WO1999009989A1 - Pharmaceutical composition containing midazolam - Google Patents

Pharmaceutical composition containing midazolam Download PDF

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Publication number
WO1999009989A1
WO1999009989A1 PCT/GB1998/002511 GB9802511W WO9909989A1 WO 1999009989 A1 WO1999009989 A1 WO 1999009989A1 GB 9802511 W GB9802511 W GB 9802511W WO 9909989 A1 WO9909989 A1 WO 9909989A1
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WO
WIPO (PCT)
Prior art keywords
composition according
patient
oral cavity
composition
midazolam
Prior art date
Application number
PCT/GB1998/002511
Other languages
French (fr)
Inventor
Ian Mcmillan
Original Assignee
R. P. Scherer Limited
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Publication date
Application filed by R. P. Scherer Limited filed Critical R. P. Scherer Limited
Priority to AU88174/98A priority Critical patent/AU8817498A/en
Publication of WO1999009989A1 publication Critical patent/WO1999009989A1/en

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Classifications

    • 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
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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

Definitions

  • This invention relates to a pharmaceutical composition, a process for the preparation of such a composition and the use of such a composition for the induction of anaesthesia, anaesthetic pre-medication, sedation, conscious sedation, the treatment of anxiety, the induction of hypnosis and/or amnesia, the treatment and/or prophylaxis of epileptic fits and/or convulsions and the relaxation of skeletal muscle.
  • Midazolam (8-chloro-6- (2 -fluorophenyl) -l-methyl-4H- imidazo [1, 5a] [1 , 4] benzodiazepine) is a water-soluble imidazobenzodiazepine which is usually formulated as the hydrochloride salt or sometimes as the maleate salt. Like other benzodiazepines, midazolam binds with high affinity to benzodiazepine receptors in the brain and spinal cord and exhibits properties typical of such action. It therefore has a number of clinical uses including induction of anaesthesia, anaesthetic pre- medication, as a sedative and as a skeletal muscle relaxant .
  • Midazolam also has amnestic properties which complement its sedative and anaesthetic induction properties. It is therefore used as a sedative and/or hypnotic for unpleasant procedures in dentistry, for endoscopy and in intensive care when a patient requires artificial respiration.
  • midazolam is used in palliative and terminal care as an adjunct to diamorphine because of its sedative, amnestic and anticonvulsant properties.
  • midazolam since midazolam also exhibits anxiolytic properties, it is often used in the treatment of panic disorders.
  • Midazolam has been found to be effective and acceptable for use in children and it is therefore commonly used for anaesthetic pre-medication for children prior to surgery, dentistry or other invasive procedures.
  • midazolam is currently most commonly used as a formulation for intramuscular or intravenous injection and administration of the drug by injection is in itself traumatic, particularly for children.
  • Midazolam has been administered in the form of an oral tablet. However, when administered in this way, midazolam is absorbed from the gastrointestinal tract into the hepatic portal system and is presented to the liver before reaching the systemic circulation. It is known that midazolam is extensively metabolised by the liver to one of three main metabolites, c.-hydroxymidazolam, 4-hydroxymidazolam or a, 4-dihydroxymidazolam, with less than 1% of the administered dose of midazolam being excreted renally in the unchanged form.
  • pages 885-91 have compared intra- nasal and sub-lingual administration of midazolam for pre-medication of paediatric patients and have found that, whilst both modes of administration are clinically effective, sub-lingual administration is better accepted by the children involved than intra-nasal administration. However, it was noted that there was a lack of total compliance with the instructions for sub-lingual administration.
  • midazolam can cause respiratory and cardiovascular depression, confusion, lethargy, slurred speech, blurred vision and dizziness. All of these effects are consistent with its action as a sedative.
  • the elderly and those with renal or hepatic impairment are more sensitive to the effects of midazolam. It is therefore particularly important for such patients that midazolam should be administered in a way which avoids first-pass metabolism and thus produces more predictable plasma levels of midazolam and hence more consistent clinical effects.
  • it is also desirable to find a way of administering midazolam which is not traumatic, does not require specialist nursing care for administration and does not require complicated instructions for compliance, especially where the drug is to be administered to children.
  • compositions for oral administration comprising a carrier and, as active ingredient, midazolam or a salt thereof, characterised in that the composition is in the form of a fast -dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
  • pre-gastric absorption thus includes buccal, sublingual, oropharyngeal and oesophageal absorption.
  • Midazolam absorbed by such pre-gastric absorption passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of midazolam absorbed in this way may also be increased. This means that the dose of midazolam may be reduced whilst still producing the desired beneficial effects and this decrease in dose could result in a corresponding reduction of unwanted side effects.
  • U.S. Patent No. 5120549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix- forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
  • U.S. Patent No. 5079018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.
  • U.S. Patent No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
  • US Patent No. 5576014 discloses fast-dispersing dosage forms in the form of intrabuccally dissolving compressed mouldings comprising a saccharide having low mouldability which has been granulated with a saccharide having high mouldability.
  • WO 95/34293 describes the preparation of fast-dispersing dosage forms comprising a three-dimensional crystalline-based porous network bound together to form a stable structure which is formed by mixing uncured shearform matrix and an additive, moulding the dosage form and curing the shearform matrix.
  • EP-A-0737473 discloses fast-dispersing dosage forms which are effervescent.
  • Each such dosage form comprises a mixture of at least one water or saliva activated effervescent agent and a plurality of microcapsules containing the active ingredient.
  • US Patent No. 5587180 describes fast-dispersing dosage forms which include an active ingredient and a particulate support matrix comprising a first polymeric component which may be a polypeptide such as a non- hydrolysed gelatin, a second polymeric component which may be a different polypeptide such as a hydrolysed gelatin and a bulking agent.
  • the dosage forms are prepared by mixing the particulate support matrix with the active ingredient and any other additives and then forming the mixture into tablets by compression.
  • fast-dispersing dosage form therefore encompasses all the types of dosage form described in the preceding paragraphs.
  • the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.
  • composition of the invention disintegrates within 1 to 60 seconds, more preferably 1 to 30 seconds, especially 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity.
  • the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components.
  • Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides ; alginates; carboxymethylcelluloses; carrageenans ; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes .
  • matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L- hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine .
