Fast Dissolving Solid Dosage Form

Abstract

There is provided a fast dissolving solid dosage form adapted for the release of a biologically active material in the oral cavity wherein the dosage form comprises at least one biologically active material, and at least one matrix forming agent, wherein the dosage form substantially dissolves in the oral cavity. A method of producing the same and a kit comprising the same are also provided.

Claims

1.-41. (canceled)

42. A fast disintegrating and dissolving freeze-dried wafer solid dosage form with a porous matrix for release of a biologically active material in an oral cavity wherein said dosage form comprises: (a) a biologically active material at a concentration from 0.02 to 95 weight % by dry weight of the dosage form; and (b) amylopectin at a concentration from 2% to 17% by dry weight of the dosage form wherein the amylopectin is not in the form of starch or modified starch; and (c) a carbohydrate chosen from the list consisting of: mannitol, dextrose, lactose, galactose and trehalose at a concentration from 5% to 80% by dry weight of the dosage form, wherein the powder x-ray diffraction (XRD) of the dosage form comprises peaks at 2-theta values at approximately 9.58 degrees, 19.68 degrees, and 20.05 degrees; wherein said dosage form disintegrates in the oral cavity; wherein said biologically active material is absorbed by diffusion directly into the systemic circulation.

43. The dosage form of claim 42 wherein the biologically active material is an anti-inflammatory agent.

44. The dosage form of claim 42 wherein the biologically active material is a complementary medicine.

45. The dosage form according to claim 42, comprising glycine present in an amount from 0.5 to 5 weight % by dry weight of the dosage form.

46. The dosage form of claim 42, wherein the dosage form comprises sodium carboxymethyl cellulose (CMC) present in an amount from 0.1 to 15% dry weight of the dosage form.

47. The dosage form according to claim 42, wherein the dosage form dissolves once placed in the oral cavity in a time period selected from the group consisting of: less than 50 seconds, less than 40 seconds, less than 30 seconds, less than 20 seconds, less than 15 seconds, less than 10 seconds, less than 7.5 seconds, less than 5 seconds, less than 4 seconds, less than 3 seconds, less than 2 seconds.

48. A kit comprising the fast disintegrating and dissolving freeze-dried wafer solid dosage form with a porous matrix for release of a biologically active material in an oral cavity, wherein the dosage form comprises: a) a biologically active material at a concentration from 0.02 to 95 weight % by dry weight of the dosage form; and b) amylopectin at a concentration from 2% to 17% by dry weight of the dosage form wherein the amylopectin is not in the form of starch or modified starch; and c) a carbohydrate chosen from the list consisting of: mannitol, dextrose, lactose, galactose and trehalose at a concentration from 5% to 80% by dry weight of the dosage form, wherein the powder x-ray diffraction (XRD) of the dosage form comprises peaks at 2-theta values at approximately 9.58 degrees, 19.68 degrees, and 20.05 degrees; wherein said dosage form disintegrates in the oral cavity; and wherein said biologically active material is absorbed by diffusion directly into the systemic circulation.

49. The kit according to claim 48, further comprising instructions for its use.

50. The kit according to claim 48, wherein the biologically active material is an anti-inflammatory agent.

51. The kit according to claim 48, wherein the biologically active material is a complementary medicine.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0114] FIG. 1 Scanning electron micrographs of the surface of wafers from batch numbers 071501B and 071502B.

[0115] FIG. 2 Scanning electron micrographs of the surface of wafers from batch numbers 0820A and 08208.

[0116] FIG. 3 Scanning electron micrograph of the surface of wafer from batch number 0905MD.

[0117] FIG. 4 Scanning electron micrographs of the cross section of wafers from batch n\Jmbers 071501B and 071502B.

[0118] FIG. 5 Scanning electron micrographs of the cross section of wafers from batch numbers 0820A and 0820B.

[0119] FIG. 6 Scanning electron micrograph of the cross section of wafer from batch number 0905MD.

[0120] FIG. 7 Powder X-ray diffraction spectra of wafers from batch number 071501A and 0715028.

