint essence
  • sweetening agents preferably sucralose and / or aspartame
  • a lubricating agent selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, stearic acid and talc, preferably sodium stearyl fumarate;
  • step iv) mixing to obtain the commonly used amorphous alprazolam granules; and optionally v) transforming the granules obtained in step iv) into orally disintegrating scored tablets or powder for extemporaneous preparation of a suspension.
  • step v) comprises subjecting the granules to direct compression to obtain tablets, and advantageously scored tablets.
  • step v) comprises the simple fractionation of the granulate and subsequent conditioning in single-dose or multi-dose units to obtain a powder for extemporaneous preparation of a suspension.
  • the content of alprazolam dissolved in ethanol is between 5 and 10% by weight with respect to the weight of ethanol.
  • the content of ethyl cellulose dissolved in ethanol is advantageously between 0.5 and 2.0% by weight with respect to the weight of ethanol.
  • the ratio of ethyl cellulose from step a) to ethyl cellulose from step b) is between 60:40 and 30:70, most preferably between 60:40 and 40:60, and particularly preferably is 60:40.
  • the ethyl cellulose fraction dissolved in ethanol in step a) inhibits, at least partially, the subsequent recrystallization of alprazolam.
  • the solid-state incorporated ethylcellulose fraction in step b) acts as a binding agent.
  • the dissolution of the amorphous alprazolam present in the premix of the composition at the first minute is greater than 20 percent with respect to the solution of crystalline alprazolam present in a physical mixture with the same components, according to the USP 35 test in buffer medium.
  • the tablets that are obtained contain between 0.25 and 2.00 milligrams of alprazolam, and preferably contain 0.25, 0.5, 1.0 or 2.0 milligrams of alprazolam.
  • the tablets advantageously have a disintegration time of less than 20 seconds and preferably less than 15 seconds by in vitro determination according to USP 37 in aqueous medium without disc.
  • the disintegration of the tablet, located in the oral cavity begins at 5 seconds and is complete at 8 seconds.
  • the suspension formed by the tablet with saliva is free of particles or troublesome agglomerates and the suspension formed has a pleasant taste.
  • the alprazolam solution of the composition obtained in step iv) in buffer medium at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 R.P.M. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65%, of the alprazolam content of the composition.
  • the tablet is for direct administration to the patient in the oral cavity or after disintegration in a small volume of water and direct administration of the suspension formed and optionally through the Type K-108 enteral probe or similar.
  • the powder for extemporaneous preparation of a suspension is suspended with water or other beverages and is for administration by incorporation of the suspension into the oral cavity or by Type K-108 enteral tube or the like.
  • the powder for the extemporaneous preparation of a suspension is presented in single-dose or multi-dose units that contain indistinctly between 0.25 and 2.00 milligrams of alprazolam in the mostly amorphous state and quickly form by simple agitation a suspension with water or another drink.
  • the alprazolar ethylcellulose ratio in the composition is between 2.5: 1 and 5: 1.
  • the alprazolar ratio crospovidone in the composition is comprised between 0.06: 1 and 0.13: 1.
  • the tablet preferably has an alprazolam content of less than 0.5 mg, preferably 0.25 mg.
  • the compounds incorporated in said step b) have a humidity of less than 1.5%, preferably less than 0.5%.
  • said premix is dried at less than 50 ° C.
  • said premix is dried until reaching a humidity lower than 1%.
  • the present invention provides innovative elements.
  • it contemplates and resolves an unexpected and significant behavior that favors prior oropharyngeal absorption through the following properties not previously described. They are: a) Unexpected rate of disintegration of the tablets:
  • disintegration begins at 5 seconds and is total at 8 seconds, and according to the USP 37 test it is less than 20 seconds and preferably 15 seconds.
  • the oral disintegration tablets of the present invention demonstrated that the dissolution of alprazolam in buffer medium, at pH 6.0, volume 900 ml and temperature 37 ° C, speed 50 rpm. in apparatus 2 according to USP 37 at 30 seconds it is greater than 45%, and at 60 seconds it is greater than 65% of the alprazolam content of the composition.
  • the pharmaceutical composition in both mentioned cases showed immediate availability of the alprazolam they contain and particularly unexpected and previously not described fast speed of dissolution of the alprazolam they contain.
  • compositions due to their novel characteristics, contribute to: a) Initiating the oropharyngeal absorption of alprazolam before swallowing with direct entry into the blood and a faster therapeutic effect than conventional oral compositions. b) and continue after swallowing the gastrointestinal absorption of the fraction not previously absorbed through the oropharyngeal mucosa.