  • sugars such as mannitol, dextrose, lactose, galactose and trehalose
  • cyclic sugars such as cyclodextrin
  • inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates
  • amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-a
  • One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification.
  • the matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant.
  • the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
  • Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard.
  • Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these.
  • Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K and thaumatic.
  • Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.
  • Midazolam may be utilised in its free base form or as a salt thereof, particularly the hydrochloride or maleate salt thereof.
  • Conventional injectable formulations of midazolam for intramuscular or intravenous use are typically administered in amounts of 3 to 6mg to produce effective sedative and anxiolytic effects with higher doses being used where a hypnotic action is required.
  • midazolam has been delivered intra-nasally and sub-lingually at dosages of 0.2mg/kg.
  • it is preferred that midazolam is present in the composition of the invention in an amount from 1 to 20mg, preferably 3 to 15mg.
  • the active ingredient is present in the composition in an amount from 0.5 to 30%, more preferably 1 to 25%, by weight of the composition.
  • a process for preparing a pharmaceutical composition as defined above which comprises bringing a carrier into association with the active ingredient.
  • the invention provides a fast- dispersing dosage form designed to release active ingredient rapidly in the oral cavity for use in delivering midazolam or a salt thereof .
  • a method of administering midazolam or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition as previously defined is also provided.
  • midazolam has been used to achieve a variety of clinical effects and the invention therefore also provides a composition as defined above for use in the induction of anaesthesia, in anaesthetic pre-medication, as a sedative, in conscious sedation, as an anxiolytic, as an hypnotic, as an amnestic, in the treatment of epileptic fits (status epilepticus) , as an anticonvulsant and/or as a skeletal muscle relaxant .
  • conscious sedation is used to describe the state in which a patient is still conscious but sedated.
  • the induction of such a state of "conscious sedation” is necessary for the performance of various medical procedures, such as endoscopy.
  • composition of the invention is particularly useful for the treatment of a patient experiencing an epileptic fit where the injection of a sedative drug is particularly difficult to achieve and swallowing of a conventional oral form is undesirable or not practical.
  • compositions as defined above for the manufacture of a medicament for the induction of anaesthesia, for anaesthetic pre-medication, for sedation, for conscious sedation, for the treatment of anxiety, especially panic disorders, for the induction of hypnosis, for the induction of short-term amnesia, for the treatment and/or prophylaxis of epileptic fits and/or convulsions and/or for the relaxation of skeletal muscle.
  • the invention provides a method of inducing anaesthesia in a patient, providing anaesthetic pre-medication in a patient, sedating a patient, inducing conscious sedation, inducing hypnosis in a patient and/or inducing amnesia in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition as defined above.
  • a method of treating anxiety, treating and/or preventing epileptic fits, treating convulsions, preventing convulsions and/or relaxing skeletal muscle is also provided which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition as defined above.
  • Gelatin (80g) and mannitol (60g) were dispersed in a portion of purified water (1600g) and heated to 60°C ⁇ 2°C to allow complete dissolution of the solids.
  • the mix was cooled down to room temperature (20-24°C) .
  • aspartame (50g) , midazolam (13.33g) and dilute hydrochloric acid (106.82g) were added sequentially to the mix.
  • the mix was then homogenised to ensure complete dissolution of the solids.
  • the remaining water (89.85g) was added to the mixer and the bulk homogenised to ensure dissolution was complete.
  • 750mg of the midazolam 0.67% dispersion formed in (a) above was dosed into each one of a series of pre-formed blister pockets having a pocket diameter of about 17mm.
  • the blister laminate comprised 200 ⁇ .m PVC coated with 40g per square metre PVdC .
  • the product was frozen immediately in a liquid nitrogen freeze tunnel .
  • the frozen product was then stored below -20°C for a minimum of 15 hours prior to freeze-drying in a freeze drier using a drying temperature of +5°C and a chamber pressure of 0.5 mbar.
  • the freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20 ⁇ m aluminium) .
  • Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely.
  • Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.
  • Each dosage unit had the following composition:
  • Gelatin (810g), mannitol (630g) , midazolam (360g) and citric acid (270g) were dispersed in a portion of purified water (15kg) by mixing thoroughly in the bowl of a vacuum mixer. The mix was then heated to 40°C + 2°C and homogenised for ten minutes to allow complete dissolution of the solids. The mix was cooled down to room temperature (20-24°C) . When cooled, the glycine (180g) , aspartame (90g) and lemon/lime flavour (90g) were added sequentially to the mix. The mix was then homogenised to ensure complete dissolution of the solids. The remaining water (570g) was added to the mixer and the bulk mix homogenised to ensure dissolution was complete.
  • the blister laminate comprised 200 ⁇ m PVC coated with 40g per square metre PVdC .
  • the product was frozen immediately in a liquid nitrogen freeze tunnel .
  • the frozen product was then stored below -20°C for a minimum of 12 hours prior to freeze- drying in a freeze drier using a drying temperature of +10 °C and a chamber pressure of 0.5 mbar .
  • the freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20/m aluminium) .
  • Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely.
  • Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.
  • Each dosage unit had the following composition:
  • Magnesium stearate and mint flavour were mixed with the dried granules, each at a level of 0.5%, and the mix was formed into fast- disintegrating tablets (with a hardness greater than 2kg) to provide a dose of 5mg midazolam (base equivalent) .
  • a shearform matrix material was prepared by mixing sucrose (84.75% w/w) , sorbitol (15.0% w/w) and Tween 80 (0.25% w/w) . This mixture was processed by flash flow processing, as detailed in WO 95/34293, to produce a spun floss material. This shearform matrix was then mixed with midazolam hydrochloride (5.55%), microcrystalline cellulose (20%) , aspartame (1%) , lemon/lime flavour (2%), lecithin (0.5%) and colloidal silicon dioxide (0.25%) . Tablets of 200 mg were formed by light compaction and were allowed to cure under conditions as given in WO 95/34293. The tablets had a composition of:
  • the ingredients listed above were directly mixed together in a suitable mixer. The contents of the mixer were then emptied and lightly compressed on a tablet press to give a tablet weight of lg. The formed tablets disintegrated rapidly in the mouth.
  • a high porosity particulate support matrix was formed by adding the following ingredients to sufficient purified water to produce a mixture with a volume of 650 ml. The mixture was then spray dried in accordance with the process described in US 5587180 to produce a low density support matrix.
  • the resultant dried matrix (35.77g) was mixed with midazolam maleate (3.63g), aspartame (0.2g), sweet peppermint flavour (0.2g) and magnesium stearate (0.2g) and then lightly compressed to form tablets that rapidly disintegrate in the mouth.
