U.S. patent application number 16/010412 was filed with the patent office on 2018-10-18 for fast dissolving pharmaceutical composition.
The applicant listed for this patent is Ferring B.V.. Invention is credited to Varinder Ahuja, Tejas Gunjikar, Shweta Gupta, Kristin Wannerberger.
Application Number | 20180297728 16/010412 |
Document ID | / |
Family ID | 44169174 |
Filed Date | 2018-10-18 |
United States Patent
Application |
20180297728 |
Kind Code |
A1 |
Gupta; Shweta ; et
al. |
October 18, 2018 |
FAST DISSOLVING PHARMACEUTICAL COMPOSITION
Abstract
The subject invention is directed to a pharmaceutical
composition comprising an open matrix network carrying a
pharmaceutically active ingredient, wherein the open matrix network
comprises levan.
Inventors: |
Gupta; Shweta; (Thane,
IN) ; Ahuja; Varinder; (Mumbai - Maharashtra, IN)
; Gunjikar; Tejas; (Nashik - Maharashtra, IN) ;
Wannerberger; Kristin; (Pully, CH) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ferring B.V. |
Hoofddorp |
|
NL |
|
|
Family ID: |
44169174 |
Appl. No.: |
16/010412 |
Filed: |
June 16, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14571883 |
Dec 16, 2014 |
10023335 |
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16010412 |
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13636758 |
Jan 29, 2013 |
8946153 |
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PCT/EP2011/054699 |
Mar 28, 2011 |
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14571883 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/47 20130101;
A61P 3/10 20180101; B65B 63/08 20130101; A61K 47/10 20130101; A61K
47/26 20130101; A61P 11/06 20180101; A61P 1/04 20180101; B65B 3/04
20130101; B65B 31/04 20130101; A61K 9/205 20130101; A61K 31/426
20130101; A61K 31/4545 20130101; A61K 31/4178 20130101; A61K 47/12
20130101; A61K 9/0056 20130101; A61K 9/2095 20130101; A61K 38/095
20190101; A61K 9/0002 20130101; A61P 37/08 20180101; A61K 47/36
20130101; A61P 13/00 20180101; A61K 38/22 20130101; B65D 75/367
20130101; A61J 1/035 20130101; A61P 1/08 20180101 |
International
Class: |
B65B 31/04 20060101
B65B031/04; B65B 3/04 20060101 B65B003/04; A61K 9/20 20060101
A61K009/20; B65D 75/36 20060101 B65D075/36; A61K 47/10 20060101
A61K047/10; A61K 47/12 20060101 A61K047/12; A61K 47/26 20060101
A61K047/26; A61K 47/36 20060101 A61K047/36; A61J 1/03 20060101
A61J001/03; A61K 38/22 20060101 A61K038/22; A61K 9/00 20060101
A61K009/00; B65B 63/08 20060101 B65B063/08; A61K 38/11 20060101
A61K038/11; A61K 31/47 20060101 A61K031/47; A61K 31/4545 20060101
A61K031/4545; A61K 31/426 20060101 A61K031/426; A61K 31/4178
20060101 A61K031/4178 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 29, 2010 |
IN |
743/DEL/2010 |
Claims
1-31. (canceled)
32. A pharmaceutical composition comprising: (a) at least one
matrix-forming agent that is levan to form an open matrix network;
and (b) at least one pharmaceutically active ingredient, wherein
the composition is an orodispersible pharmaceutical dosage
form.
33. The pharmaceutical composition according to claim 32, further
comprising one or more secondary matrix-forming agents.
34. The pharmaceutical composition according to claim 33, wherein
the one or more secondary matrix-forming agents is selected from
the group consisting of trehalose, raffinose, and mannitol.
35. The pharmaceutical composition according to claim 33, wherein
the one or more secondary matrix-forming agent is mannitol.
36. The pharmaceutical composition according to claim 33, wherein
the one or more secondary matrix-forming agent is trehalose.
37. The pharmaceutical composition according to claim 33, wherein
the one or more secondary matrix-forming agent is raffinose.
38. The pharmaceutical composition according to claim 32, wherein
the at least one pharmaceutically active ingredient is chosen from
desmopressin, desmopressin acetate, loratidine, famotidine,
montelukast sodium, and ondansetron.
39. The pharmaceutical composition according to claim 32, wherein
at least 80% of the composition dissolves within 10 seconds upon
contact with an aqueous solution or with saliva.
40. The pharmaceutical composition according to claim 32, wherein
the composition has a tensile strength from about 0.05 to about 1.6
N/mm.sup.2.
41. A pharmaceutical composition prepared by a process comprising
at least a step of sublimating a solvent from a liquid preparation
that comprises: (a) at least one matrix-forming agent that is levan
to form an open matrix network; and (b) at least one
pharmaceutically active ingredient, wherein the composition is an
orodispersible pharmaceutical dosage form.
42. The pharmaceutical composition according to claim 41, wherein
the liquid preparation further comprises one or more secondary
matrix-forming agents.
43. The pharmaceutical composition according to claim 42, wherein
the one or more secondary matrix-forming agent is mannitol.
44. The pharmaceutical composition according to claim 42, wherein
the one or more secondary matrix-forming agent is trehalose.
45. The pharmaceutical composition according to claim 42, wherein
the one or more secondary matrix-forming agent is raffinose.
46. The pharmaceutical composition according to claim 41, wherein
the at least one pharmaceutically active ingredient is chosen from
desmopressin, desmopressin acetate, loratidine, famotidine,
montelukast sodium, and ondansetron.
47. A blister pack having one or more depressions disposed therein,
wherein each of the one or more depressions comprises a
pharmaceutical composition, the composition comprising: (a) at
least one matrix-forming agent that is levan to form an open matrix
network; and (b) at least one pharmaceutically active ingredient,
wherein the composition is an orodispersible pharmaceutical dosage
form.
48. The blister pack according to claim 47, which is prepared by a
process comprising steps of: (a) introducing a liquid preparation
into one or more depressions of a blister pack, the liquid
preparation comprising the matrix forming agent and the
pharmaceutically active ingredient; and (b) sublimating the solvent
from the liquid preparation in the one or more depressions.
49. The blister pack according to claim 47, wherein the composition
further comprises one or more secondary matrix-forming agents.
50. The blister pack according to claim 48, wherein the one or more
secondary matrix-forming agents is selected from the group
consisting of trehalose, raffinose, and mannitol.
51. The blister pack according to claim 50, wherein the one or more
secondary matrix-forming agent is mannitol.
52. The pharmaceutical composition according to claim 50, wherein
the one or more secondary matrix-forming agent is trehalose.
53. The pharmaceutical composition according to claim 50, wherein
the one or more secondary matrix-forming agent is raffinose.
54. The pharmaceutical composition according to claim 47, wherein
the at least one pharmaceutically active ingredient is chosen from
desmopressin, desmopressin acetate, loratidine, famotidine,
montelukast sodium, and ondansetron.
Description
FIELD OF THE INVENTION
[0001] The subject invention relates to fast dissolving
pharmaceutical compositions, to methods of making them and to their
use in the treatment and prophylaxis of diseases in mammals,
particularly humans.
BACKGROUND OF THE INVENTION
[0002] Fast dissolving pharmaceutical dosage forms which are
designed to release an active ingredient in the oral cavity are
well known and can be used to deliver a wide range of drugs
(Critical Reviews in Therapeutic Drug Carrier Systems,
21(6):433-475 (2004); Seager H. (1998), J. Phar. Pharmacol
50:375-382; Bandari et al. (January 2008), Asian Journal of
Pharmaceutics 2-11).
[0003] In a fast dissolving dosage form, a drug may physically be
trapped in a matrix composed of e.g. mannitol and fish gelatin (EP
1501534; EP1165053), modified starch (U.S. Pat. No. 6,509,040),
pullulan in combination with an amino acid (EP1803446), or
maltodextrin in combination with sorbitol (US2004/0228919). The
solution, suspension or dispersion of the drug and the carrier
material may be filled into blister cavities, frozen and thereafter
lyophilized. However, dosage forms produced in this manner are
mostly fragile and brittle, have limited physical strength, and
cannot withstand any pressure. In addition, dosage units so
produced are difficult to pack and unpack.
SUMMARY OF THE INVENTION
[0004] The subject invention provides new fast dissolving oral
pharmaceutical compositions typically in a unit dosage form,
typically oral lyophilisates (also named orally disintegrating
tablets). Fast dissolving dosage forms of the invention have
relatively high tensile strength (i.e. force required to break a
tablet in a three-point bending test) on the one hand and a fast
disintegration/dissolution time on the other hand. This relatively
high tensile strength permits, amongst others, to easily remove the
composition from its container, typically a blister pack, without
disintegration. The unit dosage form of the invention can typically
be handled in a manner similar to that of a conventional compressed
tablet, with disintegration occurring only upon contact with an
aqueous liquid or with saliva within the mouth.
[0005] In one embodiment, the present invention provides a
pharmaceutical composition comprising an open matrix network
carrying a pharmaceutically active ingredient, wherein the open
matrix network is comprised of levan.
