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US20090197873A1 - Compositions comprising alprazolam for treating primary insomnia and insomnia associate with anxiety states and process for preparing them - Google Patents

Compositions comprising alprazolam for treating primary insomnia and insomnia associate with anxiety states and process for preparing them Download PDF

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US20090197873A1
US20090197873A1 US12/363,802 US36380209A US2009197873A1 US 20090197873 A1 US20090197873 A1 US 20090197873A1 US 36380209 A US36380209 A US 36380209A US 2009197873 A1 US2009197873 A1 US 2009197873A1
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alprazolam
sublingual
tablets
insomnia
binder
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Mario Los
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Laboratorios Bago SA
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Laboratorios Bago SA
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Assigned to LABORATORIOS BAGO S.A. reassignment LABORATORIOS BAGO S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LOS, MARIO
Publication of US20090197873A1 publication Critical patent/US20090197873A1/en
Priority to US14/102,934 priority Critical patent/US9308212B2/en
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    • 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
    • A61K9/0012—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
    • A61K9/2004—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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention refers to a method for treating patients suffering from primary insomnia and insomnia associated with anxiety states and a sublingual pharmaceutical composition containing alprazolam as the active principle useful for the treatment of primary insomnia and insomnia associated with anxiety states.
  • the invention also describes the elaboration procedure of the composition and the features of the obtained sublingual or oral tablets.
  • the invention further refers to the use of alprazolam and/or a composition comprising alprazolam for the manufacture of a medicament for the treatment of primary insomnia by sublingual administration.
  • Sleeping is a physiological process which is controlled by two biological processes, the homeostatic mechanism and the circadian rhythm. Most adults need about eight hours average of sleeping each night, on a regular basis, in order to feel rested and alert during the daytime. Any change in this routine disrupts the delicate balance between two processes that interact to regulate sleeping.
  • the homeostatic mechanism manifests itself as a growing impulse towards sleeping that accumulates through the alert period, typically during the daytime, and fades away through the sleeping period.
  • the circadian rhythm operates as a 24-hour internal clock; as a part of this cyclic process, the body releases hormones, such as melatonin, in order to help the individual know when is the right time to sleep and to wake.
  • the sleeping-wakefulness circadian rhythm shows a biphasic curve with the greater impulse toward sleeping occurring between midnight and 5 A.M., and between 2 and 4 in the afternoon.
  • Insomnia is one of the most prevalent sleeping diseases and refers to a clinical condition, which lasts at least one month, of difficulties in conceiving sleeping, or keeping the sleeping state, of waking frequently during nighttime or very early in the morning or also to an unsuitable perception of sleeping. This precludes the recovery that the body needs during the nighttime rest, the possible consequences being daytime somnolence, low concentration, tiredness and disability to feel active during the day.
  • insomnia In anxiety states the presence of associated insomnia is frequent. Specialists think that the prevalence of insomnia is also related to age and gender of individuals, the prevalence being higher in older individuals, especially adults older than 65, being women the most affected.
  • Primary insomnia is sleeplessness that is not attributable to a medical, psychiatric, or environmental cause.
  • primary insomnia is diagnosed in approximately 15% of patients with insomnia who are referred to sleep disorder centers following exclusion of other predisposing conditions. Primary insomnia is estimated to occur in 25% of all patients with chronic insomnia.
  • the ideal hypnotic or hypnophore is a drug that will induce sleeping in a quick, predictable fashion. It shall keep sleeping for a 7 to 8-hour period and avoid frequent awakenings. It must preserve sleep architecture with all its stages and must not induce adverse effects such as hang over (resaca matinal, in Spanish).
  • CNS central nervous system
  • barbiturates Early treatments for insomnia usually used central nervous system (CNS) depressants such as barbiturates. These compounds have shown a series of drawbacks. Due to their long half-life, they are typically long-acting (around 8-50 hours) and exhibit a largely known spectrum of side effects, including drowsiness, confusion, depression effects, and the next day hang over. Additionally, the chronic and wrong use of these compounds, i.e. without medical monitoring, has lead to physical and psychological dependence in some cases.
  • CNS central nervous system
  • insomnia During the '80s, the pharmacological treatment of insomnia abruptly changed from barbiturates and other CNS depressants to the class of benzodiazepines of sedative-hypnotic effect.
  • This kind of compounds produces a soothing effect, resulting in a state similar to sleeping in human beings and animals, with a greater safety range than previously used hypnotics.