[0121] FIG. 8 Powder X-ray diffraction spectra of wafers from batch numbers 0820A and 0820.B.

[0122] FIG. 9 Powder X-ray diffraction spectrum of wafer from batch number 0905MD.

[0123] FIG. 10A Typical HPLC chromatograms of standard midazolam sample at 4.05 μg/m (n=3).

[0124] FIG. 10B Typical HPLC chromatograms of midazolam powder dissolution samples at 1 minute and 5 minutes.

[0125] FIG. 10C Typical HPLC chromatograms of midazolam powder dissolution sample at 10 minutes.

[0126] FIG. 10D Typical HPLC chromatograms midazolam powder dissolution at 15 minutes.

[0127] FIG. 10E Typical HPLC chromatograms of a standard midazolam sample at 8.1 μg/ml.

[0128] FIG. 11 Typical HPLC chromatograms of dissolution wafer Sample S1 at 45 seconds and 1 minute.

[0129] FIG. 12 Typical HPLC chromatogram of dissolution wafer Sample S1 at 10 minutes.

[0130] FIG. 13 Typical HPLC chromatograms of dissolution wafer Sample S2 at 5 and 10 minutes.

[0131] FIG. 14 Typical HPLC chromatograms of dissolution wafer Sample S2 at 30 seconds and 2 minutes.

[0132] FIG. 15 Typical HPLC chromatograms of dissolution wafer Sample S3 at 20 seconds and at 1 minute.

[0133] FIG. 16 Typical HPLC chromatograms of standard midazolam sample at 1.01 μg/ml.

[0134] FIG. 17 Typical HPLC chromatograms of Midazolam powder dissolution sample at 30 seconds.

[0135] FIG. 18 Typical HPLC chromatograms of dissolution wafer 1 at 1 minute and 5 minutes.⋅

[0136] FIG. 19 Typical HPLC chromatograms of dissolution wafer 1 at 5, 10 and 15 minutes.

[0137] FIG. 20 Typical HPLC chromatogram of drug loading testwafer sample No.1.

[0138] FIG. 21 Typical HPLC chromatograms of dissolution wafer 2 at 30 seconds.

[0139] FIG. 22 Typical HPLC chromatograms of dissolution wafer 2 at 1 minute and 5 minutes.

[0140] FIG. 23 Typical HPLC chromatograms of dissolution wafer 2 at 10, 15 and 30 minutes.

[0141] FIG. 24 Typical HPLC chromatograms of drug loading test wafer sample No.2.

[0142] FIG. 25- Typical HPLC chromatograms of dissolution wafer 3 at 30 seconds.

[0143] FIG. 26 Typical HPLC chromatograms of dissolution wafer 3 at 1 minute and 5 minutes.

[0144] FIG. 27 Typical HPLC chromatograms of dissolution wafer 3 at 10 and 15 minutes.

[0145] FIG. 28 Typical HPLC chromatograms of dissolution wafer 3 at 30, 45 and 60 minutes.

[0146] FIG. 29 Typical PLC chromatograms of drug loading test wafer sample No. 3.

[0147] FIG. 30 Standard HPLC calibration curve of midazolam (1 to 32.4 μg/mL).

[0148] FIG. 31 Cumulative concentration of midazolam released from wafer and midazolam powder in phosphate buffer solution (pH 6.8) at 37° C.

[0149] FIG. 32 Standard HPLC calibration curve of fentanyl (0.5 to 10 μg/mL).

[0150] FIG. 33 Dissolution profiles of fentanyl wafer in phosphate buffer solution (pH 6.8) at 37° C., (n=4).

[0151] FIG. 34A Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at 0.5 minute.

[0152] FIG. 34B Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at 1 minute.

[0153] FIG. 34C Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at 5 minutes.

[0154] FIG. 34D Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at 10 minutes.

[0155] FIG. 34E Typical HPLC chromatograms of dissolution samples 1 to 3 of fentanyl wafers at 15 and 20 minutes.

[0156] FIG. 35A Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 1 minutes.

[0157] FIG. 35B Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 2 minutes.