[0006] In another embodiment, the present invention provides a
pharmaceutical composition comprising a matrix carrying a
pharmaceutically active ingredient, the matrix rapidly
disintegrating upon contact with an aqueous solution or with
saliva, said matrix comprising levan.
[0007] The pharmaceutical composition of the invention is unique in
that it has a relatively high tensile strength, on the one hand,
and a rapid dissolution in an aqueous medium or in saliva, on the
other hand.
[0008] The relatively high tensile strength permits the handling of
the composition in a manner similar to that of a regular compressed
tablet including, in particular, removal from a package in which
they are held, e.g. a blister pack, without risk of damaging the
dosage form between the fingers. Notwithstanding this tensile
strength, the composition of the invention disintegrates rapidly
when contacted with an aqueous medium or with saliva, in particular
the composition rapidly disintegrates when taken orally. The
disintegration in an aqueous medium or in the oral cavity upon
consumption (where it disintegrates upon contact with saliva) is
typically within less than 30 seconds, and more typically within
less than 10 seconds, at times less than 9, 8, 7, 6, 5, 4, 3, 2 or
even 1 second.
[0009] Accordingly, the invention further provides a pharmaceutical
composition comprising a pharmaceutically active ingredient, having
a tensile strength so as to allow consumer handling of the
composition (typically in a unit dosage form) in a manner similar
to that of a compressed tablet, the pharmaceutical composition of
the invention typically having a tensile strength ranging between
about 0.05 to 1.6 N/mm.sup.2 and a rapid dissolution rate such that
at least 80% of the composition is disintegrated in an aqueous
medium or in saliva in less that 30 seconds, at times less than 10
seconds and even less than 9, 8, 7, 6, 5, 4, 3, 2, or 1 second.
[0010] The pharmaceutical composition of the invention may be
obtained by subliming a solvent (e.g. water), for example in a
freeze drying process, from a liquid preparation that comprises the
active ingredient and the matrix forming agent(s) in solution.
According to one embodiment, unit dosage quantities of the liquid
preparation are introduced into depressions and sublimation is then
carried out thereby obtaining (after sublimation) a pharmaceutical
composition in a unit dosage form. The depressions may be those of
an open blister pack and following the sublimation step, and
thereby the formation of the solid unit dosage form of the
composition in the depression, a sealing film or foil is placed
over the depressions to form a sealed blister pack.
[0011] The invention further provides a process for preparing a
pharmaceutical composition that comprises subliming a solvent from
a liquid preparation comprising a pharmaceutically active
ingredient and levan in the solvent.
[0012] The invention also provides a process for the preparation of
a pharmaceutical composition comprising (a) preparing a solution
comprising levan and an active ingredient in a solvent; (b)
freezing said solution; (c) subliming the solvent from the frozen
solution, wherein the pharmaceutical composition so obtained is in
fast-dispersing dosage form which disintegrates within less than 30
seconds upon contact with an aqueous solution or with saliva.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The subject invention provides a fast-dissolving, typically
orodispersible, pharmaceutical composition, usually prepared and
provided in unit dosage form, typically an oral lyophilisate,
comprising an active ingredient and one or more excipients. At
least one of the excipients, normally the main matrix forming
agent, is the polysaccharide levan.
[0014] The following are some of the terms used above and below in
this patent specification and claims:
[0015] The terms "active ingredient" or "pharmaceutically active
ingredient" will be used interchangeably herein.
[0016] The term "pharmaceutical composition" and "composition" are
interchangeably used herein to refer to a pharmaceutical
composition of the invention.
[0017] The term "unit dosage form" or "dosage form" will be used
herein to refer to said composition which is formulated with an
amount of an active pharmaceutical ingredient (API) in a dose for
administration as a single dose to a target individual.
[0018] The unit dosage form may be adapted, depending on the nature
of the active ingredient, the indication, the disease stage and
various other factors known per se for once, twice, thrice or any
other number of daily administrations.
[0019] The term "carrying" should be understood to encompass any
form of interaction between an active ingredient and the matrix
that allows the matrix to hold and/or contain an amount of active
ingredient and release it to the aqueous medium or to saliva upon
disintegration of the matrix.
[0020] The term "matrix" should be understood to denote a solid
carrier medium for an active ingredient. The matrix comprises one
or more excipients. The excipients that form the matrix may be
referred to herein, at times, as "matrix forming agents" and each
of said agents as "matrixforming agent".
[0021] The term "an open matrix network" should be understood to
encompass a matrix of water-soluble or water-dispersible carrier
material (matrix-forming agent(s)) having interstices dispersed
throughout. The matrix rapidly disintegrates upon contact with an
aqueous solution or with saliva.
[0022] In one embodiment, levan is the sole matrix forming agent in
the composition. In another embodiment, one or more secondary
matrix forming agents may be present in the composition.
[0023] Non-limiting examples of sugars, sugar alcohols,
monosaccharides, disaccharides, trisaccharides, polysaccharides,
proteins, amino acids, gums and the like, which are useful as
secondary matrix forming agents, include without limitation,
mannitol, trehalose, raffinose, inositol, pullulan, sucrose,
lactose, dextrose, erythritol, xylitol, lactitol, maltitol,
isomalt, alanine, arginine, threonine, glycine, cysteine, serine,
histidine, valine, proline, lysine, asparagine, glutamine, ribose,
glucose, galactose, fructose, maltose, maltotriose, guargum,
xanthan gum, tragacanth gum, veegum and so forth.
[0024] Generally, the balance of the formulation can be matrix.
Thus the percentage of the levan matrix can approach 100%. The
amount of the secondary matrix forming agent useful in accordance
with the present invention may range from about 0 to about 90%.
[0025] In one embodiment of the invention, levan is the main matrix
forming agent in the composition. In another embodiment, the
composition further comprises mannitol or raffinose or trehalose or
combinations thereof as secondary matrix forming agent.
[0026] In one embodiment, levan is the matrix forming agent,
comprising 10-99.99% out of the entire weight of the composition.
In another embodiment, levan comprises 30-75% out of the entire
weight of the composition. In yet another embodiment, levan
comprises 40-70% out of the entire weight of the composition. In
yet another embodiment, levan comprises 50-65% out of the entire
weight of the composition.
[0027] In other embodiments, mannitol or trehalose or raffinose or
combinations thereof are used as secondary matrix forming agents,
comprising 0-89.99% out of the entire weight of the composition. In
one embodiment, these secondary matrix forming agents comprise
15-50% out of the entire weight of the composition. In another
embodiment, these secondary matrix forming agents comprise 25-50%
out of the entire weight of the composition.
[0028] Thus, a composition of the invention can be one comprising
levan as the main matrix-forming agent and mannitol or trehalose or
raffinose (or combinations thereof) as secondary matrix-forming
agent, with levan constituting 10-99.99% (all % of ingredient are
w/w, meaning weight of mentioned ingredient out of the weight of
all constituents of the composition combined), and the secondary
matrix forming agent constituting 0-89.99%, typically 25-50%. The
content of the active ingredient may typically (but not
exclusively) be up to 90% of the entire composition, typically in
the range of 0.01-70% depending on the nature of the active
ingredient. In one embodiment, the active ingredient comprises
0.01-1% out of the entire weight of the composition. In another
embodiment, the active ingredient comprises 0.5-2% out of the
entire weight of the composition. In yet another embodiment, the
active ingredient comprises 5-30% out of the entire weight of the
composition. In other embodiments, the active ingredient comprises
20-40% out of the entire weight of the composition. In yet other
embodiments, the active ingredient comprises 60-90% out of the
entire weight of the composition.
[0029] In one embodiment, the composition of the invention does not
contain fish gelatin. In another embodiment, the composition of the
invention does not contain a modified starch. In another
embodiment, the composition of the invention does not contain
pullulan in combination with an amino acid. In another embodiment,
the composition of the invention does not contain maltodextrin in
combination with sorbitol.
[0030] "Disintegration Time" and "Dissolution Time" are used
interchangeably herein and should be understood to mean the time
needed to dissolve or disintegrate the composition of the invention
in an aqueous solution or with saliva within the oral cavity.
[0031] "Oral dissolving Time" as used herein should be understood
to mean the time needed to dissolve the composition of the
invention in the oral cavity.
[0032] "Rapid/Fast disintegration/dissolution" as used herein
should be understood to encompass disintegration of at least 80% of
the composition of the invention, typically 90% and more typically
100% of the composition in an aqueous medium or in saliva (in the
oral cavity) within 30 seconds, typically within 10 seconds and at
times even within 9, 8, 7, 6, 5, 4, 3, 2 or 1 second.
[0033] Examples of an aqueous medium as used herein are water or a
buffer (e.g. potassium dihydrogen phosphate, dipotassium hydrogen
phosphate, sodium hydrogen phosphate) or artificial saliva as
described by Morjaria et, al (May 2004), Dissolution Technologies
12-15.
[0034] Saliva as used herein refers to the saliva in the oral
cavity of a mammal, in particular a human.