  • many benzodiazepines have side effects which limit their usefulness in certain populations of patients.
  • benzodiazepines Diseases treated with benzodiazepines are a wide range of pathologies since they have several effects.
  • the best known effects of benzodiazepines are as anticonvulsants, antipsychotic, muscle relaxants, sedatives and hypnotics.
  • benzodiazepines When benzodiazepines are used, some of their effects are desired with respect to the specific disorder treated, but others are considered side effects.
  • Some drugs which are only available as oral tablets or pills may be difficult to administer to elderly people and children, and hence it is of practical importance the availability of a pharmaceutical unit dosage form which disintegrates in a few seconds and whose active principle is absorbed through the sublingual and buccal mucosa of the patient.
  • Alprazolam (28981-97-7) is a short-acting benzodiazepine described during 1970 in patents DE 2.012.190 (24 Sep. 1970) and U.S. Pat. No. 3,987,052 (19 Oct. 1976), which has demonstrated an interesting anxiolytic activity. However, it has not yet been approved for use in the short-term treatment of insomnia, neither in the United States nor in Europe.
  • Literature indicates that when the active ingredient is absorbed through the sublingual and buccal mucosas, such absorption allows for a rapid bioavailability thereof as the active ingredient directly enters the circulatory system, thus avoiding the gastrointestinal passage and the subsequent liver passage (S. Bredenberg et al (European Journal of Pharmaceutical Sciences 20 (2003) 327-334). Thus, in the recent years the patent literature mentions, among others, the following formulations.
  • said document claims and describes generally a method for inducing sleep comprising spraying the oral mucosa of the patient with a “therapeutically effective amount” of the buccal spray containing alprazolam of the invention, it can be considered that such a statement is a mere expression of wish, because it lacks a technical basis.
  • said document is totally silent as concerns the “application as a sleeping inductor” of alprazolam, there is no specific test supporting such a statement and, consequently, it is silent as concerns how much a “therapeutically effective amount” means in said treatment, there is no disclosure about the dosing in the treatment of insomnia.
  • alprazolam is described as being utilized for the treatment of anxiety and associated symptoms such as depression, dysthymic disorders such as “neurotic chronic” depression, panic attacks, agoraphobia and other phobias, obsessive-compulsive disorders, personality disorders.
  • Rabinowitz et al. U.S. Pat. Nos. 6,737,048 B2 (May 18, 2004) and 7,060,255 B2 (Jun. 13, 2006) disclose therapeutic forms containing alprazolam, among other benzodiazepines, for its administration by inhalation.
  • both patents are not only silent as concerns suitable use and doses of alprazolam for the treatment of insomnia but rather advise the use thereof in situations wherein a sustained action of the medicament is desired, such as for example in panic attacks.
  • insomnia comprising the administration of a benzodiazepine, preferably alprazolam; not having remarkably the side effects of benzodiazepines; in a suitable pharmaceutical form of easy disintegration and absorption which allows for quick start of action, and with a dosage and daily posology which allows the patient to comply the indicated treatment better.
  • a major object of the present invention is to provide a pharmaceutical form for oral administration, preferably sublingual, of alprazolam, of rapid disintegration, rapid start of therapeutic action in the treatment of primary insomnia or associated with anxiety states and not having the disadvantages of benzodiazepines.
  • Another object of the present invention is to provide a form of administration of alprazolam for the treatment of primary insomnia or associated with anxiety states, which reduces to its minimum expression or avoids the first step of liver metabolism.
  • Another object of the present invention is to provide a form of administration of alprazolam having a beneficial clinical and pharmacological profile.
  • Another object of the present invention is to provide a form of administration of alprazolam for the treatment of primary insomnia or associated with anxiety states, which is superior to conventional routes of administration.
  • Another object of the present invention is to provide a new use of alprazolam or a composition comprising alprazolam for the manufacture of a medicament for treating primary insomnia by sublingual administration.
  • Another object of the present invention is a pharmaceutical composition in the form of sublingual tablets for the use according to the invention characterised by comprising the combination of alprazolam and a binder having mucoadhesive properties; wherein the ratio of alprazolam to the binder is in the range between 0.3:1 and 3:1.