  • the objective of this study was to compare the pharmacokinetic and pharmacodynamic profiles of midazolam resulting from the administration of a fast-dispersing formulation prepared by the method of Example 1, the sub- lingual administration of an oral tablet sold as "Dormicum” by Hoffman La Roche AG, 79630 Grenzach-Whylen, Germany and the intra-muscular administration of an injection formulation sold under the registered Trade Mark “Hypnovel” by Roche Products Ltd. P. O. Box 8, Welwyn Garden City, Herts. AL7 3AY, England.
  • An open label, randomised, crossover volunteer study was performed as follows. Five healthy male and seven healthy female subjects between the ages of 18 and 50 years, giving written informed consent, underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received study treatment in the order dictated by the pre-determined randomisation schedule. Fasted subjects were given lOmg midazolam as 2 x 5mg units of the formulation of Example 1 (placed on the tongue and allowed to dissolve) , or one "Dormicum” 7.5mg tablet (placed under the tongue and allowed to dissolve), or 5mg of "Hypnovel" injection administered intramuscularly. A minimum 3 day wash-out period was allowed between successive treatments. The formulation of example 1 disintegrated and dissolved in under 1 minute in the mouth whilst the "Dormicum” tablet took on average 15 minutes to dissolve under the tongue (range of 10 to 35 minutes) .
  • Plasma samples for the determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration), then at 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after drug administration.
  • GC-MS assays were performed to determine the concentration of midazolam in each of the blood plasma samples .
  • the following pharmacokinetic parameters were determined: Cmax (the maximum plasma concentration achieved) and tmax (the time of the maximum plasma concentration) .
  • VAS sedation visual analogue scale
  • DSST digit symbol substitution test
  • CFF critical flicker fusion test
  • the sedation VAS score was measured by the subject marking a 100mm vertical line that had a scale of 0 to 100, where 0 was equivalent to "extremely drowsy" and 100 was “fully alert”. The subject was required to record the VAS score at baseline (immediately before drug administration), then at 5 minutes, 20 minutes, 35 minutes, 1 hour 5 minutes, 1 hour 35 minutes, 2 hours 5 minutes, 3 hours 5 minutes and 4 hours 5 minutes after drug administration.
  • the digit symbol substitution test consisted of providing the subjects with a grid where the numbers 1 to 9 were matched to a symbol at the top of a sheet of paper. A series of random numbers were printed in a grid below the key and the subjects were given 90 seconds to write the corresponding symbol under each digit, working sequentially and not missing any numbers out. The number of correct symbols entered in the 90 seconds was recorded. A different random number grid was used for each occasion to prevent learning effects.
  • the DSST was completed by each subject at baseline (immediately before drug administration) , then at 35 minutes, 1 hour 5 minutes, 1 hour 35 minutes, 2 hours 5 minutes, 3 hours 5 minutes and 4 hours 5 minutes after dosing.
  • the Critical Flicker Fusion (CFF) test required the use of a flickering light source that comprised two 5mm diameter orange LEDs set 2cm apart and a button connected to a computer that recorded the frequency of the flickering light at the moment the button was pressed.
  • the test consisted of two parts. The first part involved setting the LEDs to flicker at a frequency higher than could be detected by the unaided eye so that they appeared as a constant light . The frequency was then steadily decreased and the subject was asked to press the button when they could first detect flickering of the lights. This process was repeated twice more at each timepoint. The second part was then initiated and the lights were set to a very low frequency so that the subject could easily see the flickering.
  • Example 1 produces a similar Cmax to that of the intramuscular injection, although the relative bioavailability is about half that of the injection. It is also apparent that the time to the peak plasma concentration for the formulation of Example 1 is similar to the intramuscular injection and faster than a slowly disintegrating tablet (“DORMICUM”) administered sub- lingually (see Figure 2) . This would suggest that a formulation that rapidly disintegrates in the mouth will offer the rapid onset of sedation that is associated with the intramuscular injection without the disadvantage of the pain of injection.
  • DORMICUM slowly disintegrating tablet
  • FIG. 3 compares the mean plasma midazolam concentrations for males and females who received the 22 intramuscular injection whilst Figure 4 compares the plasma midazolam concentrations for male and females who were given the formulation of Example 1. It can be seen that, when given the intramuscular injection, females on average exhibit much lower plasma concentrations than males. For subjects given the formulation of Example 1, the peak plasma concentrations are very similar between males and females . This would indicate that a more reproducible response may be expected from the formulation of Example 1 irrespective of whether the subject is male or female.
  • the pharmacodynamic profiles also show that a dose of lOmg administered as the formulation of Example 1 produces a similar pharmacological effect to that produced by injection.
  • the sedation VAS score against time profile is shown in Figure 5. This demonstrates that the formulations produce a similar reduction in the VAS score (ie. the subjects became sedated) and the recovery back to being "fully alert” is also very similar. This time for recovery is important, as this will allow patients to leave the surgical unit sooner.
  • the mean digit symbol substitution profile is shown in Figure 6 following administration of the formulation of Example 1 and the intramuscular injection.
  • the DSST test results show that, shortly after the administration of the products, the subjects are less capable of matching the numbers with the symbols according to the specific key. This is consistent with the subjects' cognitive function being affected by the drug.
  • the mean profile arising from the rapidly disintegrating formulation (Example 1) exhibits a greater decrease in response at the 35 minute timepoint, but the time of recovery to the pre-treatment score is similar to that arising after administration of the intramuscular injection.
  • the overall shape of the DSST time curves are similar to the VAS sedation data shown in Figure 5.
  • the results of the critical flicker fusion test are set out in Figure 7.
  • the decrease in the critical flicker fusion frequency shown in Figure 7 demonstrates that the subjects' psychomotor response is rapidly affected by the formulation prepared as in Example 1 and the intramuscular injection. This test is considered to be a more sensitive test than the DSST test for detecting drug-induced sedation.
  • the results demonstrate that the formulation prepared as in Example 1 is capable of producing equivalent efficacy to the intramuscular injection of midazolam.
  • Both the pharmacokinetic and the pharmacodynamic data support the use of a dosage form of midazolam that disintegrates rapidly in the mouth especially for use in premedication and conscious sedation indications.
  • the formulation of the present invention also offers a faster onset of action than a more slowly disintegrating dosage form and is more convenient for patients to take with the dosage form disappearing in seconds instead of having to be held under the tongue for several minutes .
  • the formulation of the present invention also has the advantages that it does not require special personnel for its administration and it is not painful or traumatic to receive unlike the injectable form of midazolam.