  • alprazolam is present in numerous compositions for oral use. Each composition with its own characteristics, advantages and limitations. Among them are:
  • Xanax from Pfizer Laboratories and others, with excellent therapeutic applications. All of them used as anxiolytics and with the characteristic drawbacks of conventional tablets: That is, disintegration in the stomach, enterohepatic circulation and activity always after 30 minutes of administration to the patient.
  • Niravan (from Schwartz Laboratories - Pharma) is the first described and marketed ODT-type tablet containing alprazolam.
  • the only advantage is that they do not require the use of water for administration in all cases, and as indicated also in the product information, the peak plasma concentration of alprazolam is reached at approximately 1.5 to 2.0 hours after administration (with or without water).
  • Sublingual tablets were shown to allow the presence of alprazolam to be determined in the blood after 4 minutes of sublingual administration, reaching the maximum concentration at 2 hours (Héctor Arenoso et al. - International Journal of Pharmaceutical Medicine; 2002; 16: 215 -218).
  • the present invention provides for its pharmaceutical compositions innovative elements and characteristics not previously described.
  • compositions described the following novel features ai It allows the composition to be made in the form of ODT tablets or powder for oral administration in a simple and economic way. . b) It does not require complex and high cost equipment for the elaboration. The necessary equipment is all commonly used in the pharmaceutical industry. c]
  • the active principle (alprazolam) is present in the composition mainly in the amorphous state. Characteristic that contributes to increasing its solubility in water or saliva. Particularly useful for increasing oropharyngeal absorption and minimizing enterohepatic circulation.
  • alprazolam they contain is mainly in the amorphous state, helping to promote its solubility in an aqueous medium.
  • the tablets have, according to the USP test, a disintegration time "in vitro" of about 15 seconds. But, in the oral cavity “in vivo” as it was experimentally determined that the disintegration of the tablet begins at 5 seconds and is total at 8 seconds. Behavior that contributes significantly to patient acceptability.
  • the ODT tablets of the present invention demonstrated: ⁇ Achieve similar therapeutic result with lower unit dose of alprazolam than the alprazolam composition in sublingual tablets chosen as a reference.
  • the sublingual composition of administration was chosen as the comparison term for its high bioavailability of alprazolam and rapid therapeutic effect previously described.
  • the composition of the present invention determines saving of active ingredient to achieve similar therapeutic effect
  • compositions ODT tablets and powder suspended in water due to the absence of particles or agglomerates of significant size, are optionally for administration by enteral feeding tube type K-108 or similar in patients fed exclusively by enteral feeding tube.
  • Fig. 1 X-ray Diffraction graph expanded in position 9— 9.5 (2 theta) of the active ingredient pure alprazolam and to the crystalline physical state.
  • Fig. 2 X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of Niravam 0.25 Disintegrating Tablets
  • Fig. 3 X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of the premix for making orally disintegrating tablets, and powder for suspension as described in Experimental Part.
  • Fig. 4 X-ray Diffraction graph expanded at position 9— 9.5 (2 theta) of orally disintegrating tablets (ODT) containing 2 mg of alprazolam made according to the present invention.
  • the present invention relates to a pharmaceutical composition for oral use that offers rapid or immediate availability of alprazolam in the oral cavity.
  • the suspension formed with water or another drink before administration or with saliva in the oral cavity presents the active ingredient mainly in the non-crystalline physical form.
  • composition elaboration procedure comprises the preparation of a premix that determines the homogeneous distribution of alprazolam throughout the mass together with its transformation from the crystalline state to the mostly amorphous physical state. Subsequently, together with other pharmaceutical excipients, it allows the preparation of a specific granule useful for preparing the composition of choice.
  • the commonly used granules have a pleasant taste and are free of annoying particles when placed in the oral cavity.
  • a pharmaceutical composition of choice comprises orally rapidly disintegrating (ODT) tablets and scored tablets.
  • ODT orally rapidly disintegrating
  • the disintegration of the tablets in vitro takes less than 20 seconds and preferably 15 seconds.
  • disintegration begins before 5 seconds and is complete before 8 seconds, favoring the contact of the active principle of the suspension that forms with saliva with the mucosa of the oral and sublingual cavity.
  • dissolution of alprazolam containing the composition is significant. Specifically, it is over 40% in just 30 seconds.
  • said granules formed from the premix together with other excipients for pharmaceutical use
  • said granules showed that due to its characteristics (immediate availability of mostly amorphous alprazolam and convenient flavor) it also constitutes another novel pharmaceutical composition not previously described of the powder type to form a suspension with water or another drink.