[0035] "Tensile strength" as used herein should be understood to be
the force required to break a tablet, which is measured by the
three-point bending test, wherein the tablet is subjected to a
bending stress (Mohd et al. (2002), Drug Development and Industrial
Pharmacy 28(7):809-813).
[0036] In one embodiment, a pharmaceutical composition of the
invention has a tensile strength in the range of about 0.05-1.6
N/mm.sup.2. In another embodiment, a pharmaceutical composition of
the invention has a tensile strength in the range of about 0.15-1.4
N/mm.sup.2. In yet another embodiment, a pharmaceutical composition
of the invention has a tensile strength in the range of about
0.3-0.85 N/mm.sup.2.
[0037] It is envisaged that a pharmaceutical composition of the
invention has a rapid disintegration/dissolution rate such that at
least 80% of the composition is dissolved in an aqueous medium or
in saliva within 30 seconds, typically within 10 seconds. In one
embodiment, a pharmaceutical composition of the invention has a
rapid disintegration/dissolution rate such that at least 90% of the
composition is dissolved in an aqueous medium or in saliva within
30 seconds, typically within 10 seconds.
[0038] In one embodiment, a pharmaceutical composition of the
invention has a tensile strength in the range of about 0.05-1.6
N/mm.sup.2 and a rapid disintegration/dissolution rate such that at
least 80% of the composition is dissolved in an aqueous medium or
in saliva within 30 seconds, typically within 10 seconds.
[0039] In another embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically active
ingredient, having a tensile strength ranging between about 0.15 to
1.4 N/mm.sup.2 and a rapid disintegration/dissolution rate such
that at least 80% of the composition is dissolved in an aqueous
medium or in saliva within 30 seconds, typically within 10
seconds.
[0040] In another embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically active
ingredient, having a tensile strength ranging between about 0.3 to
0.85 N/mm.sup.2 and a rapid disintegration/dissolution rate such
that at least 80% of the composition is dissolved in an aqueous
medium or in saliva within 30 seconds, typically within 10
seconds.
[0041] In one embodiment, a pharmaceutical composition of the
invention has a tensile strength in the range of about 0.05-1.6
N/mm.sup.2 and a rapid disintegration/dissolution rate such that at
least 90% of the composition is dissolved in an aqueous medium or
in saliva within 30 seconds, typically within 10 seconds.
[0042] In another embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically active
ingredient, having a tensile strength ranging between about 0.15 to
1.4 N/mm.sup.2 and a rapid disintegration/dissolution rate such
that at least 90% of the composition is dissolved in an aqueous
medium or in saliva within 30 seconds, typically within 10
seconds.
[0043] In another embodiment, the invention provides a
pharmaceutical composition comprising a pharmaceutically active
ingredient, having a tensile strength ranging between about 0.3 to
0.85 N/mm.sup.2 and a rapid disintegration/dissolution rate such
that at least 90% of the composition is dissolved in an aqueous
medium or in saliva within 30 seconds, typically within 10
seconds.
[0044] The open matrix network enables a liquid to enter the dosage
form through the interstices and permeate through its interior.
Permeation by aqueous media (such as saliva, water, etc.) exposes
the carrier material of both the interior and exterior of the
dosage form to the action of the aqueous media or saliva whereby
the network of carrier material is rapidly
disintegrated/dissolved.
[0045] The open matrix structure is of a porous nature and enhances
disintegration of the dosage form as compared with ordinary solid
shaped pharmaceutical dosage forms such as (granulated and
compressed) tablets, pills, capsules, suppositories and pessaries.
Rapid disintegration results in rapid release of the active
ingredient carried by the matrix.
[0046] In the subject invention, the carrier material of the open
matrix network is levan or a derivative thereof.
[0047] Levan (also named leaven, levulosan, polyfructosan,
polyfructose and polylevulan) is a polymer of fructose
C.sub.6H.sub.12O.sub.6. Levan is a polysaccharide with
.beta.-(2->6) linkages between the fructose rings where the
numbers describe the carbon atoms in the fructose ring which are
linked and the 3 describes the stereochemical relationship. Levans
have also been described as fructans in which the predominant
glycosidic linkage between the D-fructofuranoside monomeric units
is .beta.-(2->6). The levans are generally made by
microorganisms and do not occur as high molecular weight compounds
in plants. Some low molecular weight levans having a molecular
weight of less than 100,000 Daltons can occur in grasses.
[0048] "Levan" as used herein should be understood to encompass
levan derived from any source such as but not limited to A.
indicus, A. versicolor, Acetobacter suboxydans, Achromobacter spp.,
Actinomycenes sp., Actinomyces viscosus, Aerobacter aerogenes,
Aerobacter levanicum, Aspergillus sydowii, Azotobacter chroococcum,
Bacillus polymyxa, Bacillus licheniformis, Bacillus macerans,
Bacillus megatherium, Bacillus mesentericus, Bacillus subtilis,
Bacillus vulgatus, Corynbacterium laevaniformans, Erwinia
herbicola, Gluconobacter oxydans, Leuconostoc mesenteroides,
Odontomyces viscosus, Phytobacterium vitrosum, Phytomonas pruni,
Psuedomonas Fluorescens, Pseudomonas Syringae, Pseudomonas
prunicola, Rothis dentocariosa, Serratia kiliensis, Steptococcus
bovis, Steptococcus mutans, Steptococcus salivarius, Xanthomonas
campestris, Xanthomonas pruni, Zymomonas mobilis and so forth. In a
specific embodiment, the levan is obtained from Zymomonas and
Bacillus species. In a more specific embodiment, the levan is
obtained from Zymomonas mobilis.
[0049] It should be understood that also derivatives of levan (e.g.
as described in WO98/03184) can be used in place of levan.
[0050] The pharmaceutically active ingredient may encompass any
pharmaceutical ingredient such as a drug, a compound, a peptide, a
nucleotide, and so forth.
[0051] Non-limiting examples of drugs which can be carried by the
open matrix network of the subject invention are analgesics, alpha
blockers, anti-allergy, anti-asthma, (allergic rhinitis, chronic
uticaria), anti-inflammatory, antacids, anthelmintics,
anti-arrhythmic agents, anti-arthritis, anti-bacterial,
anti-anxiety, anti-coagulants, anti-depressants, anti-diabetics,
anti-diarrheals, anti-diuretics, anti-epileptics, anti-fungal,
anti-gout, anti-hypertensive, anti-incontinence, anti-insomnia,
anti-malarials, anti-migraine, anti-muscarinic, anti-neoplastic and
immunosuppressants, anti-protozoal, anti-rheumatics, anti-rhinitis,
anti-spasmatic, anti-thyroid, antivirals, anxiolytics, sedatives,
hypnotics and neuroleptics, beta-blockers, anti-benign hyperplasia
(BHP), cardiac inotropic, corticosteroids, cough suppressants,
cytotoxics, decongestants, diabetic gastric stasis, diuretics,
enzymes, anti-parkinsonian, gastro-intestinal, histamine receptor
antagonists, infertility, endometriosis, hormone replacement
therapy, lipid regulating agents, local anesthetics, neuromuscular
agents, nitrates and anti-anginal agents, menstrual disorders,
motion sickness, anti-pain, anti-nausea, movement disorders,
nutritional agents, opioid analgesics, oral vaccines, proteins,
peptides and recombinant drugs, prevention of chemotherapy induced
and post operative nausea and vomiting proton pump inhibitors,
schizoprenia, sex hormones and contraceptives, seizure/panic
disorder, sexual dysfunction (male and female), spermicides,
stimulants voiding dysfunctions, veterinary medicines and so
forth.
[0052] Specific non-limiting examples of these drugs are: [0053]
Alfa blockers: Tamsulosine [0054] Analgesics and anti-inflammatory
agents: aspirin, aloxiprin, auranofin, azapropazone, benorylate,
diflunisal, ctodolac, fcnbufen, fenoprofen calcium, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic
acid, nabumetone, naproxen, oxaprozin, oxyphenbutazone,
phenylbutazone, piroxicam, sulindac, paracetamol. [0055] Antacids:
aluminum hydroxide, magnesium carbonate, magnesium trisilicate,
hydrotalcite, dimethicone. [0056] Antihelmintics: albendazole,
bephenium hydroxynaphthoate, cambendazole, dichlorophen,
ivermectin, mebendazole, oxamniquine, oxfendazole, oxantel
embonate, praziquantel, pyrantel embonate, thiabendazole. [0057]
Anti-allergic: des loratidine, loratidine, Montelukast, Montelukast
sodium, Cetirizin, Fexofenadin, Ebastine. [0058] Anti-arrhythmic
agents: amiodarone HCl, disopyramide, flecainide acetate, quinidine
sulphate. [0059] Anti-bacterial agents: benethamine penicillin,
cinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine,
cloxacillin, demeclocycline, doxycycline, erythromycin,
ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin,
spiramycin, sulphabenzamide, sulphadoxine, sulphamerazine,
sulphacetamide, sulphadiazine, sulphafurazole, sulphamethoxazole,
sulphapyridine, tetracycline, trimethoprim. [0060] Anti-coagulants:
dicoumarol, dipyridamole, nicoumalone, phenindione. [0061]
Anti-depressants: amoxapine, ciclazindol, maprotiline HCl,
mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine
maleate. [0062] Anti-diabetics: acetohexamide, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamrnide, tolbutamide.