Abstract

This invention relates to a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, midazolam or a salt thereof, characterized in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity. A process for the preparation of such a composition and the use of such a composition for the induction of anaesthesia, anaesthetic pre-medication, sedation, conscious sedation, the treatment of anxiety, the induction of hypnosis and/or amnesia, the treatment and/or prophylaxis of epileptic fits and/or convulsions and the relaxation of skeletal muscle are also provided.

Description

PHARMACEUTICAL COMPOSITION CONTAINING MIDAZOLAM
This invention relates to a pharmaceutical composition, a process for the preparation of such a composition and the use of such a composition for the induction of anaesthesia, anaesthetic pre-medication, sedation, conscious sedation, the treatment of anxiety, the induction of hypnosis and/or amnesia, the treatment and/or prophylaxis of epileptic fits and/or convulsions and the relaxation of skeletal muscle.
Midazolam (8-chloro-6- (2 -fluorophenyl) -l-methyl-4H- imidazo [1, 5a] [1 , 4] benzodiazepine) is a water-soluble imidazobenzodiazepine which is usually formulated as the hydrochloride salt or sometimes as the maleate salt. Like other benzodiazepines, midazolam binds with high affinity to benzodiazepine receptors in the brain and spinal cord and exhibits properties typical of such action. It therefore has a number of clinical uses including induction of anaesthesia, anaesthetic pre- medication, as a sedative and as a skeletal muscle relaxant . Midazolam also has amnestic properties which complement its sedative and anaesthetic induction properties. It is therefore used as a sedative and/or hypnotic for unpleasant procedures in dentistry, for endoscopy and in intensive care when a patient requires artificial respiration. In addition, midazolam is used in palliative and terminal care as an adjunct to diamorphine because of its sedative, amnestic and anticonvulsant properties. Moreover, since midazolam also exhibits anxiolytic properties, it is often used in the treatment of panic disorders.
Midazolam has been found to be effective and acceptable for use in children and it is therefore commonly used for anaesthetic pre-medication for children prior to surgery, dentistry or other invasive procedures. However, midazolam is currently most commonly used as a formulation for intramuscular or intravenous injection and administration of the drug by injection is in itself traumatic, particularly for children.
Midazolam has been administered in the form of an oral tablet. However, when administered in this way, midazolam is absorbed from the gastrointestinal tract into the hepatic portal system and is presented to the liver before reaching the systemic circulation. It is known that midazolam is extensively metabolised by the liver to one of three main metabolites, c.-hydroxymidazolam, 4-hydroxymidazolam or a, 4-dihydroxymidazolam, with less than 1% of the administered dose of midazolam being excreted renally in the unchanged form. Moreover, of these metabolites, only α-hydroxymidazolam is thought to be pharmacologically active, and thus capable of contributing to the clinical effects, and this metabolite has a half-life even shorter than that of the parent drug. The high but variable first-pass metabolism of midazolam after oral administration can therefore lead to unpredictable effects in contrast to injectable presentation.
There have been a number of literature reports detailing the rapid absorption of midazolam following sub-lingual administration. For instance, Fujii et al in J. Pharmacobiodyn. , (1988), Vol. 11(3), pages 206-209, compared a 15mg dose of midazolam maleate administered sub-lingually with oral administration of the same dose and found that sub- lingual administration resulted in a four-fold increase in bioavailability compared with oral administration, possibly due to avoidance of the first- pass effect. In addition, Karl et al in Anesthesiology, (1993), Vol. 78(5), pages 885-91 have compared intra- nasal and sub-lingual administration of midazolam for pre-medication of paediatric patients and have found that, whilst both modes of administration are clinically effective, sub-lingual administration is better accepted by the children involved than intra-nasal administration. However, it was noted that there was a lack of total compliance with the instructions for sub-lingual administration.
As a benzodiazepine, midazolam can cause respiratory and cardiovascular depression, confusion, lethargy, slurred speech, blurred vision and dizziness. All of these effects are consistent with its action as a sedative. The elderly and those with renal or hepatic impairment are more sensitive to the effects of midazolam. It is therefore particularly important for such patients that midazolam should be administered in a way which avoids first-pass metabolism and thus produces more predictable plasma levels of midazolam and hence more consistent clinical effects. Moreover, it is also desirable to find a way of administering midazolam which is not traumatic, does not require specialist nursing care for administration and does not require complicated instructions for compliance, especially where the drug is to be administered to children.
According to the present invention there is therefore provided a pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, midazolam or a salt thereof, characterised in that the composition is in the form of a fast -dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
It has been found that such fast-dispersing dosage forms facilitate pre-gastric absorption of the active ingredient, that is, absorption of the active ingredient from that part of the alimentary canal prior to the stomach. The term "pre-gastric absorption" thus includes buccal, sublingual, oropharyngeal and oesophageal absorption. Midazolam absorbed by such pre-gastric absorption passes straight into the systemic circulatory system thereby avoiding first pass metabolism in the liver. Accordingly, bioavailability of midazolam absorbed in this way may also be increased. This means that the dose of midazolam may be reduced whilst still producing the desired beneficial effects and this decrease in dose could result in a corresponding reduction of unwanted side effects.
In addition, such fast-dispersing dosage forms are easy for patients to take and do not require special instructions or specialist nursing care for their administration .
One example of a fast -dispersing dosage form is described in U.S. Patent No. 4855326 in which a melt spinnable carrier agent, such as sugar, is combined with an active ingredient and the resulting mixture spun into a "candy-floss" preparation. The spun "candy-floss" product is then compressed into a rapidly dispersing, highly porous solid dosage form.
U.S. Patent No. 5120549 discloses a fast-dispersing matrix system which is prepared by first solidifying a matrix-forming system dispersed in a first solvent and subsequently contacting the solidified matrix with a second solvent that is substantially miscible with the first solvent at a temperature lower than the solidification point of the first solvent, the matrix- forming elements and active ingredient being substantially insoluble in the second solvent, whereby the first solvent is substantially removed resulting in a fast-dispersing matrix.
U.S. Patent No. 5079018 discloses a fast-dispersing dosage form which comprises a porous skeletal structure of a water soluble, hydratable gel or foam forming material that has been hydrated with water, rigidified in the hydrated state with a rigidifying agent and dehydrated with a liquid organic solvent at a temperature of about 0°C or below to leave spaces in place of hydration liquid.
Published International Application No. WO 93/12769 (PCT/JP93/01631) describes fast-dispersing dosage forms of very low density formed by gelling, with agar, aqueous systems containing the matrix- forming elements and active ingredient , and then removing water by forced air or vacuum drying.
U.S. Patent No. 5298261 discloses fast-dispersing dosage forms which comprise a partially collapsed matrix network that has been vacuum-dried above the collapse temperature of the matrix. However, the matrix is preferably at least partially dried below the equilibrium freezing point of the matrix.
Published International Application No. WO 91/04757 (PCT/US90/05206) discloses fast-dispersing dosage forms which contain an effervescent disintegration agent designed to effervesce on contact with saliva to provide rapid disintegration of the dosage form and dispersion of the active ingredient in the oral cavity.