  • Another object of the present invention is a process for preparing a pharmaceutical composition according to the invention, wherein the preparation procedure comprises the following steps:
  • Another object of the invention is to provide a new use of a composition of alprazolam for the manufacture of a pharmaceutical composition according to the invention for treating anxiety states and for preventing panic attack.
  • FIG. 1 describes X-ray diffraction graphs expanded for the la position Delta 9-12.5 (2 theta) corresponding to 3 different overlapped samples containing alprazolam.
  • Sample A corresponds to pure.
  • Sample B corresponds to the physical mixture of all components of the sublingual tablets, in the same proportion as used according to what is described in example 1 of the present invention.
  • Sample C Corresponds to tablets with a content of 0.5 mg alprazolam made according to the procedure of Example 11 and ground.
  • FIG. 2 describes graphs corresponding to the 3 overlapped samples of X-ray diffraction expanded for the position Delta 9-12.5 (2 theta), in the same way as FIG. 1 .
  • Sample C was prepared according to the formula an procedure described in Example 2 of the present invention. Both sample B (physical mixture of all components) and C (ground tablets of the invention) comprise 1 mg alprazolam.
  • FIG. 3 describes graphs corresponding to the 4 overlapped samples of X-ray diffraction expanded for the position Delta 9-12.5 (2 theta), for tablets containing 0.5 mg alprazolam manufactured by the procedure described in example 1, with a 36-month aging from its elaboration date
  • Sample A reference alprazolam, pure crystalline powder.
  • Sample B reference of the physical mixture of all components except alprazolam and in the same proportion as used according to what is described in example 1 of the present invention.
  • Sample C reference of the physical mixture of all components including alprazolam, in the same proportion as used according to what is described in example 1.
  • Sample D corresponds to tablets with the same alprazolam content (0.5 mg) prepared according to example 1, ground and submitted to a 36-month aging from its elaboration date, and ground.
  • Administration of active principles for therapeutic use by sublingual route aims at achieving good absorption, high bioavailability and immediate therapeutic effect. It is an interesting route for the treatment of acute processes, and more convenient for the patient than the injectable form. However, there exist technical problems which do not make it always possible to dispose of this interesting administration route.
  • U.S. Pat. No. 6,197,349 describes that amorphous novobiocine is 10 times more soluble than the crystalline form and is orally absorbed. It is known that solid crystalline substances have a defined form according to established crystallographic systems which they maintain even after fine grinding, as the arrangement of molecules in the lattice remains intact. Substances in their amorphous state do not have a defined structure, show irregularities in three dimensions, are thermodynamically less stable and confer the active principle its maximum solubility.
  • disintegration is a feature of significant importance for tablets intended for oral administration and even more relevant for sublingual tablets, since active principles are preferably absorbed in the buccal cavity through the buccal or sublingual mucosa. Also, it is well known that the greater the disintegration rate the faster the drug availability in the medium to be absorbed.
  • different pharmacopoeias specify a maximum time for tablet disintegration in order to assure its efficacy.
  • Pharmacopeia USP XXIII requires for isosorbide dinitrate or nitroglycerine sublingual tablets a maximum disintegration time not greater than 2 minutes and for ergotamine tartrate, not higher than 5 minutes. It also mentions others with greater disintegration time. Said background references remark the practical importance of disintegration time directly associated with therapeutic activity and efficacy of each product.
  • binders are alginic acid, methyl-cellulose, gelatin, acacia gum, microcrystalline cellulose and polyvinylpyrrolidone.
  • the binder of choice is polyvinylpyrrolidone.
  • Lubricants include magnesium stearate or sodium stearyl fumarate. Most preferred is sodium stearyl fumarate.
  • lactose As diluents, lactose, microcrystalline cellulose, xylitol, mannitol or cross-linked carboxymethyl-cellulose (AC-DI-SOL) may be used. Preference is given to cross-linked carboxymethylcellulose.
  • Suitable flavorings are also employed.
  • the solvents to be used may be organic or mixtures of organic and inorganic solvents. Between the organics, there may be mentioned methylene chloride or ethanol since they are easily removed. Ethanol is the preferred solvent and following removal there is no possibility of presence of contaminating solvents in the pharmaceutical form. As a solvent mixture, ethanol-water and ethanol-methylene chloride are preferred.
  • the sublingual tablets obtained according to the present invention have the following characteristics.
  • alprazolam present in the sublingual tablet prepared according to the procedure described in the experimental examples dose not completely turn back to crystalline state; or occasionally recovers said crystalline state.