[0063] Anti-diarrheals: atropine sulphate, codeine phosphate,
co-phenotrope, difenoxin, loperamide hydrochloride, suphasolazine,
mesalazine, olsalazine, corticosteroids, prednisolone. [0064]
Anti-diuretics: desmopressin, desmopressin acetatc. [0065]
Anti-epileptics: beclamide, carbamazepine, clonazepam, ethotoin,
methoin, methsuximide, methylphenobarbitone, oxcarbazepine,
paramethadione, phenacemide, phenobarbitone, phenytoin,
phensuximidc, primidone, suithiame, valproic acid. [0066]
Anti-fungal agents: amphotericin, butoconazole nitrate,
clotrimazole, econazole nitrate, fluconazole, flucytosine,
griseofulvin, itraconazole, ketoconazole, miconazole, natamycin,
nystatin, sulconazole nitrate, terbinafine HCl, terconazole,
tioconazole, undecenoic acid. [0067] Anti-gout agents: allopurinol,
probenecid, sulphinpyrazone. [0068] Anti-hypertensive agents:
amlopidine, benidipine, darodipine, dilitazem HCl, diazoxide,
felodipine, guanabenz acetate, indoramin, isradipine, minoxidil,
nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl,
prazosin HCl, reserpine, terazosin HCl. [0069] Anti-insomnia:
Zolpidem [0070] Anti-malaria: amnodiaquine, chloroquine,
chloroproguanil HCl, halofantrine HCl, mefloquine HCl, proguanil
HCl, pyrimethamine, quinine sulphate. [0071] Anti-migraine agents:
rizatriptan, dihydroergotamine mesylate, ergotamine tartrate,
methysergide maleate, pizotifen maleate, sumatriptan succinate,
caffeine. [0072] Anti-muscarinic agents: oxybutinin, tolterodin,
atropine, benzhexol HCl, biperiden, ethopropazine HCl, hyoscine
butyl bromide, hyoscyamine, mepenzolate bromide, orphenadrine,
oxyphencylcimine HCl, tropicamide. [0073] Anti-neoplastic agents
and Immunosuppressants: aminoglutethimide, amsacrine, azathioprene,
busulphan, chlorambucil, cyclosporin, dacarbazine, estramustine,
etoposide, lomustine, melphalan, mercaptopurine, methotrexate,
mitomycin, mitotane, mitozantrone, procarbazine HCl, tamoxifen
citrate, testolactone. [0074] Anti-protozoal agents: benznidazole,
clioquinol, decoquinate, diiodohydroxyquinoline, diloxanide
furcate, dinitolmide, furzolidone, metronidazole, nimorazole,
nitrofurazone, ornidazole, tinidazole. [0075] Anti-rheumatics:
ibuprofen, aceclofenac, acemetacin, azapropazone, diclofenac
sodium, diflunisal, etodolac, ketoprofen, indomethacin, mefenamic
acid, naproxen, piroxicam, aspirin, benorylate, auranofin,
penicillamine. [0076] Anti-rhinitis, anti-uticaria: Cetirizin,
fexofenadin, ebastine, loratidin, montelukast [0077]
Anti-spasmatic: phloroglucinol anhydre [0078] Anti-thyroid agents:
carbimazole, propylthiouracil. [0079] Antivirals: acyclovir,
amantadine hydrochloride, famciclovir, zidovadine, didanosine,
zalcitabine, foscarnet sodium. [0080] Anxiolytic, sedatives,
hypnotics and neuroleptics: alprazolam, amylobarbitone, barbitone,
bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone,
carbromal, chlordiazepoxide, Chlorpheniramine, chlormethiazole,
chlorpromazine, clobazani, clonazepan, clotiazepam, clozapine,
diazepam, droperidol, ethinamate, flunanisone, flunitrazepam,
fluopromazine, flupenthixol decanoate, fluphenazine decanoate,
flurazepam, haloperidol, lorazepam, lormetazepam, medazepam,
meprobamate, methaqualone, midazolam, nitrazepam, oxazepam,
pentobarbitone, perphenazine phenylephrine, pimozide,
prochlorperazine, pseudoephedrineHCL, sulpride, temazepam,
thioridazine, triazolam, zopiclone. [0081] .beta.-Blockers:
acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol,
oxprenolol, pindolol, propanolol. [0082] Cardiac inotropic agents:
amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.
[0083] Corticosteroids: beclomethasone, betamethasone, budesonide,
cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone
acetate, flunisolide, flucortolone, fluticasone propionate,
hydrocortisone, methylprednisolone, prednisolone, prednisone,
triamcinolone. [0084] Cough suppressants: codeine phosphate
dexomethorphan, guaifenesin, pholcodine, diamorphine, methadone.
[0085] Cytotoxics: ifosfamide, chlorambucil, melphalan, busulphan,
cytotoxic antibodies, doxorubicin, epirubicin, plicamnycin,
bleomycin, methotrexate, cytarabine, fludarabine, gencitabine,
fluorouracil, mercaptopurine, thioguanine, vincristine,
vinblastine, vindesine, etoposide. [0086] Decongestants:
pseudoephedrine hydrochloride. [0087] Diuretics: acetazolamide,
amiloride, bendrofluazide, bumetanide, chlorothiazide,
chlorthalidone, ethacrynic acid, frusemide, metolazone,
spironolactone, triamterene. [0088] Enzymes: pancreatin, pepsin,
lipase. [0089] Epilepsy: Gabapentin [0090] Anti-parkinsonian
agents: bromocriptine mesylate, lysuride maleate, selegiline,
para-fluoroselegiline, lazabemide, rasagiline, 2-BUMP
[N-(2-butyl)-N-methylpropargylamine], M-2-PP
[N-methyl-N-(2-pentyl)-propargylamine], MDL-72145
[beta-(fluoromethylene)-3,4-dimethoxy-benzeneethanamine],
mofegiline, apomorphine, N-propylnoraporphine, cabergoline,
metergoline, naxagolide, pergolide, piribedil, ropinirole,
terguride, quinagolide. [0091] Gastro-intestinal agents: bisacodyl,
cimetidine, cisapride, diphenoxylate HCl, domperidone,
metoclopramide, famotidine, loperamide, mesalazine, nizatidine,
esomeprazole, mctopimazine, pantoprazolc, ondansetron HCl,
Granisetron, tropisetron, dolasetron, ranitidine HCl,
sulphasalazine. Lanzoprazole, [0092] Histamine Receptor
Antagonists: acrivastine, astemizole, cinnarizine, cyclizine,
cyproheptadine HCl, dimenhydrinate, flunarizine HCl, loratadine,
meclozine HCl, oxatomide, terfenadine, triprolidine. [0093] Hormone
replacement therapy: dydrogesterone [0094] Hypertension: Enalapril
[0095] Lactation: Oxytocin, oxytocin agonists [0096] Lipid
regulating agents: bezafibrate, clofibrate, fenofibrate,
gemfibrozil, probucol. [0097] Local anaesthetics: amethocaine,
amylocaine, benzocaine, bucricaine, bupivacaine, butacaine,
butanilicaine, butoxycaine, butyl aminobenzoate, carticaine,
chloroprocaine, cinchocaine, clibucaine, clormecaine, coca,
cocaine, cyclomethycaine, dimethisoquin, diperodon, dyclocaine,
ethyl chloride, ethyl p-piperidinoacetylaminobenzoate, etidocaine,
hexylcaine, isobutamben, ketocaine, lignocaine, mepivacaine,
meprylcaine, myrtecaine, octacaine, oxethazaine, oxybuprocaine,
parethoxycaine, pramoxine, prilocaine, procaine, propranocaine,
propoxycaine, proxymetacaine, ropivacaine, tolycaine, tricaine,
trimecaine, vadocaine. [0098] Motion sickness: diphenhydramine
[0099] Neuro-muscular agents: pyridostigmine. [0100] Nitrates and
other anti-anginal agents: amyl nitrate, glyceryl trinitrate,
isosorbide dinitrate, isosorbide mononitrate, pentaerythritol
tetranitrate. [0101] Nutritional agents: betacarotene, vitamins,
such as vitamin A, vitamin B.sub.2, vitamin D, vitamin E, vitamin
K, minerals. [0102] Opioid analgesics: codeine,
dextropropyoxyphene, diamorphine, dihydrocodeine, meptazinol,
methadone, morphine, nalbuphine, pentazocine. [0103] Oral vaccines:
to prevent or reduce the symptoms of diseases such as Influenza,
Tuberculosis, Meningitis, Hepatitis, Whooping Cough, Polio,
Tetanus, Diphtheria, Malaria, Cholera, Herpes, Typhoid, HIV, AIDS,
Measles, Lyme disease, Traveller's Diarrhea, Hepatitis A, B and C,
Otitis Media, Dengue Fever, Rabies, Parainfluenza, Rubella, Yellow
Fever, Dysentery, Legionnaires Disease, Toxoplasmosis, Q-Fever,
Haemorrhegic Fever, Argentina Haemorrhegic Fever, Caries, Chagas
Disease, Urinary Tract Infection caused by E. coli, Pneumococcal
Disease, Mumps, Chikungunya, IIayfever, Asthma, Rheumatoid
Arthritis, Carcinomas, Coccidiosis, Newcastle Disease, Enzootic
pneumonia, Feline leukemia, Atrophic rhinitis, Erysipelas, Foot and
Mouth disease and Swine pneumonia, or to prevent or reduce the
symptoms of diseases caused by Vibrio species, Salmonella species,
Bordetella species, Haemophilus species, Toxoplasmosis gondii,
Cytomegalovirus, Chlamydia species, Streptococcal species, Norwalk
Virus, Escherischia coli, Helicobacter pylori, Rotavirus, Neisseria
gonorrhae, Neisseria meningiditis, Adenovirus, Epstein Barr Virus,
Japanese Encephalitis Virus, Pneumocystis carini, Herpes simplex,
Clostridia species, Respiratory Syncytial Virus, Klebsiella
specics, Shigella species, Pseudomonas aeruginosa, Parvovirus,
Campylobacter species, Rickettsia species, Varicella zoster,
Yersinia species, Ross River Virus, J.C. Virus, Rhodococcus equi,
Moraxella catarrhalis, Borrelia burgdorferi and Pasteurella
haemolytica. [0104] Voiding dysfunctions: Tamsulosine, trospium
chloride, tolterodine, oxybutinin Proteins, peptides and
recombinant drugs: recombinant hormones and iso-hormones,
recombinant cytokines, recombinant plasminogens, TNF receptor
fusion protein, monoclonal antibodies, nucleic acids, antisense
oligonucleotides, oligonucleotides, glycoproteins and adhesion
molecules. [0105] Veterinary Arthiritis: Tepoxalin [0106] Sex
hormones and Contraceptives: clomiphene citrate, danazol,
desogestrel, ethinyloestradiol, ethynodiol, ethynodiol diacetate,
levonorgestrel, medroxyprogesterone acetate, mestranol,
methyltestosterone, norethisterone, norethisterone enanthate,
norgestrel, estradiol, conjugated estrogens, dydrogesterone,
progesterone, stanozolol, stilboestrol, testosterone, tibolone.