[0158] FIG. 35C Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 3 minutes.

[0159] FIG. 35D Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 4 minutes.

[0160] FIG. 35E Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 5 minutes.

[0161] FIG. 35F Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 7 minutes.

[0162] FIG. 35G Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 10 minutes.

[0163] FIG. 35H Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 10 minutes.

[0164] FIG. 35I Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 10 minutes.

[0165] FIG. 35J Typical HPLC chromatograms of dissolution samples 4 to 6 of fentanyl wafers at 10 minutes.

DETAILED DESCRIPTION OF THE INVENTION

.General

[0166] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and materials referred to or indicated in the specification, individually or collectively and any and all combinations or any two or more of the steps or features.

[0167] The present invention is not to be limited—in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only.

[0168] Functionally equivalent products, compositions and methods are clearly within the scope of the invention as described herein.

[0169] The invention described herein may include one or more ranges of values (e.g. size, concentration etc). A range of values will be understood to include all values within the range, including the values defining the range, and values adjacent to the range that lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.

[0170] The entire disclosures of all publications (including patents, patent applications, journal articles, laboratory manuals, books, or other documents) cited herein are hereby incorporated by reference. Inclusion does not constitute an admission is made that any of the references constitute prior.sub.v art or are part of the common general knowledge of those working in the field to which this invention relates.

[0171] Throughout this specification, unless the context requires otherwise, the word _“comprise” or variations, such as “comprises” or “comprising” will be understood to imply the inclusion of a stated integer, or group of integers, however not the exclusion of any other integers or group of integers. It is also noted that in this disclosure, and particularly in the claims and/or paragraphs, terms such. as “comprises”, “comprised”, “comprising” and the like can have the meaning attributed to it in US Patent law; e.g., they can mean “includes”, “included”, “including”, and the like.

[0172] “Therapeutically effectiv amount” as used herein with respect to methods of treatment and in particular drug dosage, shall mean that dosage that provides the specific pharmacological response for which the drug is administered in a significant number of subjects in need of such treatment. It is emphasized that “therapeutically effective amount,” administered to a particular subject in a particular instance will not always be effective in treating the diseases described herein, even though such dosage is deemed a “therapeutically effective amount” by those skilled in the art. It is to be further understood that drug dosages are, in particular instances, measured as oral dosages, or with-reference to drug levels as measured in blood.

[0173] The term “inhibit” is defined to include its generally accepted meaning which includes ⋅ prohibiting, preventing, restraining, and lowering, stopping, or reversing progression or severity, and such action on a resultant symptom. As such the present invention includes both medical therapeutic and prophylactic administration, asappropriate. The term “biologically active material” is defined to mean a biologically active ⋅ compound or a substance which comprises a biologically active compound. In this definition, a compound is generally taken to mean a distinct chemical entity where a chemical formula or formulas can be used to describe the substance. Such compounds would generally, however not necessarily be identified in the literature by a unique classification system such as a CAS number. Some compounds may have a more complex and have a mixed chemical structure. For such compounds they may only have an empirical formula or be qualitatively indentified. A compound would generally be—a pure material, although it would be expected that up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be other impurities and the like. Examples of biologically active compounds are, however not limited to, fungicides, pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics, complementary medicines, natural products, vitamins, nutrients, neutraceuticals, pharmaceutical actives, biologics, amino acids, proteins, peptides, nucleotides, nucleic acids, additives, foods and food ingredients and analogs, homologs and first order derivatives thereof. A substance that contains a biological active compound is any substance which has as one of its components a biological active compound. Examples of substances containing biologically active compounds are, however not limited to, pharmaceutical formulations and products, cosmetic formulations .and products, industrial formulations and products, agricultural formulations and products, foods, seeds, cocoa and cocoa solids, coffee, herbs, spices, other plant materials, minerals, animal products, shells and other skeletal material.

[0174] Any of the terms, “biologiyal(ly) active”, “active”, “active material” shall have the same meaning as biologically active material.