  • the alprazolam active principle comprised in the medicament is in a non-crystalline or partially crystalline form, according to an X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta).
  • non-crystalline state means that it has a content lower than 10%, preferably lower than 5%, of the crystalline state in respect of the total content of alprazolam.
  • alprazolam is not significantly detected in its crystalline form according to X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta)” is used, it must be considered to be equivalent to say that there is a content lower than 10%, preferably lower than 5%, of the crystalline state in respect of the total content of alprazolam.
  • the loss of crystalline state of alprazolam in the sublingual tablets may be observed by comparison of the X-ray spectra described in FIGS. 1-3 of the present invention.
  • a Panalytical X-Ray Diffraction equipment was used, with a K-Cal source, length 1.54184 angstroms (Hardware X-Per pro, X Ray Diffractions Systems; Software X-Per Industry and X-Per High Score).
  • Bibliografia Powder Diffraction File-ICDD; Cambridge Crystallography Data Center; Inorganic Crystal Structure Database).
  • FIGS. 1-3 X-ray diffraction graphs are described expanded for the position Delta 9-12.5 (2 theta) corresponding to different overlapped samples.
  • FIG. 1 a very intense signal is observed in the position indicated for pure alprazolam. Said signal has diminished intensity as compared to the reference for the physical mixture of all components of the sublingual tablets in the same proportion as used in the elaboration of tablets according to the procedure described in the present invention. Such decrease in intensity is attributable to dilution of alprazolam among the other components in la composition (0.5 mg alprazolam in an average weight of 35 mg). Meanwhile, for the sublingual tablets with 0.5 mg alprazolam elaborated according to the procedure of the present invention and ground, no remarkable signal is observed which means evidence of crystallinity of alprazolam.
  • FIG. 3 a very intense signal can also be observed at the position indicated for the reference of pure alprazolam in crystalline powder form. For the reference of the physical mixture of all components except alprazolam, no signal thereof is observed.
  • sublingual tablets according to the present invention when sublingual tablets according to the present invention are prepared which have very high disintegration rate as mentioned and alprazolam with little or no crystallinity in the composition, they are particularly suitable for sublingual administration. Also, this characteristic of the pharmaceutical composition contributes to the total “availability” thereof in the buccal cavity in a remarkably short period of time, and therefore assures the absorption of the drug will take place preferably through the sublingual and buccal mucosa. Such absorption is also favored by the indication to the patient to place the tablet under the tongue for the following reasons.
  • a polyvinylpyrrolidone of choice in particular povidone K-30, in the tablets described in the present invention due to its mucoadhesive activity could: i) increase the time of contact between alprazolam from the disintegration of the tablet (less than 15 seconds) and the sublingual mucosa, an effect not sought in oral-type tablets; ii) decrease the passage to the gastrointestinal tract of alprazolam due to deglutition.
  • the formulations of the invention exhibit a greater shortening, in statistically significant terms, of the latency time of sleeping, with the same dose of alprazolam, as compared to conventional formulations.
  • PSQI is a brief, simple questionnaire, and it is well accepted by patients. In the general population, it can be used as a screening element for detecting “good” and “bad” sleepers. In a psychiatric population, it may identify patients having a sleep disorder concomitant with their mental process. It is capable of orienting the clinician about the most damaged components of sleep. It allows for monitoring of patients in order to follow the natural history of the sleep disorder they suffer; the influence of the sleep alteration on the course of psychiatric processes; the response to specific treatments, etc.
  • PSQI is an auto-administered questionnaire consisting of 19 items auto-assessed by the patient and 5 questions assessed by his/her bed-partner. The latter five questions are used as clinical information, but do not contribute to the overall PSQI scoring.
  • the 19 items analyze the different determining factors of the quality of sleep, which are grouped in 7 components: quality of sleep, latency of sleep, sleep duration, sleep efficiency, sleep alterations, use of medication for sleeping and daytime dysfunction. Each component is scored from 0 to 3. From the sum of all 7 components the overall PSQI scoring is obtained, which ranges from 0 to 21 points. The greater the scoring, the poorer the quality of sleep.
  • alprazolam The efficacy of alprazolam was assessed in sublingual tablets containing 0.5 mg alprazolam according to the present invention in the short-term treatment versus conventional tablets of 0.5 mg alprazolam (Xanax®, Pfizer) as sleep inductors in disorders thereof in the short-term treatment of insomnia associated with anxiety states.