[0107] Schizoprenia; Olanzapine, Nicergoline Sexual dysfunction:
Cabergolin, oxytocin, tadalafil, sildenafil, vardenafil [0108]
Spermicides: nonoxynol 9. [0109] Stimulants: amphetamine,
dexamphetamine, dexfenfluramine, fenfluramine, mazindol,
pemoline.
[0110] In a specific, non-limiting embodiment, the active
ingredient is desmopressin acetate. In this embodiment the dosage
form can be used in voiding postponement or in the treatment or
prevention of incontinence, primary nocturnal enuresis (PNE),
nocturia or central diabetes insipidus. In one embodiment, the
amount of desmopressin acetate in the composition comprises
0.01-2.00% w/w. In another embodiment, the amount of desmopressin
acetate in the composition comprises 0.04-1.00% w/w.
[0111] In a specific, non-limiting embodiment, the active
ingredient is loratidine. In this embodiment the dosage form can be
used e.g. for the relief of nasal or non-nasal symptoms of allergic
rhinitis and chronic idiopathic urticaria. In one embodiment, the
amount of loratidine in the composition comprises 20-40% w/w. In
another embodiment, the amount of loratidine in the composition
comprises about 25-40% w/w.
[0112] In a specific, non-limiting embodiment, the active
ingredient is famotidine. In this embodiment the dosage form can be
used e.g. in the treatment of gastroesophageal reflux disease,
duodenal and gastric ulcer, pathological hypersecretory conditions
(e.g. Zollinger-Ellison syndrome and multiple endocrine adenomas).
In one embodiment, the amount of famotidine in the composition
comprises 50-90% w/w. In another embodiment, the amount of
famotidine in the composition comprises 60-90% w/w.
[0113] In a specific, non-limiting embodiment, the active
ingredient is montelukast sodium. In this embodiment the dosage
form can be used e.g. in prophylaxis and chronic treatment of
asthma, allergic rhinitis and exercise-induced bronchoconstriction.
In one embodiment, the amount of montelukast sodium in the
composition comprises 5-40% w/w. In another embodiment, the amount
of montelukast sodium in the composition comprises 5-30% w/w.
[0114] In a specific, non-limiting embodiment, the active
ingredient is ondansetron. In this embodiment the dosage form can
be used e.g. in the prevention of postoperative nausea and/or
vomiting and also in the prevention of nausea and/or associated
with cancer chemotherapy and radiotherapy. In one embodiment, the
amount of ondansetron in the composition comprises 10-30% w/w. In
another embodiment, the amount of ondansetron in the composition
comprises about 20% w/w.
[0115] A pharmaceutical dosage form of the invention disintegrates,
thereby releasing the active ingredient, upon contact with a fluid
(an aqueous medium or saliva).
[0116] Typically, a pharmaceutical dosage form of the invention is
an orodispersible pharmaceutical dosage form which disintegrates in
the mouth within 30 seconds, typically 10 seconds or less.
[0117] The term "orodispersible" as used herein should be
understood to encompass a solid dosage form which disintegrates or
dissolves in the mouth within (at most) 30 seconds. In further
embodiments, the orodispersible dosage form disperses in the mouth
within 10, 9, 8, 7, 6, 5, 4, 3, 2, or even within 1 second.
[0118] A suitable route of administration for the dosage form of
the subject invention is oral administration including buccal and
sublingual administration. In a specific embodiment, the dosage
form is administered sublingually. Dosage forms of the invention
may also be placed on the tongue or against the cheek or
gingiva.
[0119] Pharmaceutical dosage forms of the present invention are
adapted to supply the active ingredient to e.g. the oral cavity.
The active may be absorbed across the mucosa at the site of
administration, e.g. sublingual mucosa, and/or otherwise, in the
case of oral administration, from the oral cavity (e.g. across the
buccal and/or gingival mucosa) and/or from the gastrointestinal
tract for systemic distribution.
[0120] The exact dose and regimen of administration of the dosage
form will necessarily be dependent upon the therapeutic effect to
be achieved and may vary with the particular active ingredient, the
route of administration, and the age and condition of the
individual subject to whom the medicament is to be administered. At
times patients may be instructed to take two or any other number of
unit dosage forms in a single administration or at times only a
portion, such as half or a quarter of the unit dosage form in a
single administration.
[0121] The dosage form of the invention achieves a balance of
performance: tensile strength, stability and fast disintegration.
It may be produced by known lyophilisate technology. It can be
stored (and packed) in blisters but due to its tensile strength,
can also be stored and/or packaged in bottles or bulk. The
invention achieves these results in a single processing step,
without the need to resort to multiple steps including
granulation.
[0122] In addition to the ingredients previously discussed, the
matrix may also include other excipients (auxiliary agents,
accessory agents) such as, but not limited to fillers,
matrix-forming agents, thickeners (including but not limited to
guar gum and xanthum gum), binders, diluents, lubricants, pH
adjusting agents, protecting agents, viscosity enhancers, wicking
agents, non-effervescent disintegrants, effervescent disintegrants,
surfactants, anti-oxidants, wetting agents, colorants, flavouring
agents, taste-masking agents, sweeteners, preservatives and so
forth.
[0123] In one embodiment, a composition of the invention is
obtainable by subliming solvent from a liquid preparation
comprising an active ingredient, levan and optionally secondary
matrix forming agent(s) in a solvent. Typically, the liquid
preparation is placed in a mould, e.g. such that following
sublimination a solid composition, typically in a dosage unit, is
formed within the mould. The mould can be an open blister pack
whereby the solid dosage unit is formed within the blister pack's
depression which is thereafter sealed by a sealing film or
foil.
[0124] In one embodiment, the process comprises introducing unit
dosage quantities of said preparation into depressions of an open
blister pack; and then subliming the preparation to obtain solid
dosage forms within said depressions.
[0125] The sublimation can be carried out by freeze drying the
preparation comprising the active ingredient, levan and optionally
secondary matrix forming agent(s) in a solvent. In one embodiment,
the solvent is water.
[0126] The invention thus discloses a process for preparing
fast-dispersing dosage forms by lyophilizing a combination of an
active ingredient, levan and optionally secondary matrix forming
agent(s). The fast-dispersing dosage form contains a network of the
active ingredient and the carrier levan and optionally the
secondary matrix forming agent(s), the network having been obtained
by subliming solvent from the liquid preparation that contains the
active ingredient, levan and the other optional matrix forming
agents. Said preparation may be a solution, suspension or
dispersion.
[0127] Typically, an initial preparation comprising an active
ingredient, levan and optionally secondary matrix forming agent(s)
in a solvent is prepared, followed by sublimation. The sublimation
can be carried out by freeze drying the preparation.
