Classifications

• • 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
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
  • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• • 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
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Definitions

• SM-l controlled-release, three-in-one composition
• the active ingredients of SM-l include diphenhydramine HC1, zolpidem tartrate, and lorazepam.
• SM-l increases total sleep time in patients with transient insomnia.
• SM-l contains the lowest effective dose of zolpidem tartrate and lorazepam, the side effects of these two drugs are still a concern.
• zolpidem The commonly reported side effects of zolpidem include dizziness, drowsiness, weakness, unsteady gait, difficulty with balance, uncontrollable shaking and headache, and it is associated with drug tolerance and substance dependence.
• FDA approved label changes specifying lower dosage recommendations for zolpidem products because of concerns regarding next-morning impairment. Since zolpidem is metabolized by liver through CYP3A4, patients with liver problems should not take zolpidem as it can damage liver cells, thereby contributing to liver problems.
• Described herein is a controlled-release formulation for aiding sleep.
• the formulation comprises diphenhydramine HC1 and a sleep aid which is zolpidem tartrate or lorazepam, wherein the formulation is formulated for releasing each drug at a specific time and a specific dose in a subject after the formulation is administered to the subject.
• the formulation is formulated for two stages of release, wherein each stage initiates release of a drug in a subject at a specific time point after administration of the formulation to the subject.
• the time interval between the initiations of each stage of release can be 0.5 to 23 hours.
• the first stage can be for immediate release of diphenhydramine HC1
• the second stage can be for delayed release of zolpidem tartrate or lorazepam.
• the formulation is a tablet or capsule for oral administration.
• the tablet or capsule can contain a plurality of particles, each particle including a drug core and a polymeric composition encapsulating the core, wherein the drug core contains one or more drugs for aiding sleep.
• the formulation comprises diphenhydramine HC1 and a sleep aid which is zolpidem tartrate or lorazepam, as the sole active ingredients.
• the formulation consisting essentially of diphenhydramine HC1 and a sleep aid which is zolpidem tartrate or lorazepam.
• the method includes administering the above-described formulation to a subject in need thereof.
• the two-drug compositions can reduce the burden of drug intake in patients with transient insomnia, and therefore avoid the side effects as described above and metabolic burden of the eliminated drug.
• PSQ Postsleep Questionnaire
• the article“a” or“an” means one or more than one (that is, at least one) of the grammatical object of the article, unless otherwise made clear in the specific use of the article in only a singular sense.
• disturbed sleep refers to a condition characterized by waking up feeling unrestored, waking up in the middle of the night, difficulty returning to sleep after waking, difficulty falling asleep, and/or waking too early. Stress, a health condition, pain, a medication, jet lag, and noise are some factors that can lead to disturbed sleep. Disturbed sleep can be acute (i.e., short-termed) or chronic in duration.
• An individual with insomnia experiences frequent and long-term disturbed sleep with daytime impairment or distress despite having adequate opportunity and circumstance for sleep.
• Disturbed sleep can have various negative consequences such as fatigue, lack of energy, initiative reduction, daytime sleepiness, tension headache, gastrointestinal symptoms, irritability, anxiety, mood disturbance, reduced motivation, and impairment in cognitive functions (attention, concentration, and memory).
• Whether a subject has disturbed sleep or insomnia can be determined by a skilled practitioner in the art.
• beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
• Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
• the term“animal”,“subject” or“patient” as used herein includes, but is not limited to, humans and non-human vertebrates such as wild, domestic and farm animals, preferably humans.
• Described herein is a controlled-release formulation comprising diphenhydramine HC1 and a sleep aid which is zolpidem tartrate or lorazepam.
• the controlled-release formulation is formulated to release diphenhydramine HC1 and a sleep aid selected from zolpidem tartrate and lorazepam.
• the formulation releases diphenhydramine HC1 and the sleep aid at two stages. Each stage initiates release of diphenhydramine HC1 and the sleep aid at a specific time after administration of the formulation.
• the formulation can release a first dose of diphenhydramine HC1 immediately, release a second dose of the sleep aid 0.5-6 hour after release of the first dose.
• the time interval between the initiation of each stage of release can be 30 minutes to 23 hours (e.g., 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12.5 hours, 13 hours, 15 hours, 20 hours, 22 hours, and 23 hours).
• Each stage can release a dose of a drug in the range of 0.01 mg to 100 mg (e.g., 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.4 mg, 0.5 mg, 0.6 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, and 100 mg).