  • it is only necessary to fractionate the granules of common use and subsequent conditioning in sachets or sachets, or in single-dose or multi-dose containers.
  • the powder for suspension allows different forms of administration to the patient. For example; suspend in water and administer to the patient or incorporate the suspension formed into food or directly incorporate the powder into food.
  • the choice of alprazolam administration form in the form of a powder for suspension is wide, novel and it is only conditioned on the condition of the patient.
  • ODT orally disintegrating tablets
  • the present invention solves through the commonly used premix and granules the mentioned technological absences and offers the patient significant practical advantages not previously described.
  • the presence of alprazolam in the oral cavity is immediate due to the suspension that is formed prior to administration with water. or another drink.
  • the pharmaceutical composition presents the active ingredient in the amorphous state.
  • FIGURE 1 Describe the expanded X-ray Diffraction graph at position 9— 9.5 (2 theta) of the active substance pure alprazolam and the crystalline physical state. The signal of crystalline alprazolam is intense and is cut off at the top of the figure.
  • FIGURE 2 Describe the expanded X-ray Diffraction chart at position 9— 9.5 (2 theta) of Niravam 0.25 Disintegrating Tablets (Lot: 850024 — Schwartz-Pharma). The presence of the characteristic signal of crystalline Alprazolam is observed at position 9—9.5 (2 theta). The signal is naturally weaker than in Figure 1 because the Niravan product contains only 0.25 mg of alprazolam along with the other excipients that make up the tablet.
  • FIGURE 3 Describe the expanded X-ray Diffraction chart at position 9— 9.5 (2 theta) of the premix for making orally disintegrating tablets, and powder for suspension as described in Experimental Part. No signs of alprazolam in the crystalline state are observed. The way of preparing the premix determines that in said premix, the alprazolam is present as a non-crystalline active ingredient
  • FIGURE 4 Describes the expanded X-ray Diffraction graph at position 9— 9.5 (2 theta) of orally disintegrating tablets (ODT) containing 2 mg of alprazolam made according to the present invention.
  • ODT orally disintegrating tablets
  • the characteristic signal of alprazolam to the crystalline physical state is not observed even when the content of alprazolam in the tablets is 2 mg. That is, 8 times greater than the content in the NIRAVAN tablets used as a comparison term, which only contain 0.25 mg of crystalline alprazolam and whose signal is clearly visible (Fig. 2)
  • ODT tablets made according to the present invention are largely free of crystalline alprazolam.
  • the premix with which the composition is made allows to increase the dissolution rate of the alprazolam it contains compared to a physical mixture with identical components.
  • a commonly used granulate is subsequently obtained for the preparation of the pharmaceutical composition of choice.
  • the premix includes:
  • Ethyl cellulose successively as a crystallization inhibitor, flavor masker and binder.
  • the two stages of preparation of the premix are:
  • the solvent of choice for the active ingredient and up to 60% of the total ethyl cellulose in the composition is ethanol. Necessary condition for both to be dissolved and subsequently determine the presence of alprazolam mainly in the amorphous state.
  • ethylcellulose in the solvent is necessary and sufficient to avoid the massive crystallization of the active ingredient and simultaneously contribute to its homogeneous distribution over the entire mass and also to the partial masking of the taste of the active ingredient.
  • the double behavior of ethylcellulose in the premix is practical and novel in that it reduces the number of excipients necessary to fulfill the same functions. That is: a) In solution, it allows to inhibit the recrystallization of alprazolam by eliminating the solvent. b) And the solid state in the same premix acts a posteriori as a binder.
  • the premix obtained is dried to final humidity between 0.5 and 1.5% and finally ground and homogenized in the Quadro Comill Mill (sieve: 991 microns - speed: 2400 rpm).
  • the premix demonstrated a higher dissolution rate of alprazolam contained therein than in the physical mixture with the same components in quality and quantity, which is subsequently transmitted to the pharmaceutical compositions that are made with said premix.
  • the premix obtained in the subsequent stage is transformed into the commonly used granules that are applicable to the preparation of the pharmaceutical composition of choice (ODT tablets or powder for suspension) as described in the Experimental Part
  • the incorporation is carried out simply by mixing for 30 minutes and incorporating with stirring sodium stearyl fumarate to obtain the final granulate that contains alprazolam mainly in the amorphous state and necessary to subsequently elaborate the composition.
  • oral disintegration tablets (ODT) are obtained. as described in the Experimental Part, and the tablets have the following general characteristics:
  • the dissolution rate of alprazolam of the orally disintegrating tablets (ODT) described against sublingual Tranquinal was practically 220% higher.