[0128] In a freeze drying procedure, the preparation (in liquid
form) that comprises an active ingredient, levan and any other
optional matrix forming agent in a solvent is filled into moulds.
Each mould typically contains a defined amount of such solution
with a defined amount of active ingredient. The preparation in the
mould is then frozen, for example by passing gaseous cooling medium
over the mould. After the preparation has been frozen, the solvent
is sublimed therefrom. The sublimation is carried out in a freeze
dryer. In consequence an open matrix network of levan optionally
together with other matrix forming agents included in the solution,
carrying the active ingredient, is thereby formed.
[0129] The preparation is contained in a mould during the
freeze-drying process to produce a solid form in any desired shape.
Prior to the lyophilization, the mould may be cooled and frozen
(e.g. in a fast-freeze tunnel or on the shelves of the
lyophilizer), for example using liquid nitrogen or solid carbon
dioxide. In one embodiment, the freezing rate is from 0.1 to
2.degree. C./minute. In another embodiment, the freezing rate is
from 0.5 to 1.5.degree. C./minute. In yet another embodiment, the
freezing rate is from 10 to 260.degree. C./minute. In another
embodiment, the freezing rate is from 20 to 260.degree. C./minute.
In a further embodiment, the freezing rate is from 20 to
160.degree. C./minute.
[0130] After lyophilization, the freeze dried compositions can
either be removed from the mould if desired or stored therein until
later use. Typically, each mould is so designed so to produce a
unit dosage form of the composition. The composition so obtained is
fast-dispersing and disintegrates within at most 30 seconds upon
contact with fluid, typically within less than 10 seconds.
[0131] The solvent is typically water but may optionally also
contain a co-solvent (such as an alcohol e.g. tert-butyl alcohol)
to improve the solubility of the chemical.
[0132] The composition may contain a pH adjusting agent to adjust
the pH of a solution from which the dosage form is prepared within
the range of from 2 to 10, typically from 3.5 to 9.5 or from 4.5 to
8. Citric acid, sodium hydroxide, and sodium carbonate can be used
as pH adjusting agent, but others including hydrochloric acid and
malic acid can also be used. Non-volatile pH adjusting agents will
not be removed by freeze drying or other sublimation processes and
so may be present in the final product.
[0133] When preparing a fast dissolving dosage form of the
invention using the main matrix forming agent levan without adding
secondary matrix forming agents, an annealing process (temperature
shifts) may be used during the lyophilization process in order to
smoothen the surface of the dosage form. Such an annealing step is
carried out for an esthetic purpose only and has no influence on
the dissolution time nor on the tensile strength of the resulting
dosage form. When secondary matrix forming agents are present,
there is no need for such a smoothing annealing step.
[0134] The mould may comprise a series of cylindrical or other
shape depressions in it, each of a size corresponding to a desired
size of a dosage form to be formed.
[0135] In one embodiment, the mould is a depression in a sheet of
filmic material. The filmic material may contain more than one
depression. The filmic material may be similar to that employed in
conventional blister packs which are used for packaging oral
contraceptive tablets and like medicament forms. For example the
filmic material may be made of thermoplastic material with the
depressions formed by thermoforming or coldforming. Polyvinyl
chloride film can be used as filmic material. Laminates of filmic
material may also be used.
EXAMPLES
[0136] The invention is further described in the following
examples, which are not in any way intended to limit the scope of
the inventions as claimed.
A. Materials Used in the Examples Presented Below
TABLE-US-00001 [0137] Material Obtained from Levan (Zymomonas spp.)
RealBiotech, Korea Levan (Bacilus spp.) Montana Polysaccharides,
USA Citric acid Merck, India Mannitol Merck, India Desmopressin
acetate Manufactured by Polypeptide Labs A/S, and supplied by
Ferring Loratadine Ultratech India Ltd Famotidine Exim Pharma
International, India Montelukast Sodium MSN Pharma Chem Pvt. Ltd.,
India Ondansetron base Cadila Pharma Ltd., India Guar gum Merck,
India Sodium lauryl sulphate (SLS) Merck, India Xanthan gum SD Fine
Chem Ltd., India Sodium citrate Merck, India Pullulan Hyashibara,
Japan Glycine Sigma Aldrich Hydropropyl methyl cellulose Shin-Etsu
Chemical Co. Japan (HPMC) Methyl cellulose Shin-Etsu Chemical Co.
Japan Gum tragacanth Merck, India Fish gelatin Croda Chemicals Pvt.
Ltd, India Sodium methyl paraben Alta Lab Pvt. Ltd., India
Raffinose Loba Chemie Pvt. Ltd., India Trehalose Loba Chemie Pvt.
Ltd., India Sodium propyl paraben Prayosha Healthcare, India
Hydroxy propyl .beta. cyclodextrin Gangwal Chemicals Pvt. Ltd.,
India Sodium hydroxide Merck, India Neotame Nutrasweet, USA
Strawberry flavour Virginia Dare, USA Cherry flavour Virginia Dare,
USA
B. Method for Preparing Placebo Formulation
[0138] 1) Dissolve Levan, and other excipients, if present, in
purified water under stirring at 200 to 500 revolutions per minute
(rpm). [0139] 2) Optionally adjust the pH of the solution using
citric acid solution or NaOH. [0140] 3) Make up the final volume of
the solution using purified water. [0141] 4) Mix the solution under
stirring at 200 to 500 rpm for 15 minutes. [0142] 5) Dose the
solution into each cavity of preformed blister sheets (typically
using dispensing pipette). [0143] 6) Freeze the filled blisters at
a temperature in the range of -20 to -110.degree. C. [0144] 7)
Freeze dry the blisters in a lyophilizer [0145] 8) Place the
blister sheet containing dried lyophilisates on the punched carrier
web of a blister packaging machine to transport the blister sheets
through the sealing station of the packaging machine. [0146] 9)
Seal the blisters with a lidding foil and punch into final
blisters.
C1. Formulations
[0147] The following formulations were prepared using the method
described in the method section "B" above, by freezing the blisters
at the rate of 0.1-2.degree. C./minute in step 6.
Example-1
TABLE-US-00002 [0148] Component Amount/unit % w/w Levan (Bacilus
spp.) 25 mg 100 Purified water q.s to 250 .mu.l --
Example-2
TABLE-US-00003 [0149] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 100 Purified water q.s to 250 .mu.l --
Example-3
TABLE-US-00004 [0150] Component Amount/unit % w/w Levan (Bacilus
spp.) 37.5 mg 100 Purified water q.s to 250 .mu.l --
Example-4
TABLE-US-00005 [0151] Component Amount/unit % w/w Levan (Zymomonas
spp.) 37.5 mg 100 Purified water q.s to 250 .mu.l --
Example-5
TABLE-US-00006 [0152] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 100 Purified water q.s to 250 .mu.l --
Example-6
TABLE-US-00007 [0153] Component Amount/unit % w/w Levan (Zymomonas
spp.) 12.5 mg 100 Purified water q.s to 250 .mu.l --
Example-7
TABLE-US-00008 [0154] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 99.99 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH
4.5 Purified water q.s to 250 .mu.l --
Example-8
TABLE-US-00009 [0155] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 99.99 Citric acid (5% w/v) q.s to pH 5.0 q.s to pH
5.0 Purified water q.s to 250 .mu.l --
Example-9
TABLE-US-00010 [0156] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 99.99 0.1N NaOH q.s to pH 7.0 q.s to pH 7.0 Purified
water q.s to 250 .mu.l --
Example-10
TABLE-US-00011 [0157] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 99.99 0.1N NaOH q.s to pH 8.0 q.s to pH 8.0 Purified
water q.s to 250 .mu.l --
Example-11
TABLE-US-00012 [0158] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 99.99 0.1N NaOH q.s to pH 9.0 q.s to pH 9.0 Purified
water q.s to 250 .mu.l --
Example-12
TABLE-US-00013 [0159] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 75 Mannitol 6.25 mg 25 Purified water q.s to 250
.mu.l --
Example-13
TABLE-US-00014 [0160] Component Amount/unit % w/w Levan (Zymomonas
spp.) 12.5 mg 50 Mannitol 12.5 mg 50 Purified water q.s to 250
.mu.l --
C2. Formulations
[0161] The following formulations were prepared using the method
described in "B" herein above, by freezing the blisters at a rate
of 20-160.degree. C./minute in .ltoreq.4 minutes in step 6.