US Patent No. 5576014 discloses fast-dispersing dosage forms in the form of intrabuccally dissolving compressed mouldings comprising a saccharide having low mouldability which has been granulated with a saccharide having high mouldability.
Published International Application No. WO 95/34293 describes the preparation of fast-dispersing dosage forms comprising a three-dimensional crystalline-based porous network bound together to form a stable structure which is formed by mixing uncured shearform matrix and an additive, moulding the dosage form and curing the shearform matrix.
EP-A-0737473 discloses fast-dispersing dosage forms which are effervescent. Each such dosage form comprises a mixture of at least one water or saliva activated effervescent agent and a plurality of microcapsules containing the active ingredient.
US Patent No. 5587180 describes fast-dispersing dosage forms which include an active ingredient and a particulate support matrix comprising a first polymeric component which may be a polypeptide such as a non- hydrolysed gelatin, a second polymeric component which may be a different polypeptide such as a hydrolysed gelatin and a bulking agent. Generally, the dosage forms are prepared by mixing the particulate support matrix with the active ingredient and any other additives and then forming the mixture into tablets by compression.
The term "fast-dispersing dosage form" therefore encompasses all the types of dosage form described in the preceding paragraphs. However, it is particularly preferred that the fast-dispersing dosage form is of the type described in U.K. Patent No. 1548022, that is, a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water- dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent.
It is preferred that the composition of the invention disintegrates within 1 to 60 seconds, more preferably 1 to 30 seconds, especially 1 to 10 seconds and particularly 2 to 8 seconds, of being placed in the oral cavity.
In the case of the preferred type of fast- dispersing dosage form described above, the composition will preferably contain, in addition to the active ingredient, matrix forming agents and secondary components. Matrix forming agents suitable for use in the present invention include materials derived from animal or vegetable proteins, such as the gelatins, dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides ; alginates; carboxymethylcelluloses; carrageenans ; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide/protein or polysaccharide complexes such as gelatin-acacia complexes .
Other matrix forming agents suitable for use in the present invention include sugars such as mannitol, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminium silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L-aspartic acid, L-glutamic acid, L- hydroxyproline, L-isoleucine, L-leucine and L- phenylalanine .
One or more matrix forming agents may be incorporated into the solution or suspension prior to solidification. The matrix forming agent may be present in addition to a surfactant or to the exclusion of a surfactant. In addition to forming the matrix, the matrix forming agent may aid in maintaining the dispersion of any active ingredient within the solution or suspension. This is especially helpful in the case of active agents that are not sufficiently soluble in water and must, therefore, be suspended rather than dissolved.
Secondary components such as preservatives, antioxidants, surfactants, viscosity enhancers, colouring agents, flavouring agents, pH modifiers, sweeteners or taste-masking agents may also be incorporated into the composition. Suitable colouring agents include red, black and yellow iron oxides and FD & C dyes such as FD & C blue No. 2 and FD & C red No. 40 available from Ellis & Everard. Suitable flavouring agents include mint, raspberry, liquorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavours and combinations of these. Suitable pH modifiers include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid. Suitable sweeteners include aspartame, acesulfame K and thaumatic. Suitable taste-masking agents include sodium bicarbonate, ion-exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives.
Midazolam may be utilised in its free base form or as a salt thereof, particularly the hydrochloride or maleate salt thereof. Conventional injectable formulations of midazolam for intramuscular or intravenous use are typically administered in amounts of 3 to 6mg to produce effective sedative and anxiolytic effects with higher doses being used where a hypnotic action is required. Similarly, for anaesthetic pre- medication in children, midazolam has been delivered intra-nasally and sub-lingually at dosages of 0.2mg/kg. Accordingly, it is preferred that midazolam is present in the composition of the invention in an amount from 1 to 20mg, preferably 3 to 15mg. It is also preferred that the active ingredient is present in the composition in an amount from 0.5 to 30%, more preferably 1 to 25%, by weight of the composition.
According to another aspect of the invention there is provided a process for preparing a pharmaceutical composition as defined above which comprises bringing a carrier into association with the active ingredient.
In a further aspect, the invention provides a fast- dispersing dosage form designed to release active ingredient rapidly in the oral cavity for use in delivering midazolam or a salt thereof . A method of administering midazolam or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition as previously defined is also provided.
As mentioned above, midazolam has been used to achieve a variety of clinical effects and the invention therefore also provides a composition as defined above for use in the induction of anaesthesia, in anaesthetic pre-medication, as a sedative, in conscious sedation, as an anxiolytic, as an hypnotic, as an amnestic, in the treatment of epileptic fits (status epilepticus) , as an anticonvulsant and/or as a skeletal muscle relaxant .
In this context, the term "conscious sedation" is used to describe the state in which a patient is still conscious but sedated. The induction of such a state of "conscious sedation" is necessary for the performance of various medical procedures, such as endoscopy.
The composition of the invention is particularly useful for the treatment of a patient experiencing an epileptic fit where the injection of a sedative drug is particularly difficult to achieve and swallowing of a conventional oral form is undesirable or not practical.
According to a further aspect of the invention there is provided the use of a composition as defined above for the manufacture of a medicament for the induction of anaesthesia, for anaesthetic pre-medication, for sedation, for conscious sedation, for the treatment of anxiety, especially panic disorders, for the induction of hypnosis, for the induction of short-term amnesia, for the treatment and/or prophylaxis of epileptic fits and/or convulsions and/or for the relaxation of skeletal muscle.
In another aspect, the invention provides a method of inducing anaesthesia in a patient, providing anaesthetic pre-medication in a patient, sedating a patient, inducing conscious sedation, inducing hypnosis in a patient and/or inducing amnesia in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition as defined above. A method of treating anxiety, treating and/or preventing epileptic fits, treating convulsions, preventing convulsions and/or relaxing skeletal muscle is also provided which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition as defined above.
This invention is further illustrated by the following examples.
Example 1
Preparation of a fast-dispersing dosage form containing midazolam (a) Preparation of midazolam 0.67% dispersion
Gelatin (80g) and mannitol (60g) were dispersed in a portion of purified water (1600g) and heated to 60°C± 2°C to allow complete dissolution of the solids. The mix was cooled down to room temperature (20-24°C) . When cooled, aspartame (50g) , midazolam (13.33g) and dilute hydrochloric acid (106.82g) were added sequentially to the mix. The mix was then homogenised to ensure complete dissolution of the solids. The remaining water (89.85g) was added to the mixer and the bulk homogenised to ensure dissolution was complete.
(b) Preparation of midazolam 5mg units