[0175] As used herein “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for oral administration.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

[0176] A formulation of the present invention was prepared in accordance with the method and ingredients as set out below in Table 1:

TABLE-US-00001 TABLE 1 Compositions of Fast Dissolving Solid Dosage Form Formulation Ingredient Amount (g) % by weight Sodium carbonate BP/USP 10 0.075 Sodium carboxymethylcellulose BP/USP 20 0.149 Polyethylene glycol 2000 BP/USP 50 0.374 Glycine BP/USP 100 0.747 Microcrystalline cellulose BP/USP 200 1.495 Amylopectin BP/USP 500 3.737 Lactose BP/USP 1000 7.474 Mannitol BP/USP 1500 11.211 Purified water BP/USP 10000 74.738

[0177] Sodium carboxymethylcellulose and amylopectin Were added in a portion of purified water by mixing thoroughly with a stirrer. The mixture was then heated to 50° C. for ten minutes to allow dissolving of the polymers. Once the solution cooled down to room temperature, polyethylene glycol 2000, glycine, sodium carbonate, microcrystalline cellulose, lactose and mannitol were added individually, under stirring to obtain a homogenously solution. The viscosity of the solution was measured at 25° C. using a Brookfield Digital Viscon:ieter (Brookfield Engineering Laboratories Inc, MA, USA).

[0178] The re ulting mixture was transferred by pipette and accurately weighed into pre-⋅ formed blister packs, and then transferred into a freezer (−30° C.) for approximately 24 hours. After freezing, the sample was freeze-dried (DYNAVAC, Australia) for 24 ⋅ hours. The prepare sample was stored in desiccator over silica gel at a room temperature.

[0179] The following additional formulations were prepared by the method as set out above. Essentially Samples 1 to 6 are based on the formulation described above, with the addition of flavour and/or colour agents.

TABLE-US-00002 Sample 1. Sample 1 additionally contained a flavour. Ingredient Amount (g) ′  % by weight Sodium carbonate  1 0.08 Sodium carboxymethylcellulose  2 0.15 Polyethylene glycol .2000  5 0.37 Orange flavor 10 0.74 Glycine 10 0.74 Microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 Lactose 100  7.42 Mannitol 150  11.13 Purified water 1000•  74.18

TABLE-US-00003 Sample 2. Additional contained a flavour and a pH adjuster (citric acid). Ingredient Amount (g) % by weight Sodium carbonate 1 0.07 Sodium carboxymethylcellulose 2 0.15 Citric acid 5 0.37 Polyethylene glycol 2000 5 0.37 Mint flavor 10 0.74 Glycine 10 0.74 Microcrystalline cellulose 20 1.48 Amylopectin 50 3.70 Lactose 100 7.39 Mannitol 150 11.09 Purified water 1000 73.91

TABLE-US-00004 Sample 3. Additionally contained flavour and a colouring agent Ingredient Amount (g) % by weight FD& C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethylcellulose 2 0.15 Polyethylene glycol 2000 5 0.37 Grape flavor 9.9 0.74 Glycine 10 0.74 Microcrystalline cellulose .20 1.48 Amylopectin - 50 - 3.71.sup.   Lactose 100 7.42 Mannitol 150 11.13  Purified water 1000 74.18 

TABLE-US-00005 Sample 4. Additionally contained flavour, a colouring agent and an absorption enhancer. Ingredient Amount (g) % by weight FD & C blue   0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethylcellulose 2 0.15 P-Cyclodextrin 5 0.37 Polyethylene glycol 2000 5 0.37 Grape flavor   9.9 0.73 Glycine 10  0.74 Microcrystalline cellulose - 20 .sup.  1.48 Amylopectin 50  3.71 Lactose 100  7.42 Mannitol 145  10.76 Deionsed water 1000   74.19

TABLE-US-00006 Sample 5. Additionally contained a colouring agent and a sweetener Ingredient Amount (g) % by weight FD & C red   0.1 0.01 Sodium carbonate  .sup.  1 - 0.07 Sodium′ carboxymethylcellulose 2 0.15 Aspartame 5 0.37 Polyethylene glycol 2000 5 0.37 Cherry flavor   9.9 0.73 Glycine 10  0.74 Microcrystalline cellulose 20  1.48 Amylopectin 50  3.71 Lactose 100  7.42 Mannitol 145  10.76 Deionsed water 1000   74.19