Example-14
TABLE-US-00015 [0162] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 100 Purified water q.s to 250 .mu.l --
Example-15
TABLE-US-00016 [0163] Component Amount/unit % w/w Levan (Zymomonas
spp.) 25 mg 99.99 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH 4.5
Purified water q.s to 250 .mu.l --
Example-16
TABLE-US-00017 [0164] Component Amount/unit % w/w Levan (Zymomonas
spp.) 16.25 mg 64.99 Mannitol 8.75 mg 34.99 Citric acid (5% w/v)
q.s to pH 4.0 q.s to pH 4.0 Purified water q.s to 250 .mu.l --
Example-17
TABLE-US-00018 [0165] Component Amount/unit % w/w Levan (Zymomonas
spp.) 16.25 mg 64.99 Mannitol 8.75 mg 34.99 Citric acid (5% w/v)
q.s to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-18
TABLE-US-00019 [0166] Component Amount/unit % w/w Levan (Zymomonas
spp.) 16.25 mg 64.99 Mannitol 8.75 mg 34.99 Citric acid (5% w/v)
q.s to pH 5.0 q.s to pH 5.0 Purified water q.s to 250 .mu.l --
Example-19
TABLE-US-00020 [0167] Component Amount/unit % w/w Levan (Zymomonas
spp.) 12.5 mg 49.99 Mannitol 12.5 mg 49.99 Citric acid (5% w/v) q.s
to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-20
TABLE-US-00021 [0168] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 74.99 Mannitol 6.25 mg 24.99 Citric acid (5% w/v)
q.s to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-21
TABLE-US-00022 [0169] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 75.0 Raffinose 6.25 mg 25.0 Purified water q.s to
250 .mu.l --
Example-22
TABLE-US-00023 [0170] Component Amount/unit % w/w Levan (Zymomonas
spp.) 18.75 mg 74.99 Trehalose 6.25 mg 24.99 Citric acid (5% w/v)
q.s. to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
D. Method for Preparing Dosage Forms Containing Desmopressin
[0171] 1) Dissolve Levan, and other excipients, if present, in
purified water under stirring at 200 to 500 rpm; [0172] 2) Dissolve
Desmopressin acetate in purified water and add to the solution
prepared in step 1. [0173] 3) Adjust the pH of the solution using
citric acid solution (5% w/v). [0174] 4) Make up the final volume
of the solution using purified water. [0175] 5) Mix the solution
under stirring at 200 to 500 rpm for further 5-15 min. [0176] 6)
Dose the solution into cavities of preformed blister sheets
(typically using dispensing pipette). [0177] 7) Freeze the filled
blisters at a temperature in the range of -20 to -110.degree. C.
[0178] 8) Freeze dry the blisters in a lyophilizer [0179] 9) Place
the blister sheet containing dried lyophilisates on the punched
carrier web of the blister packaging machine, to transport the
blister sheets through the sealing station of the packaging
machine. [0180] 10) Seal the blister with a lidding foil and punch
into final blisters.
E. Desmopressin Formulations
[0181] The following desmopressin lyophilisate formulations were
prepared using the method described in "D" above, by freezing the
blisters at the rate of 0.1-2.degree. C./minute or 20-160.degree.
C./minute in step 7.
Example-23
TABLE-US-00024 [0182] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 0.63 equivalent to Desmopressin Levan (Bacilus
spp.) 37.5 mg 99.36 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH
4.5 Purified water q.s to 250 .mu.l --
Example-24
TABLE-US-00025 [0183] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 1.3 equivalent to Desmopressin Levan (Zymomonas
spp.) 18.75 mg 98.7 Citric acid (5% w/v) q.s to pH 4.5 q.s to pH
4.5 Purified water q.s to 250 .mu.l --
Example-25
TABLE-US-00026 [0184] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 1.3 equivalent to Desmopressin Levan (Zymomonas
spp.) 18.75 mg 98.7 Citric acid (5% w/v) q.s to pH 5.0 q.s to pH
5.0 Purified water q.s to 250 .mu.l --
Example-26
TABLE-US-00027 [0185] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 0.95 equivalent to Desmopressin Levan (Zymomonas
spp.) 16.25 mg 64.4 Mannitol 8.75 mg 34.7 Citric acid (5% w/v) q.s
to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-27
TABLE-US-00028 [0186] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 1.26 equivalent to Desmopressin Levan (Zymomonas
spp.) 18.75 mg 98.73 Sodium Citrate buffer (2.5 mM) q.s to pH 4.5
q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-28
TABLE-US-00029 [0187] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 1.26 equivalent to Desmopressin Levan (Zymomonas
spp.) 18.75 mg 98.73 Sodium Citrate buffer (5.0 mM) q.s to pH 4.5
q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-29
TABLE-US-00030 [0188] Component Amount/unit % w/w Desmopressin
acetate 240 .mu.g 0.79 equivalent to Desmopressin Levan (Zymomonas
spp.) 19.5 mg 64.48 Mannitol 10.5 mg 34.72 Sodium Citrate buffer
(5.0 mM) q.s to pH 4.5 q.s to pH 4.5 Purified water q.s to 250
.mu.l --
Example-30
TABLE-US-00031 [0189] Component Amount/unit % w/w Desmopressin
acetate 60 .mu.g 0.19 equivalent to Desmopressin Levan (Zymomonas
spp.) 19.5 mg 64.87 Mannitol 10.5 mg 34.93 Citric acid (5% w/v) q.s
to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-31
TABLE-US-00032 [0190] Component Amount/unit % w/w Desmopressin
acetate 25 .mu.g 0.08 equivalent to Desmopressin Levan (Zymomonas
spp.) 19.5 mg 64.94 Mannitol 10.5 mg 34.97 Citric acid (5% w/v) q.s
to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
Example-32
TABLE-US-00033 [0191] Component Amount/unit % w/w Desmopressin
acetate 10 .mu.g 0.03 equivalent to Desmopressin Levan (Zymomonas
spp.) 19.5 mg 64.97 Mannitol 10.5 mg 34.99 Citric acid (5% w/v) q.s
to pH 4.5 q.s to pH 4.5 Purified water q.s to 250 .mu.l --
F. Method for Preparing Dosage Forms Containing Loratadine
[0192] 1) Disperse guar gum in purified water under stirring.
[0193] 2) Prepare solution of levan and other excipients in water
under stirring, and add this solution in the guargum solution
obtained in step 1 under stirring at 200-500 rpm. [0194] 3) Add
loratadine to the solution obtained in step 2 under continuous
stirring at 200-500 rpm. [0195] 4) Homogenize the Loratadine
suspension for 10-20 minutes to form a uniform suspension. [0196]
5) Adjust the pH of the suspension using citric acid solution (5%
w/v). [0197] 6) Make up the final volume of the suspension using
purified water. [0198] 7) Mix the suspension under stirring at 200
to 500 rpm for further 5-15 min. [0199] 8) Dose prepared suspension
into each cavity of preformed blister sheets with intermediate
stirring of the suspension to maintain uniformity. [0200] 9) Freeze
the filled blisters at a temperature in the range of -20 to
-110.degree. C. [0201] 10) Freeze dry the blisters in a lyophilizer
[0202] 11) Place the blister sheet containing dried lyophilisates
on the punched carrier web of the blister packaging machine, to
transport the blister sheets through the sealing station of the
packaging machine. [0203] 12) Seal the blister with a lidding foil
and punch into final blisters.
G. Loratadine Formulations
[0204] The following Loratidine lyophilisate formulation were
prepared using the method described in "F" above, by freezing the
blisters at the rate of 0.1-2.degree. C./minute or 20-160.degree.
C./minute in step 9.
Example-33
TABLE-US-00034 [0205] Component Amount/unit % w/w Loratadine 10 mg
28.5 Levan (Zymomonas spp.) 25 mg 70.5 Guargum 0.437 mg 0.01 Citric
acid (5% w/v) q.s to pH 4.3 q.s to pH 4.3 Purified water q.s to350
.mu.l --
Example-34
TABLE-US-00035 [0206] Component Amount/unit % w/w Loratadine 10 mg
35.8 Levan (Zymomonas spp.) 17.5 mg 62.6 Guargum 0.437 mg 0.01
Citric acid (5% w/v) q.s to pH 4.8 q.s to pH 4.8 Purified water q.s
350 .mu.l --
Example-35
TABLE-US-00036 [0207] Component Amount/unit % w/w Loratadine 10 mg
35.7 Levan (Zymomonas spp.) 17.5 mg 62.4 Guargum 0.437 mg 0.01 SLS
0.087 mg 0.003 Citric acid (5% w/v) q.s to pH 4.8 q.s to pH 4.8
Purified water q.s 350 .mu.l --
H. Method for Preparing Dosage Forms Containing Famotidine
[0208] 1) Disperse xanthan gum or guar gum in purified water under
stirring. [0209] 2) Dissolve levan in the solution obtained in step
1 under stirring at 200-500 rpm. [0210] 3) Add Famotidine to the
solution of step 2 under continuous stirring at 200-500 rpm till
proper suspension is formed. [0211] 4) Homogenize the Famotidine
suspension obtained in step 3 for 10 min to form uniform
suspension. [0212] 5) Adjust the pH of the suspension using 0.1N
NaOH. [0213] 6) Make up the final volume of the suspension using
purified water. [0214] 7) Mix the suspension under stirring at 200
to 500 rpm for further 5-15 min, [0215] 8) Dose prepared suspension
into each cavity of preformed blister sheets with intermediate
stirring of the suspension to maintain uniformity. [0216] 9) Freeze
the filled blisters at a temperature in the range of -20 to
-110.degree. C. [0217] 10) Freeze dry the blisters in a lyophilizer
[0218] 11) Place the blister sheet containing dried lyophilisates
on the punched carrier web of the blister packaging machine, to
transport the blister sheets through the sealing station of the
packaging machine. [0219] 12) Seal the blister with a lidding foil
and punch into final blisters,
I. Famotidine Formulations
[0220] The following Famotidine orodispersible dosage forms were
prepared using the method described above in "H", by freezing the
blisters at the rate of 0.1-2.degree. C./minute or 20-160.degree.