750mg of the midazolam 0.67% dispersion formed in (a) above was dosed into each one of a series of pre-formed blister pockets having a pocket diameter of about 17mm. The blister laminate comprised 200μ.m PVC coated with 40g per square metre PVdC . The product was frozen immediately in a liquid nitrogen freeze tunnel . The frozen product was then stored below -20°C for a minimum of 15 hours prior to freeze-drying in a freeze drier using a drying temperature of +5°C and a chamber pressure of 0.5 mbar. The freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20μm aluminium) . Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely. Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name. Each dosage unit had the following composition:
Ingredient Weight (mg) %by wt of composition
Purified Water EP/USP* 633.700 84.49
Midazolam EP 5.000 0.67
Gelatin EP/USNF 30.000 4.00
Mannitol EP/USP 22.500 3.00
Dilute Hydrochloric acid 40.050 5.34
Aspartame EP/USNF 18.750 2.50
Total 750.000 100.00
* signifies removed during the lyophilisation process
Example 2
Preparation of a fast-dispersing dosage form containing midazolam
(a) Preparation of midazolam 2.0% dispersion
Gelatin (810g), mannitol (630g) , midazolam (360g) and citric acid (270g) were dispersed in a portion of purified water (15kg) by mixing thoroughly in the bowl of a vacuum mixer. The mix was then heated to 40°C + 2°C and homogenised for ten minutes to allow complete dissolution of the solids. The mix was cooled down to room temperature (20-24°C) . When cooled, the glycine (180g) , aspartame (90g) and lemon/lime flavour (90g) were added sequentially to the mix. The mix was then homogenised to ensure complete dissolution of the solids. The remaining water (570g) was added to the mixer and the bulk mix homogenised to ensure dissolution was complete.
(b) Preparation of midazolam 5mg units
250mg of the midazolam 2.0% dispersion formed in (a) above was dosed into each one of a series of preformed blister pockets having a pocket diameter of 12mm. The blister laminate comprised 200μm PVC coated with 40g per square metre PVdC . The product was frozen immediately in a liquid nitrogen freeze tunnel . The frozen product was then stored below -20°C for a minimum of 12 hours prior to freeze- drying in a freeze drier using a drying temperature of +10 °C and a chamber pressure of 0.5 mbar . The freeze dried units were then inspected for the presence of critical defects and the remainder of the batch sealed with lidding foil consisting of a paper/foil laminate (20/m aluminium) . Each blister was then coded with a batch number and overwrapped in a preformed sachet by placing the blister in the sachet and sealing the open end of the sachet completely. Each sachet was then labelled with the product name, batch number, date of manufacture and suppliers name.
Each dosage unit had the following composition:
Ingredient Weight %by wt of composition
Purified Water EP/USP* 216.250 86.50 Midazolam EP 5.000 2.00 Gelatin EP/USNF 11.250 4.50 Mannitol EP/USP 8.750 3.50 Citric acid EP/USP 3.750 1.50 Glycine USP 2.500 1.00 Lemon Lime Flavour 1.250 0.50 Aspartame EP/USNF 1.250 0.50
Total 250.000 100.00
* signifies removed during the lyophilisation process
The following examples further exemplify formulations which can be prepared using the processes described in Examples 1 and 2 above. Example 3
Ingredient Weight %by wt of composition
Purified Water EP/USP* 437. .500 87.50 Midazolam EP 10. .000 2 00 Gelatin EP/USNF 21. .250 4.25 Mannitol EP/USP 15. .000 3.00 Citric acid EP/USP 6. .250 1 25 Poloxamer 188 USNF 3, .750 0.75 Grapefruit Flavour 3. .750 0.75 Aspartame EP/USNF 2. .500 0.50
Total 500.000 100.00
* signifies removed during the lyophilisation process
Example 4
Ingredient Weight %by wt of composition
Purified Water EP/USP* 218.702 87.48 Midazolam hydrochloride 5.548 2.22 Gelatin EP/USNF 10.000 4.00 Mannitol EP/USP 8.750 3.50 Citric acid EP/USP 0.750 0.30 Poloaxmer 188 USNF 2.500 1.00 Lemon Lime Flavour 2.500 1.00 Aspartame EP/USNF 1.250 0.50
Total 250.000 100.00
* signifies removed during the lyophilisation process Example 5
Ingredient Weight %by wt of composition
Purified Water EP/USP* 220 595 88 .24 Midazolam maleate 6 780 2 .71 Gelatin EP/USNF 10 000 4, .00 Mannitol EP/USP 8 750 3 .50 Citric acid EP/USP 0 750 0, .30 Spearmint Flavour 1 250 0 .50 Aspartame EP/USNF 1 875 0, .75
Total 250.000 100.00
* signifies removed during the lyophilisation process
Example 6
Ingredient Weight (mg) %by wt of comp>osition
Purified Water EP/USP* 613.025 81.74 Midazolam EP 10.000 1.33 Gelatin EP/USNF 30.000 4.00 Mannitol EP/USP 22.500 3.00 Dilute Hydrochloric acid 40.725 5.43 Sweet Peppermint Flavour 7.500 1.00 Cherry Flavour 7.500 1.00 Aspartame EP/USNF 18.750 2.50
Total 750.000 100.00
* signifies removed during the lyophilisation process Example 7
Ingredient Weight (mg) %by wt of composition
Purified Water EP/USP* 650.535 86.74 Midazolam maleate 20.340 2.71 Gelatin EP/USNF 30.000 4.00 Mannitol EP/USP 26.250 3.50 Citric acid EP/USP 2.250 0.30 Lemon Flavour 7.500 1.00 Mint Flavour 7.500 1.00 Aspartame EP/USNF 5.625 0.75
Total 750.000 100.00
* signifies removed during the lyophilisation process
Example 8
Ingredient Weight (mg) % by wt of composition
Purified Water EP/USP* 634.125 84.55 Midazolam hydrochloride 5.550 0.74 Gelatin EP/USNF 30.000 4.00 Mannitol EP/USP 22.500 3.00 Dilute Hydrochloric acid 20.325 2.71 Blackcurrant Flavour 7.500 1.00 Grape Flavour 7.500 1.00 Aspartame EP/USNF 22.500 3.00
Total 750.000 100.00
* signifies removed during the lyophilisation process
Further varieties of fast-dispersing dosage form containing midazolam and processes for their preparation are described in the following examples:- Example 9
A solution of maltose (20g) , dissolved in purified water (190g) , was used to granulate a mixture of mannitol (380g) and midazolam maleate (9.8g) in a fluidised bed granulator using process conditions similar to those described in US 5576014. Magnesium stearate and mint flavour were mixed with the dried granules, each at a level of 0.5%, and the mix was formed into fast- disintegrating tablets (with a hardness greater than 2kg) to provide a dose of 5mg midazolam (base equivalent) .
Example 10
A shearform matrix material was prepared by mixing sucrose (84.75% w/w) , sorbitol (15.0% w/w) and Tween 80 (0.25% w/w) . This mixture was processed by flash flow processing, as detailed in WO 95/34293, to produce a spun floss material. This shearform matrix was then mixed with midazolam hydrochloride (5.55%), microcrystalline cellulose (20%) , aspartame (1%) , lemon/lime flavour (2%), lecithin (0.5%) and colloidal silicon dioxide (0.25%) . Tablets of 200 mg were formed by light compaction and were allowed to cure under conditions as given in WO 95/34293. The tablets had a composition of:
Ingredient mg/tablet % w/w
Midazolam hydrochloride 11.1 5.55
Shearform matrix 141.4 70.70
Microcrystalline cellulose 40.0 20.00
Aspartame 2.0 1.00
Lemon/lime flavour 4.0 2.00
Lecithin 1.0 0.50
Colloidal silicon dioxide 0.5 0.25
Total 200.000 100.00 Example 11
Ingredient mg/tablet % w/w
Midazolam hydrochloride 11.1 1.11
Sorbitol 332.0 33.20
Compressible sugar binder 331.9 33.19
Citric acid 125.0 12.50
Sodium bicarbonate 100.0 10.00
Grape flavoured powder 15.0 1.50
Aspartame 40.0 4.00
Monopotassium phosphate 25.0 2.50
Magnesium stearate 20.0 2.00
Total 1000.000 100.00
The ingredients listed above were directly mixed together in a suitable mixer. The contents of the mixer were then emptied and lightly compressed on a tablet press to give a tablet weight of lg. The formed tablets disintegrated rapidly in the mouth.
Example 12
A high porosity particulate support matrix was formed by adding the following ingredients to sufficient purified water to produce a mixture with a volume of 650 ml. The mixture was then spray dried in accordance with the process described in US 5587180 to produce a low density support matrix.
Figure imgf000020_0001
The resultant dried matrix (35.77g) was mixed with midazolam maleate (3.63g), aspartame (0.2g), sweet peppermint flavour (0.2g) and magnesium stearate (0.2g) and then lightly compressed to form tablets that rapidly disintegrate in the mouth.
Example 13
Comparative pharmacokinetic and pharmacodynamic study
The objective of this study was to compare the pharmacokinetic and pharmacodynamic profiles of midazolam resulting from the administration of a fast-dispersing formulation prepared by the method of Example 1, the sub- lingual administration of an oral tablet sold as "Dormicum" by Hoffman La Roche AG, 79630 Grenzach-Whylen, Germany and the intra-muscular administration of an injection formulation sold under the registered Trade Mark "Hypnovel" by Roche Products Ltd. P. O. Box 8, Welwyn Garden City, Herts. AL7 3AY, England.