TABLE-US-00007 Sample 6. Additionally contained a colouring agent and a pH adjuster Ingredient Amount (g) % by weight FD & C red 0.1 0.01 Sodium carbonate 1 0.07 Sodium carboxymethylcellulose 2 0.15 Sodium hydrogen carbonate, 5 0.37 Polyethylene glycol 2000 5 0.37 Raspberry flavor 9.9 0.73 Glycine 10 0.74 Microcrystalline cellulose 20 1.48 Amylopectin 50 3.71 Lactose 100 7.42 Mannitol 145 10.76 Deionsed water 1000 74.19

[0180] Various batches of fast dissolving solid dosage form were then prepared based on the formulation shown in }″able 1 and prepared as set out in Example 1 above. The batch number and the ingredients are listed in Table 2.

TABLE-US-00008 TABLE 2 Compositions of the Formulations Used for Investigations Batch Batch Batch Batch Batch Batch 071501B 071502B 0820A 0820B 0905MD 1003FEN Amount Amount Amount Amount Amount Amount Ingredient (g) (g) (g) (g) (g) (g) Amylopectin 1.0 1.0 1.0 0.00 1.0 0.5 Mannitol 3.0 3.0 3.0 3.0 3.0 1.5 Lactose 2.0 2.0 2.0 2.0 2.0 1.0 Glycine 0.2 0.2 0.5 0.3 0.2 0.1 PEG 2000 0.1 0.1 0.1 0.1 0.1 0.05 Sodium 0.04 0.04 0.04 0.04 0.04 0.02 Carboxymethyl cellulose Sodium carbonate 0 0.02 0 0 0.02 0.01 Starch 1.0 0 0 0 0 0 Avicel 0.2 0.2 0.00 0.2 0.2 0.1 Active 0 .0 0 0 0.255 midazolam 0.004 fentanyl pharmaceutical (base) citrate (2.5 mg ingredient fentanyl base) Purified water 40 40 40 40 40 20

[0181] General Observations

[0182] The procedure of Example 1 was repeated, except that polyethylene glycol 1000 was employed instead of polyethylene glycol 2000, to thereby yield a fast dissolving dosage form. Applicant found that there was no significant difference between the use of polyethylene glycpl 1000 or polyethylene glycol 2000 (results not shown). Applicant found the addition of starch resulted in a hard wafer, and was less suitable for the fast dissolving solid dosage form of the present invention.

[0183] Uniformity of Weight

[0184] The uniformity of the weight of the fast dissolving dosage form (wafer) was tested in accordance with the British Pharmacopoeia (BP) 2009 test. That is, 20 wafers from each of the formulations listed in the above Table 2 were individually weighed, and the average weight and relative standard was calculated. All the prepared wafers from different formulations were within the accepted weight variation from between 0.25 to 2%.

[0185] ⋅ Hardness

[0186] The hardness of the dosage formulations listed in Table 2 was also tested. The mechanical strength of tablet is referred to as “hardness”. The hardness of the wafer was determined using an Erweka Hardness Tester ⋅,(Germany). The values of hardness from different formulations ranged from 0.5 to 4.0 kg. It was observed that the hardness of the formulation increased when Avicel was added to the formulation (results not shown).

[0187] Friability

[0188] The strength of the fast dissolving solid dosage forms (wafers), i.e. their ability to be reduced from a solid substance into smaller pieces was measured. The test was conducted according to BP 2009 method (i.e. friability of uncoated tablets), using the Erweka friability tester (Germany). A sample of 20 wafers was weighed accurately and placed in the apparatus. A rotation time of four minutes at 25 rpm was used. Wafers were removed and reweighed and the percentage weight loss was calculated. It was found that the weight loss of 20 wafters ranged from 8 tci 20%.