  • the described ODT tablets offer unexpected and rapid availability in the oral cavity of alprazolam that contains the suspension that they form with saliva to initiate their oral, sublingual absorption, prior to swallowing and subsequently to continue the absorption of available alprazolam through the tract. gastrointestinal. 4)
  • the tablets are made by simple compression with simple and inexpensive equipment.
  • the granulate also allows the pharmaceutical composition to be presented directly in the form of a "powder" to prepare a suspension by pouring the powder into water or another drink that is easy to administer to the patient. Due to the characteristics of the granulate, it is only necessary to fractionate and condition it conveniently.
  • compositions made with the commonly used granules are useful for the treatment of normal patients, patients with swallowing difficulties or X dysphagia with a faster therapeutic effect than commercially available oral or sublingual tablets.
  • compositions QDT tablets powder dipped in water were shown to be applicable for administration by enteral tube type K-108 or similar without drawbacks.
  • the powder contained in each unit subsequently suspended in water forms a suspension characterized by the absence of residue, a pleasant taste and is easy to administer.
  • the powder for the suspension is a novel pharmaceutical composition that offers practical administration in geriatrics, pediatrics and in patients with swallowing problems. Including patients who do not have feeding problems, but who do have difficulty swallowing the usual oral tablets.
  • Another feature of the present invention is the ability to mask the taste of the active ingredient.
  • the premix and in particular the final granules in common use to optionally elaborate each one of the mentioned compositions ensure the pleasant taste of the composition and facilitate its administration to the patient. Particularly significant property for administration of the composition in pediatrics.
  • disintegrants cross-linked carboxymethyl cellulose, modified starch, croscarmellose sodium, sodium glycollate starch, carboxymethyl hydroxypropyl starch, starch.
  • microcrystalline cellulose lactose, sucralose, dextrose, sorbitol, mannitol.
  • flavorings grapefruit, strawberry, cherry, vanilla essences and others.
  • lubricants magnesium stearate, zinc stearate, stearic acid and talc.
  • the necessary condition is that the active ingredient in the premix is practically present in the amorphous state, in order to increase the dissolution rate of the alprazolam it contains and to ensure the characteristics mentioned for the pharmaceutical composition.
  • -_Property particularly useful for patients with anxiety disorders, panic disorders with agoraphobia or panic disorders without agoraphobia.
  • alprazolam The Spanish Medicines Agency, Food and Drug Administration and other medical entities mention contraindications linked to the use of high doses of alprazolam. These include: hypersensitivity to benzodiazepines, myasthemia gravis, respiratory failure, liver failure, acute glaucoma, and others.
  • the described premix contains:
  • Alprazolam as the active substance.
  • a disintegrant crosslinked carboxymethyl cellulose.
  • Ethyl cellulose in two different physical forms (dissolved in the solvent and in the solid state).
  • STAGE I a) 250 grams of ethanol, 12.5 grams of alprazolam were incorporated in a stainless steel container successively and with stirring. It was heated to 35 ° C and stirred until alprazolam was completely dissolved. b) 3 grams of ethyl cellulose were incorporated and stirred at room temperature (20-25 ° C) until complete dissolution of the ethyl cellulose.
  • the premix formed was dried in a fluid bed dryer at less than 50 ° C until residual humidity less than 1.5% and preferably 0.5%. £ 1 Went through Quadro Cornil Mod 197 S Conical Screen Mill with 991 micron 2A-039R03125 mesh and 2400 rpm speed.
  • the obtained premix was kept protected from humidity and temperature in a double Polyethylene bag and envelopes containing indicator-activated silicagel until it was transformed into the granules applicable to the preparation of the pharmaceutical composition of choice.
  • Step I (b) the residue from the evaporation of the solution described in Step I (b) lacks mostly crystals. Only irregular clusters are observed (NIKON Mod. YS 100 Microscope with Nikon E4500 camera — 400X magnification objective).
  • Figure 3 corresponds to the X-ray diffraction graph of the premix prepared as described. In this case, in the same position (Delta 9-9.5 -2 theta) no signal of crystalline alprazolam is observed.
  • the dissolution rate of alprazolam in the premix prepared as described was determined and compared with the dissolution rate of alprazolam from a physical mixture containing the same composition, but in this case alprazolam at the usual or crystalline physical state.
  • Example I The procedure described in Example I was applied using 25.0 grams of alprazolam together with the other excipients in equal amount to Example I.
  • the final granules obtained were kept protected from humidity and temperature in a double polyethylene bag and envelopes containing indicator-activated silica gel until their application to the preparation of the corresponding composition.