An open label, randomised, crossover volunteer study was performed as follows. Five healthy male and seven healthy female subjects between the ages of 18 and 50 years, giving written informed consent, underwent a thorough medical examination to establish their fitness to participate in the study. Subjects received study treatment in the order dictated by the pre-determined randomisation schedule. Fasted subjects were given lOmg midazolam as 2 x 5mg units of the formulation of Example 1 (placed on the tongue and allowed to dissolve) , or one "Dormicum" 7.5mg tablet (placed under the tongue and allowed to dissolve), or 5mg of "Hypnovel" injection administered intramuscularly. A minimum 3 day wash-out period was allowed between successive treatments. The formulation of example 1 disintegrated and dissolved in under 1 minute in the mouth whilst the "Dormicum" tablet took on average 15 minutes to dissolve under the tongue (range of 10 to 35 minutes) .
Blood samples for the determination of pharmacokinetic parameters were taken at baseline (immediately before drug administration), then at 10 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours after drug administration. GC-MS assays were performed to determine the concentration of midazolam in each of the blood plasma samples . The following pharmacokinetic parameters were determined: Cmax (the maximum plasma concentration achieved) and tmax (the time of the maximum plasma concentration) .
The pharmacodynamic effects were measured by use of a sedation visual analogue scale (VAS) , a digit symbol substitution test (DSST) and a critical flicker fusion test (CFF) .
The sedation VAS score was measured by the subject marking a 100mm vertical line that had a scale of 0 to 100, where 0 was equivalent to "extremely drowsy" and 100 was "fully alert". The subject was required to record the VAS score at baseline (immediately before drug administration), then at 5 minutes, 20 minutes, 35 minutes, 1 hour 5 minutes, 1 hour 35 minutes, 2 hours 5 minutes, 3 hours 5 minutes and 4 hours 5 minutes after drug administration.
The digit symbol substitution test (DSST) consisted of providing the subjects with a grid where the numbers 1 to 9 were matched to a symbol at the top of a sheet of paper. A series of random numbers were printed in a grid below the key and the subjects were given 90 seconds to write the corresponding symbol under each digit, working sequentially and not missing any numbers out. The number of correct symbols entered in the 90 seconds was recorded. A different random number grid was used for each occasion to prevent learning effects. The DSST was completed by each subject at baseline (immediately before drug administration) , then at 35 minutes, 1 hour 5 minutes, 1 hour 35 minutes, 2 hours 5 minutes, 3 hours 5 minutes and 4 hours 5 minutes after dosing.
The Critical Flicker Fusion (CFF) test required the use of a flickering light source that comprised two 5mm diameter orange LEDs set 2cm apart and a button connected to a computer that recorded the frequency of the flickering light at the moment the button was pressed. The test consisted of two parts. The first part involved setting the LEDs to flicker at a frequency higher than could be detected by the unaided eye so that they appeared as a constant light . The frequency was then steadily decreased and the subject was asked to press the button when they could first detect flickering of the lights. This process was repeated twice more at each timepoint. The second part was then initiated and the lights were set to a very low frequency so that the subject could easily see the flickering. The frequency of the flickering was then gradually increased and the subject was asked to press the button when he could no longer detect the flickering of the LEDs. This was also repeated twice at each timepoint. The average of the six frequency readings taken at each timepoint was taken as the measure of the Critical Flicker Fusion. The CFF test was completed by each subject at baseline (immediately before drug administration), then at 20 minutes, 40 minutes, 1 hour 5 minutes, 1 hour 35 minutes, 2 hours 5 minutes, 3 hours 5 minutes and 4 hours 5 minutes after dosing . The results of the pharmacokinetic study are shown in graphical form in Figures 1 to 4 where each figure is a plot of the concentration of midazolam in a blood plasma sample versus the time at which the sample was taken. The results of the pharmacodynamic studies are shown in graphical form in Figures 5 to 7.
The mean plasma midazolam profiles for the three treatments are shown in Figure 1 and a summary of the data is given in Table 1 below.
Table 1
Figure imgf000023_0001
It is apparent from these results that the formulation of Example 1 produces a similar Cmax to that of the intramuscular injection, although the relative bioavailability is about half that of the injection. It is also apparent that the time to the peak plasma concentration for the formulation of Example 1 is similar to the intramuscular injection and faster than a slowly disintegrating tablet ("DORMICUM") administered sub- lingually (see Figure 2) . This would suggest that a formulation that rapidly disintegrates in the mouth will offer the rapid onset of sedation that is associated with the intramuscular injection without the disadvantage of the pain of injection.
Another potential advantage of a rapidly disintegrating formulation shown by this study is the similarity in Cmax and tmax seen for both males and females . Figure 3 compares the mean plasma midazolam concentrations for males and females who received the 22 intramuscular injection whilst Figure 4 compares the plasma midazolam concentrations for male and females who were given the formulation of Example 1. It can be seen that, when given the intramuscular injection, females on average exhibit much lower plasma concentrations than males. For subjects given the formulation of Example 1, the peak plasma concentrations are very similar between males and females . This would indicate that a more reproducible response may be expected from the formulation of Example 1 irrespective of whether the subject is male or female.
The pharmacodynamic profiles also show that a dose of lOmg administered as the formulation of Example 1 produces a similar pharmacological effect to that produced by injection. The sedation VAS score against time profile is shown in Figure 5. This demonstrates that the formulations produce a similar reduction in the VAS score (ie. the subjects became sedated) and the recovery back to being "fully alert" is also very similar. This time for recovery is important, as this will allow patients to leave the surgical unit sooner.
The mean digit symbol substitution profile is shown in Figure 6 following administration of the formulation of Example 1 and the intramuscular injection. The DSST test results show that, shortly after the administration of the products, the subjects are less capable of matching the numbers with the symbols according to the specific key. This is consistent with the subjects' cognitive function being affected by the drug. The mean profile arising from the rapidly disintegrating formulation (Example 1) exhibits a greater decrease in response at the 35 minute timepoint, but the time of recovery to the pre-treatment score is similar to that arising after administration of the intramuscular injection. The overall shape of the DSST time curves are similar to the VAS sedation data shown in Figure 5.
The results of the critical flicker fusion test are set out in Figure 7. The decrease in the critical flicker fusion frequency shown in Figure 7 demonstrates that the subjects' psychomotor response is rapidly affected by the formulation prepared as in Example 1 and the intramuscular injection. This test is considered to be a more sensitive test than the DSST test for detecting drug-induced sedation. The results demonstrate that the formulation prepared as in Example 1 is capable of producing equivalent efficacy to the intramuscular injection of midazolam.
Both the pharmacokinetic and the pharmacodynamic data support the use of a dosage form of midazolam that disintegrates rapidly in the mouth especially for use in premedication and conscious sedation indications. The formulation of the present invention also offers a faster onset of action than a more slowly disintegrating dosage form and is more convenient for patients to take with the dosage form disappearing in seconds instead of having to be held under the tongue for several minutes . The formulation of the present invention also has the advantages that it does not require special personnel for its administration and it is not painful or traumatic to receive unlike the injectable form of midazolam.