[0189] Although this weight loss does not comply with the BP 2009 standard of about⋅1% weight loss for compressed tablets, there is no such standard for wafers in either the BP or USP monograph.

[0190] Moisture Analysis

[0191] The moisture content of the wafers was analysed after lyophilisation using the 870 Karl Fisher Titrino Plus (Metrohm Ag, Germany). The results show that the residual moisture content was varied from 1% to 5% for different formulations.

[0192] Scanning Electron Microsopic Analysis

[0193] Surface morphology and cross-sections of selected wafer formulations were observed using scanning electron microscope (SEM) (Zeiss, EVO 40 XVP, the Oxford Instrument, UK). Cross-section sample were prepared by cutting a thin slice of the wafer using a scalpel. Samples were coated with carbon prior to examination. The accelerating voltage was 10 kV.

[0194] The SEM images shown in FIGS. 1 to 6 illustrate the highly porous nature of the wafers on both surface and the inner structure. Clearly, there were morphological differences between different formulations. These differences indicated that the excipients used influence the microstructure of the wafer. In addition, the microstructure might give an explanation about the different hardness, friability, disintegration time, and even the dissolution profiles of wafer prepared fromdifferent formulations.

[0195] Powder X-ray Diffraction (XRD)

[0196] X-ray diffraction experiments were performed using⋅Bruker D8 Advance (Germany) with detector LynEye. The radiation used was nickel filtered CuKa, which was generated using an a<?celeration voltage of 40 kV and a cathode current of 40 mA. The samples were scanned over a 2 theta range of 7.5 to 70 degree, and counting time at 1 second per 0.02 degree.

[0197] The physical state of the materials in the wafer was evident in the X-ray diffraction spectra. Spectra for three different formulations as prepared in accordance with Table 2 are shown in FIGS. 7 to 9. It was observed that all the powder patterns of wafer prepared are dominated by intense scattering peaks approximately located at 2-theta of 9.58°, 19, 68° and 20.05°, which indicating a crystalline nature. This finding was also supported by the data generated from the SEM (see FIGS. 1-6).

[0198] Indeed, the excipients used in the formulations, such as glycine, lactose, mannitol and microcrystalline cellulose are crystalline in nature. It was observed that there was minimal physical state change in the solid dispersion.

[0199] Disintearation and Dissolution Analysis

[0200] Disintegration and dissolution tests were carried out using Apparatus I (BP 2009, Basket apparatus). The Erweka dissolution apparatus (Hesenstamm, Germany) was used for both tests. The temperature of the medium was kept at 37±0.5° C.

[0201] For the disintegration tes , a wafer was placed in the cylindrical basket and wetted on the underside by contact with distilled water in the cylindrical vessel. The time of total dissolution of each wafer was noted, and a mean value was calculated.

[0202] For the dissolution testing:

[0203] (i) a wafer (Batch 0905MD) containing midazolam as a model drug was used to ⋅ determine the mechanism of drug release from the system following the both BP basket and USP paddle methods (see FIG. 17). Dissolution medium was 500 ml phosphate buffer solution (pH value is closed to saliva fluid at 6.8), with a paddle rotation speed at 75 rpm. At given interval (e.g., 0.5, 1, 2, 3, 5 10 15, 2.0 and 30 min), 2 ml of solution was sampled and replaced with an equal volume of fresh medium to maintain a constant total volume. Samples were filtered through a 0.2 μm Millipore filter. The drug released was measured by HPIC.

[0204] . The HPIC system consisted of a Waters 1525 pump, a Waters Symmetry C.sub.18 column (5 μm, 150×4.6 mm), and Waters UV 484 defector. The mobile phase was acetonitrile: 10 mM ammonium acetate buffer (40:60, v/v, pH 4.10) and the flow rate was 1.2 ml/min at ambient temperature. The peaks were recorded at 220 nm, and the limit of quantitatio_n was approximately 1 ng/ml. The calibration curve for the concentrations 1-32.4 μg/ml (six-point calibration) was linear [y=870714x+52057 (r=0.9998), y representing the peak area of midazolam and x the concentration of the samples].