  • EXAMPLE IV Preparation of orally disintegrating scored tablets (ODT) containing 0.5 mg alprazolam Tablets mostly absent from crystals of the active substance
  • Example III The granules obtained in Example III were compressed to a theoretical weight of 150 mg in
  • the orally disintegrating tablets had the following properties:
  • the dissolution rate of alprazolam from the described orally disintegrating tablets was determined and compared to the dissolution rate in commercially available tablets that also contain alprazolam.
  • the reference product was: Tranquinal sublingual, sublingual tablets of 0.50 mg (Laboratorios Bagó S.A. - Lot: Al 8 H). Orally disintegrating tablets according to the present invention are identified as ODT 0.50-E 011.
  • Buffer medium pH 6.0. Volume: 900 mi. Temperature: 37 ° C. Speed: 50 rpm. Apparatus 2: paddle.
  • the alprazolam contained in the oral disintegration tablet object of the present invention demonstrated the highest dissolution rate.
  • Example III oral disintegration scored tablets containing 0.25 milligrams of alprazolam per unit were also prepared according to the present Example IV but at half weight.
  • Example II The highest alprazolam content (25.0 grams) prepared according to Example II, subsequent preparation of granules according to Example III and finally according to the procedure described in Example IV for the preparation of oral disintegration tablets.
  • the weight difference selected during the compression operation of the commonly used granules determined in the orally disintegrating tablets (ODT) respectively the presence of 1.0 or 2.0 mg of mostly non-crystalline alprazolam
  • Figure IV describes the X-ray diffraction graph expanded in the Delta 9-9.5 position (2 theta) for the tablets obtained and previously ground to perform the physical determination.
  • the latency time or time during which the animal maintains its position in the rotarod without falling was determined.
  • the rotation movement was fixed and the speed was 16 rpm.
  • the objective of the study was to evaluate the time in which each composition begins to exert its pharmacological action and as a consequence of the absorption rate of the alprazolam they contain.
  • the tablet suspended in 0.3 ml of water in a syringe was administered into the oral cavity using a probe.
  • M31 _ Oral tablets (brand Xanax 0.5 mg— Lot D 104— Vto. 03 (2015)):
  • the suspension formed could be administered by nasogastric or nasoenteric feeding probes type K 108 or similar.
  • oral disintegration tablets of the present invention offer convenient logical flexibility, helping to administer to the patient the smallest but necessary amount of alprazolam to achieve similar therapeutic effect.
  • CHARACTERISTICS a) The dispersion of an envelope (150 mg) in 10 ml of water was fast, homogeneous and did not require more than 10 seconds. The suspension formed had a pleasant taste and its ingestion practically left no troublesome particles in the oral cavity.
  • the suspension due to the aforementioned characteristics, was also administered by prior incorporation into food.
  • multidose compositions were prepared under two presentations. a) in fractional aluminum-aluminum sachets. b) in a multidose High Density polyethylene bottle with a Polypropylene Cap with an insert for an oral dispenser to reconstitute with water accompanied by a measure for the fractionation of the suspension formed and administration.
  • the suspension formed must be kept at a low temperature.

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Abstract

L'invention concerne une composition d'alprazolam amorphe avec activité anxiolytique qui comprend: a) un prémélange qui contient: - entre 0,33 et 0,66% p/p d'alprazolam; - entre 0,07 et 0,2% p/p d'éthylcellulose comme agent agglutinant; - un agent désintégrant, un agent diluant, un aspartame et un agent masqueur du goût; b) le prémélange est combiné avec: - entre 4 et 6% p/p de crospovidone insoluble dans l'eau comme agent désintégrant, - un agent lubrifiant; - des agents aromatisants, des agents édulcorants et q.s. 100% de mannitol granulaire comme diluant; où: - la relation de l'alprazolam à l'éthylcellulose dans le prémélange se trouve dans la plage comprise entre 2,5:1 et 5:1; et - la relation de l'alprazolam à la crospovidone insoluble dans l'eau se trouve dans la plage comprise entre 0,06:1 et 0,13:1; et le degré de cristallinité de l'alprazolam est inférieur à 10%.
PCT/IB2018/059911 2018-12-12 2018-12-12 Compositions d'alprazolam amorphe avec activité anxiolytique, avec éthylcellulose et crospovidone, et procédés correspondants Ceased WO2020121027A1 (fr)

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CN113876961A (zh) * 2021-09-28 2022-01-04 珠海市东辰制药有限公司 一种共处理辅料及其制备方法和用途
CN113876961B (zh) * 2021-09-28 2024-01-30 珠海市东辰制药有限公司 一种共处理辅料及其制备方法和用途

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