  • PSQI Pittsburgh Sleep Quality Questionnaire
  • the conventional oral form As regards the preference for the conventional oral form, it was not associated with a better response but with its lack of flavour, neutral choice due to the fast deglutition of the oral pharmaceutical form and less time in contact with the oral mucous membrane, while the choice of sublingual form of the present invention was associated with the quick action and the quality of the sleep achieved. From the 10 patients who chose the conventional oral form, 6 patients had a lower latency period with the sublingual pharmaceutical form.
  • alprazolam administered in sublingual tablets in doses of 0.5 mg according to the present invention showed to be more effective for a short-term treatment than when administered the same amount of alprazolam but in the conventional oral form.
  • the pharmaceutical composition also showed to be useful as an anxiolytic and in the treatment of panic disorder, especially in the panic crisis due to its quick action.
  • the sublingual or buccal tablets have a little size and a considerable disintegration rate. This allows them to be used at any time and place, therefore these do not require the use of water or other beverages to assist in their administration.
  • alprazolam 5 g alprazolam were dissolved in 130 g of ethanol to prepare 10,000 tablets. Then, 3.5 g povidone were dissolved in this solution.
  • the dried granulate was calibrated in a conical sieve mill until a uniform particle size was obtained.
  • the granulate obtained was added to a container.
  • the flavorings were added, as well as 75% of the amount calculated of cross-linked carboxymethylcellulose, all of them were calibrated previously in the same manner, then dried in the type V mixer during 20 minutes.
  • the indicated amount of sodium stearyl fumarate was added, and it was stirred during 5 minutes. Then, compression was performed in a rotating compressor.
  • Disintegration time (USP Apparatus): less than 30 seconds.
  • Alprazolam 10 g Cross-linked carboxymethylcellulose 3.5 g Flavorings q.s. Lactose 82 g Povidone 3.5 g Sodium stearyl fumarate 3.5 g Mycrocrystalline cellulose q.s. 350 g
  • the dried granulate was calibrated in a conical sieve mill until a uniform size of particle was obtained.
  • the obtained granulate was added to a container.
  • the flavorings were added, as well as 75% of the amount calculated of cross-linked carboxymethylcellulose, all of them were previously calibrated in the same manner, then dried in the type V mixer during 20 minutes.
  • the indicated amount of sodium stearyl fumarate was added, and it was stirred during 5 minutes. Then, compression was performed in a rotating compressor.
  • Disintegration time (USP Apparatus): Less than 30 seconds.
  • the dried granulate was calibrated in a conical sieve mill until a uniform size of particle was obtained.
  • the obtained granulate was added to a container.
  • the flavorings were added, as well as 75% of the amount calculated of cross-linked carboxymethylcellulose, all of them were previously calibrated in the same manner, then dried in the type V mixer during 20 minutes.
  • the indicated amount of sodium stearyl fumarato was added, and it was stirred during 5 minutes. Finally, compression was performed in a rotating compressor.
  • Disintegration time (USP Apparatus): Less than 30 seconds.
  • the samples were analyzed by high pressure liquid phase chromatography (HPLC) according to the procure described in the stability studies according to Pharmacopeia USP 29, General method ⁇ 905>.
  • HPLC high pressure liquid phase chromatography
  • a high-pressure liquid phase chromatograph was used, equipped with an ultraviolet light and a diode array.
  • the column was filled with silica microparticles chemically bonded to octadecylsylane Rp-18 (3-5 ⁇ L).
  • the working temperature was 40° C. with a flow rate: 1 ml/min.
  • the alprazolam detection was effected by radiation with ultraviolet light at 220 nm; and the quantitation was carried out by means of an electronic integration of the peak area corresponding to alprazolam.
  • the chromatographic system to be applied must comply with the adequacy parameters requiring that the relative standard deviation (SD %) of 5 (five) injections of a reference solution must be ⁇ 2.0%.
  • the samples were packed in PVC (250) and printed aluminium blisters, and then stored at a temperature of 30° C. ⁇ 2° C., with a humidity content of 70% ⁇ 5% RH.
  • Percent alprazolam is calculated by the following formula
  • alprazolam sublingual tablets meet the following requirements:

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US20220257610A1 (en) * 2019-07-28 2022-08-18 Debasish Banerjee Enhancing drug activity through accentuated buccal/sublingual administration.

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