• the first stage of release can be an immediate release, in which release of diphenhydramine HC1 is initiated shortly (e.g., within 30 minutes) after administration of the formulation.
• the first stage of release can also be a delayed released.
• the above-described controlled-release formulation can be a tablet (e.g., a pill) or a capsule (e.g., a hard-shelled capsule or a softgel) for oral administration.
• Other formulations such as implants and patches can also be used.
• controlled-release formulations are known in the art. See, e.g., Hong Wen and Kinam Park, 2010, Oral Controlled Release Formulation Design and Drug Delivery: Theory to Practice, John Wiley & Sons, Inc.
• controlled-release formulations can be designed based on particular physical mechanisms, e.g., dissolution, diffusion, osmosis, and ion exchange.
• a drug e.g., diphenhydramine HC1, zolpidem tartrate or lorazepam
• a polymeric composition e.g., a polymeric membrane or a polymeric matrix
• the drug is released when the polymeric composition dissolves.
• Properties of the polymeric composition e.g., thickness and dissolution rate, determine drug release.
• the active ingredient has to diffuse through a polymeric composition (e.g., a polymeric membrane or a polymeric matrix) in order to be released.
• the drug is encapsulated by a polymeric coating that swells and erupts from osmotic pressure, thereby releasing the drug.
• Ion exchange formulation relies on attaching drug molecules to ionic groups. The drug molecules are then displaced by other ions and released.
• the controlled-release formulation described herein can utilize one release mechanism or a combination of release mechanisms.
• the above-described controlled-release formulation can be a tablet with multiple cores or layers.
• the drug or combination of drugs for each stage of release can be surrounded by polymeric layer. The drug or combination of drugs is released as the layer dissolves.
• a multiparticulate system is employed.
• the drugs are each delivered in multiple particles (e.g., small beads or microspheres ranging from 0.05 to 3.00 mm in size), each particle exhibiting the desired characteristics (e.g., release time and rate).
• the above-described controlled-release formulation can include a plurality of particles.
• Each particle contains a core including a drug or combination of drugs for aiding sleep and a controlled-release polymeric composition (containing one or more polymers) encapsulating the core.
• Properties of the controlled-release polymeric composition in each particle determine the drug release profile of each particle.
• the formulation can include uncoated particles for immediate release of a drug.
• any of the above-described or other release mechanisms can be employed in a multiparticulate system.
• the plurality of particles can be encapsulated in a capsule or compressed into a tablet for oral administration.
• a three-stage release formulation can contain three types of particles, each type for each stage of release. Each dose of a drug for each stage of release is delivered by multiple particles.
• Natural and synthetic polymers for controlled-release formulations are known in the art. Such polymers include, but are not limited to, proteins, polysaccharides, nucleotides, alginate, chitosan, heparin, xanthan gum, starch, pectin, gelatin, kit-carrageenan, hydroxypropylmethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethycellulose, methylcellulose, polyvinyl alcohol, polyacrylic acid, polyethylene oxide, poloxamers, pluronics, polymethacrylate, cellulose, collagen, nylon, polyalkylcyanoacrylate, polyethylene, polyethylene-co-vinylacetate, polyhydroxythyl methacrylate, polyhydroxypropyl ethyl methacrylate, polymethyl methacrylate, polyurethane, and silicon. Commercially available polymers for pharmaceutical applications include EETDRAGIT.RTM. polymethacrylates.
• the controlled-release formulation employs an enteric coating or other coatings for delaying drug release until the drug reaches the small intestine or the colon. Delaying drug release in this manner would also control drug release time. Such coatings are known in the art.
• Each stage of release can have a specific release rate. For example, a stage can have a pulsatile-release profile, in which a drug is released rapidly and completely following a period of no release. A stage can also have a first-order release rate, in which a drug is released at a decreasing release rate. A zero-order release rate, i.e., a constant release rate, can also be employed.
• an entire dose (or a significant portion thereof) of a drug can be released within a short period or over an extended period.
• the formulation can be designed to release at least 50% (e.g., more than 60%, 70%, 75%, 80%, 85%, 90%, or 95%) of a dose of a drug or combination of drugs within 30 minutes of the initiation of release.
• the controlled-release formulation can also include one or more pharmaceutical excipients, e.g., binders, plasticizers, lubricants, diluents, fillers, coloring agents, flavoring agents, glidants, and preservatives.
• pharmaceutical excipients e.g., binders, plasticizers, lubricants, diluents, fillers, coloring agents, flavoring agents, glidants, and preservatives.
• pharmaceutical excipients are known in the art.
• the controlled-release formulation can be administered to a patient daily or as needed to induce and maintains sleep.
• Hard gelatin capsules for releasing diphenhydramine HC1 i.e., 2-