Claims

1. A pharmaceutical composition for oral administration comprising a carrier and, as active ingredient, midazolam or a salt thereof, characterised in that the composition is in the form of a fast-dispersing dosage form designed to release the active ingredient rapidly in the oral cavity.
2. A composition according to claim 1 in which the composition is in the form of a solid fast-dispersing dosage form comprising a network of the active ingredient and a water-soluble or water-dispersible carrier which is inert towards the active ingredient, the network having been obtained by subliming solvent from a composition in the solid state, that composition comprising the active ingredient and a solution of the carrier in a solvent .
3. A composition according to claim 1 or claim 2 in which the composition disintegrates within 1 to 60 seconds of being placed in the oral cavity.
4. A composition according to any one of the preceding claims in which the active ingredient is present in an amount of from 1 to 20mg.
5. A composition according to any one of the preceding claims for use in the induction of anaesthesia.
6. A composition according to any one of claims 1 to 4 for use in anaesthetic pre-medication.
7. A composition according to any one of claims 1 to 4 for use as a sedative.
8. A composition according to any one of claims 1 to 4 for use in conscious sedation.
9. A composition according to any one of claims 1 to 4 for use as an anxiolytic.
10. A composition according to any one of claims 1 to 4 for use as an hypnotic.
11. A composition according to any one of claims 1 to 4 for use as an amnestic.
12. A composition according to any one of claims 1 to 4 for use in the treatment of an epileptic fit.
13. A composition according to any one of claims 1 to 4 for use as an anticonvulsant .
14. A composition according to any one of claims 1 to 4 for use as a skeletal muscle relaxant.
15. A process for preparing a pharmaceutical composition according to any one of the preceding claims which comprises bringing a carrier into association with the active ingredient.
16. A fast-dispersing dosage form designed to release active ingredient rapidly in the oral cavity for use in delivering midazolam or a salt thereof.
17. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the induction of anaesthesia.
18. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for anaesthetic pre-medication.
19. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for sedation.
20. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for conscious sedation.
21. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of anxiety.
22. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the induction of hypnosis.
23. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the induction of amnesia.
24. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment of an epileptic fit.
25. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and/or prophylaxis of convulsions.
26. Use of a composition according to any one of claims 1 to 4 for the manufacture of a medicament for the relaxation of skeletal muscle.
27. A method of administering midazolam or a salt thereof to a patient which comprises introducing into the oral cavity of the patient a composition according to any one of claims 1 to 4.
28. A method of inducing anaesthesia in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
29. A method of providing anaesthetic pre-medication in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
30. A method of sedating a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
31. A method of inducing conscious sedation in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
32. A method of treating anxiety which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition according to any one of claims 1 to 4.
33. A method of inducing hypnosis in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
3 . A method of inducing amnesia in a patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
35. A method of treating an epileptic fit in patient which comprises introducing into the oral cavity of the patient a selected amount of a composition according to any one of claims 1 to 4.
36. A method of treating convulsions which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition according to any one of claims 1 to .
37. A method of preventing convulsions which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition according to any one of claims 1 to 4.
38. A method of relaxing skeletal muscle which comprises introducing into the oral cavity of a patient a therapeutically effective amount of a composition according to any one of claims 1 to 4.
PCT/GB1998/002511 1997-08-21 1998-08-20 Pharmaceutical composition containing midazolam WO1999009989A1 (en)

Priority Applications (1)

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GB9717770.3 1997-08-21
GBGB9717770.3A GB9717770D0 (en) 1997-08-21 1997-08-21 Pharmaceutical composition

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GB (1) GB9717770D0 (en)
WO (1) WO1999009989A1 (en)

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EP1323422A1 (en) * 2001-12-24 2003-07-02 Special Products Limited Pharmaceutical composition comprising midazolam for buccal administration
WO2006002836A1 (en) * 2004-07-01 2006-01-12 Losan Pharma Gmbh Effervescent compositions of sleeping drugs
WO2017009446A1 (en) * 2015-07-16 2017-01-19 Christer Sjögren Compositions of midazolam for buccal administration in the treatment of seizures to obtain rapid onset of action
US10744086B2 (en) 2009-10-30 2020-08-18 Ix Biopharma Ltd. Fast dissolving solid dosage form

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EP1323422A1 (en) * 2001-12-24 2003-07-02 Special Products Limited Pharmaceutical composition comprising midazolam for buccal administration
US6936605B2 (en) 2001-12-24 2005-08-30 Special Products Limited Pharmaceutical composition
WO2006002836A1 (en) * 2004-07-01 2006-01-12 Losan Pharma Gmbh Effervescent compositions of sleeping drugs
US10744086B2 (en) 2009-10-30 2020-08-18 Ix Biopharma Ltd. Fast dissolving solid dosage form
WO2017009446A1 (en) * 2015-07-16 2017-01-19 Christer Sjögren Compositions of midazolam for buccal administration in the treatment of seizures to obtain rapid onset of action
CN108024952A (en) * 2015-07-16 2018-05-11 斯威普有限公司 It is used to buccal in treatment breaks out apply to obtain the midazolam compositions of quick acting

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GB9717770D0 (en) 1997-10-29

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