[0205] A standard HPIC calibration curve for Midazolam is shown in FIG. 30. The results as shown in FIG. 31 demonstrate that the average disintegration times were less than 15 seconds; and the dissolution studies also indicated a fast release rate of midazolam, Almost 75% of midazolam had dissolved in one minute. The raw midazolam powder was considerably slower. This may indicate the changing of midazolam crystal form in the wafer, which was also evident in the X-ray. The X-ray spectrum pointed to an amorphization of midazolam during the freeze-drying process.

[0206] The results of the HPIC analysis on various samples of the formulation as prepared in accordance with Table 1 are shown in FIGS. 11 to 29. FIGS. 10 A to 10 E illustrate the HPIC of standard midazolam sample, and midazolam powder dissolution samples. FIGS. 11 to 16 are HPIC chromatograms of dissolution wafer samples 1 to 3 (S1, S2 a,nd S3, BP basket method). Briefly, the samples 1, 2 and 3 were prepared according to Table 1 and are triplicate samples of the same formulation. FIG. 17 illustrates the HPIC chromatogram of Batch 0905MD, which . contains midazolam as a model drug.

[0207] FIGS. 18 to 29 reflect the HPIC chromatograms of another three dissolution wafer samples (USP paddle methods). As discussed above, the dissolution rate of the wafer containing test drug midazolam was measured. Samples were taken at 0.5 minute, 1 minute, 5, minutes, 10 minutes and 15 minutes.

[0208] The results of wafers 1 to 3 (Batch 0905MD) are shown over these time limits in FIGS. 18 to 29. A drug loading test was also conducted for another three wafers (Batch 0905MD).

[0209] It was shown that the wafers of the present invention were able to completely dissolve in about 15 seconds and did not leave behind any residue.

[0210] (ii) a wafer (Batch 1003FEN) containing fentanyl as a model drug was used to determine the mechar:iism of drug release from the system following the BP basket method. The dissolution rates of the wafer were determined in a small volume (10 ml phosphate buffer solution, pH 6.8) with a basket rotation speed at 50 rpm. At given interval (e.g., 0._ 5, 1, 2, 3, 4, 5, 7, 10 and 15 min), 0.5 ml of solution was sampled and replaced with an equal volume of fresh medium. The drug released was measured by HPIC.

[0211] Themobile phase was methanol: 0.4% phosphoric acid (50: 50,v/v, pH 2.3) and the flow rate was 1.2 ml/min at ambient temperature. The monitoring wavelength was at 210 nm. The calibration curve for the concentrations 0.5-10 μg/ml (eight-point calibration) was linear [y=316668x+4675.7, (r=0.9999), y representing the peak area of fentanyl and x the concentration of the samples]. The assay standard curve is shown in FIG. 32.

[0212] The prepared fentanyl wafer (batch 1003FEN) showed a weight variation of ±2.55%, and the mean percentage fentanyl content of the wafer was 91.32% (BP standard for uniformity content limits 85 to 115%). The average disintegration times were less than 15 seconds; and the dissolution studies also indicated a fast release rate of fentanyl. Almost 90% of fentanyl had dissolved in one minute. The dissolution profiles are presented in igure 33.

[0213] The HPLC chromatograms of six dissolution samples of fentanyl wafers were collected and is shown in FIGS. 34 A to E {samples 1 to 3) and FIGS. 35 A to J. (samples 4 to 6). The sampling of each test wafer was conducted at time of 0.5, 1, 5, 10, 15 and 20 minutes for dissolution samples 1 to 3, and at 1, 2, 3, 4, 5, 7 and 10 minutes for dissolution samples 4 to 6.

[0214] The fast dissolving dosage form is a solid dispersion of drug into a porous matrix. After administration, this dosage form quickly disintegrates in the oral cavity, and allows rapidly dissolving drug to be absorbed by diffusion directly into the systemic circulation, and the first-pass effect is avoided. This invention has the potential to provide an alternate route of drug administration and results in lower rates of side effect.