• the capsules were designed to release the three drugs in a staged sequence controlled via pH-dependent coatings: uncoated diphenhydramine HC1 for immediate release, coated zolpidem for release about 0.5-3 hours after administration, and coated lorazepam for release about 2-6 hours after administration.
• SM-l contained the following agents: (1) 50 mg of uncoated diphenhydramine HC1; (2) 5 mg of zolpidem tartrate in multiparticulate form coated with Eudragit ® L100 D-55, which dissolves at above pH 5.5; and (3) 0.5 mg of lorazepam in multiparticulate form coated with Eudragit ® L100/S100 (1 : 1), which dissolves at above pH 6.5.
• the coatings were selected to achieve release of zolpidem tartrate with gastric emptying and release of lorazepam when the drug reaches the intestines.
• the diphenhydramine HC1 plus zolpidem tartrate (D+Z) capsule contained the following agents: (1) 50 mg of uncoated diphenhydramine HC1; and (2) 5 mg of zolpidem tartrate in multiparticulate form coated with Eudragit ® L100 D-55, which dissolves at above pH 5.5.
• the diphenhydramine HC1 plus lorazepam (D+L) capsule contained the following agents: (1) 50 mg of uncoated diphenhydramine HC1; and (2) 0.5 mg of lorazepam in multiparticulate form coated with Eudragit ® L100/S100 (1 : 1), which dissolves at above pH 6.5.
• Example 3 Efficacy Assessment for the Formulations in Human Subjects with Short-Term Insomnia
• This study was a randomized, double-blind, single dose, 4-way crossover study to assess the efficacy of the capsules (as described in Examples 1 and 2 above) compared with placebo in a phase advance model of transient insomnia in subjects who reported previous transient insomnia.
• Sleep disturbance was induced using a 5-hour phase advance model with 8 hours (960 thirty-second epochs) of PSG recording as the primary efficacy assay.
• the study consisted of the following periods: 1. Screening period (Visit 1); 2. Treatment and PSG periods (Visits 2-5); and 3. Post-discharge follow-up safety phone call.
• TST total sleep time
• D diphenhydramine HC1
• L lorazepam
• Z zolpidem tartrate
• SM-1 50-mg diphenhydramine HC1, 5-mg delayed-release zolpidem tartrate, and 0.5-mg delayed- release lorazepam
• D+Z 50-mg diphenhydramine HC1 and 5-mg delayed-release zolpidem tartrate
• D+L 50- mg diphenhydramine HC1 and 0.5-mg delayed-release lorazepam
• placebo identical in appearance to SM-1, D+Z and D+L and had the same excipients, but no diphenhydramine HC1, zolpidem tartrate, lorazepam, or delayed-release coating materials.
• Visit 2 subjects checked in at the study center approximately 7 hours earlier than their median habitual bedtime as calculated from their diary data and returned their paper diary to study personnel for review. Visit 2 procedures were performed and according to the timing of sleep study events relative to each subject’s habitual bedtime. Each treatment and PSG period visit lasted approximately 11 to 12 hours. After the eligibility had been reconfirmed, subjects were randomly assigned to 1 of 4 treatment sequences as shown in Table 1.
• Subjects went to bed (“Lights Out”) 5 hours ( ⁇ 30 minutes) before their median habitual bedtime. Approximately 90 minutes before Lights Out, baseline DSST measurements were obtained and subjects were provided a light, low-fat snack (e.g., fruit and crackers). Approximately 60 minutes before Lights Out, PSG electrodes were applied to the subject and the machine was calibrated. Subjects were administered their assigned treatment by study personnel 30 minutes before Lights Out, and an oral cavity check was performed to assure compliance with treatment. At the assigned Lights Out time the subject went to bed, PSG biocalibration was performed, and PSG recording began. The recording continued for 8 hours.
• Lights Out 5 hours ( ⁇ 30 minutes) before their median habitual bedtime. Approximately 90 minutes before Lights Out, baseline DSST measurements were obtained and subjects were provided a light, low-fat snack (e.g., fruit and crackers). Approximately 60 minutes before Lights Out, PSG electrodes were applied to the subject and the machine was calibrated. Subjects were administered their assigned treatment by study personnel 30 minutes before Lights
• Transient insomnia was successfully induced using the 5-hour phase advance model in this study, as evidenced by the decreased sTST in the placebo group (range: 45-540 minutes) compared to the sleep duration recorded in the sleep diary during the screening period (range: 330-670 minutes).
• treatments with SM-l, D+Z and D+L resulted in 95.8 minutes, 95.1 minutes and 90.3 minutes increased TST relative to placebo (P ⁇ 0.000l), respectively. Differences between SM-l and D+Z or D+L were not statistically significant.
• SM-l, D+Z and D+L were all effective therapies in a 5-hour phase advance model of transient insomnia as evidenced in an increased TST in SM-l, D+Z and D+L treatments compared with placebo.
• SM-l, D+Z and D+L also showed a robust improvement in sleep maintenance.
• the observed efficacy i.e., TST

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Citations (4)

• 2018
  • 2018-11-06 AU AU2018448857A patent/AU2018448857A1/en not_active Abandoned
  • 2018-11-06 JP JP2021525041A patent/JP2022509759A/ja active Pending
  • 2018-11-06 EP EP18939542.9A patent/EP3876915A1/en not_active Withdrawn
  • 2018-11-06 SG SG11202104661WA patent/SG11202104661WA/en unknown
  • 2018-11-06 CN CN201880099296.3A patent/CN113271929A/zh active Pending
  • 2018-11-06 WO PCT/US2018/059327 patent/WO2020096569A1/en unknown

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