C./minute in step 9.
Example-36
TABLE-US-00037 [0221] Component Amount/unit % w/w Famotidine 20 mg
65.5 Levan (Zymomonas spp.) 10.5 mg 34.4 Xanthangum 0.023 mg 0.07
0.1N NaOH q.s to pH 18.0 q.s to pH 8.0 Purified water q.s 250 .mu.l
--
Example-37
TABLE-US-00038 [0222] Component Amount/unit % w/w Famotidine 20 mg
60.8 Levan (Zymomonas spp.) 12.5 mg 38.0 Xanthangum 0.37 mg 1.1
0.1N NaOH q.s to pH 8.0 q.s to pH 8.0 Purified water q.s 250 .mu.l
--
Example-38
TABLE-US-00039 [0223] Component Amount/unit % w/w Famolidine 20 mg
65.10 Levan (Zymomonas spp.) 10.5 mg 34.18 Xanthangum 0.219 mg 0.71
0.1N NaOH q.s to pH 8.0 q.s to pH 8.0 Purified water q.s 250 .mu.l
--
Example-39
TABLE-US-00040 [0224] Component Amount/unit % w/w Famotidine 40 mg
88.03 Levan (Zymomonas spp.) 5 mg 11.00 Guar gum 0.437 mg 0.96 0.1N
NaOH q.s to pH 18.0 q.s. to pH 8.0 Purified water q.s 250 .mu.l
--
J. Method for Preparing Dosage Forms Containing Montelukast
Sodium
[0225] 1) Dissolve Montelukast in purified water under stirring.
[0226] 2) Dissolve Levan, and other excipients if present, in the
Montelukast solution of step 1 under stirring at 200-500 rpm.
[0227] 3) Make up the final volume of the solution using purified
water. [0228] 4) Mix the solution under stirring at 200 to 500 rpm
for further 15 min. [0229] 5) Dose the solution into each cavity of
preformed blister. [0230] 6) Freeze the filled blisters at a
temperature in the range of -60 to -80.degree. C. [0231] 7) Freeze
dry the blisters in a lyophilizer [0232] 8) Place the blister sheet
containing dried lyophilisates on the punched carrier web of the
blister packaging machine, to transport the blister sheets through
the sealing station of the packaging machine. [0233] 9) Seal the
blister with a lidding foil and punch into final blisters.
K. Montelukast Sodium Formulations
[0234] The following Montelukast orodispersible dosage forms were
prepared using the method described in "J" above, by freezing the
blisters at the rate of 0.1-2.degree. C./minute or 20-160.degree.
C./minute in step 6.
Example-40
TABLE-US-00041 [0235] Component Amount/unit % w/w Montelukast
Sodium 10 mg 28.57 equivalent to Montelukast Levan 25 mg 71.42
Purified water q.s to 250 .mu.l --
Example-41
TABLE-US-00042 [0236] Component Amount/unit % w/w Montelukast
Sodium 10 mg 28.57 equivalent to Montelukast Levan 18.75 mg 53.57
Mannitol 6.25 mg 17.85 Purified water q.s to 250 .mu.l --
Example-42
TABLE-US-00043 [0237] Component Amount/unit % w/w Montelukast
Sodium 10 mg 27.93 equivalent to Montelukast Levan 18.75 mg 52.37
Mannitol 6.25 mg 17.45 Neotame 0.3 mg 0.83 Cherry flavour 0.5 mg
1.39 Purified water q.s to 2.50 .mu.l --
Example-43
TABLE-US-00044 [0238] Component Amount/unit % w/w Montelukast
Sodium 10 mg 27.93 equivalent to Montelukast Levan 18.75 mg 52.37
Mannitol 13.5 mg 17.45 Hydroxy Propyl .beta.- 11.3 mg cyclodextrin
Neotame 0.3 mg 0.83 Cherry flavour 0.5 mg 1.39 Purified water q.s
to 250 .mu.l --
Example-44
TABLE-US-00045 [0239] Component Amount/unit % w/w Montelukast
Sodium 10 mg 17.84 equivalent to Montelukast Levan 18.75 mg 33.45
Mannitol 14.0 mg 24.97 Trehalose 12.5 mg 22.30 Neotame 0.3 mg 0.53
Cherry flavour 0.5 mg 0.89 Purified water q.s to 250 .mu.l --
Example-45
TABLE-US-00046 [0240] Component Amount/unit % w/w Montelukast
Sodium 4.0 mg 13.64 equivalent to Montelukast Levan 18.75 mg 63.94
Mannitol 6.25 mg 21.31 Neotame 0.12 mg 0.41 Cherry flavour 0.2 mg
0.68 Purified water q.s to 250 .mu.l --
Example-46
TABLE-US-00047 [0241] Component Amount/unit % w/w Montelukast
Sodium 4.0 mg 8.06 equivalent to Montelukast Levan 18.75 mg 37.82
Mannitol 14.0 mg 28.24 Trehalose 12.5 mg 25.21 Neotame 0.12 mg 0.24
Cherry flavour 0.2 mg 0.41 Purified water q.s to 250 .mu.l --
Example-47
TABLE-US-00048 [0242] Component Amount/unit % w/w Montelukast
Sodium 5.0 mg 9.89 equivalent to Montelukast Levan 18.75 mg 37.08
Mannitol 14.0 mg 27.68 Trehalose 12.5 mg 24.72 Neotame 0.12 mg 0.23
Cherry flavour 0.2 mg 0.39 Purified water q.s to 250 .mu.l --
L. Method for Preparing Dosage Forms Containing Ondansetron
[0243] 1) Dissolve levan, mannitol, methyl parabens, propyl
parabens, pH adjusting agent, sweeteners and/or flavours in
purified water under stirring. [0244] 2) Disperse Ondansetron under
stirring at 200-500 rpm in the solution obtained in step 1. [0245]
3) Make up the final volume of the solution using purified water.
[0246] 4) Mix the solution under stirring at 200 to 500 rpm for
further 15 minutes. [0247] 5) Dose the solution into each cavity of
preformed blister. [0248] 6) Freeze the filled blisters at a
temperature in the range of -60 to -80.degree. C. [0249] 7) Freeze
dry the blisters in a lyophilizer. [0250] 8) Place the blister
sheet containing dried lyophilisates on the punched carrier web of
the blister packaging machine, to transport the blister sheets
through the sealing station of the packaging machine. [0251] 9)
Seal the blister with a lidding foil and punch into final
blisters.
M. Ondansetron Formulations
[0252] The following Ondansetron orodispersible dosage forms were
prepared using the method described in "L" above, by freezing the
blisters at the rate of 0.1-2.degree. C./minute or 20-160.degree.
C./minute in step 6.
Example-48
TABLE-US-00049 [0253] Component Amount/unit % w/w Ondansetron 8.0
mg 20.64 Levan 24.0 mg 61.94 Mannitol 6.25 mg 16.12 Methyl paraben
0.133 mg 0.34 Propyl paraben 0.016 mg 0.04 Neotame 0.1 mg 0.26
Strawberry flavour 0.25 mg 0.64 Purified water q.s to 250 .mu.l
--
Example-49
TABLE-US-00050 [0254] Component Amount/unit % w/w Ondansetron 8.0
mg 20.72 Levan 24.0 mg 62.18 Mannitol 6.25 mg 16.19 Neotame 0.1 mg
0.26 Strawberry flavour 0.25 mg 0.65 0.1N NaOH q.s to pH 8.0 q.s to
pH 8.0 Purified water q.s to 250 .mu.l --
N. Comparative Examples
Example-50
[0255] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but using pullulan in place
of levan and freezing the blisters at the rate of 20-260.degree.
C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00051 Component Amount/unit % w/w Pullulan 25 mg 100
Purified water q.s 250 .mu.l --
Example-51
[0256] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking HPMC in place of
levan and freezing the blisters at the rate of 0.1-2.degree.
C./minute in step 6.
TABLE-US-00052 Component Amount/unit % w/w HPMC 25 mg 100 Purified
water q.s 250 .mu.l --
Example-52
[0257] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking HPMC in place of
levan and freezing the blisters at the rate of 20-160.degree.
C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00053 Component Amount/unit % w/w HPMC 25 mg 100 Purified
water q.s 250 .mu.l --
Example-53
[0258] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking methyl cellulose
in place of levan and freezing the blisters at the rate of
0.1-2.degree. C./minute in step 6.
TABLE-US-00054 Component Amount/unit % w/w Methyl cellulose 25 mg
100 Purified water q.s 250 .mu.l --
Example-54
[0259] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking methyl cellulose
in place of levan and freezing the blisters at the rate of
20-160.degree. C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00055 Component Amount/unit % w/w Methyl cellulose 25 mg
100 Purified water q.s 250 .mu.l --
Example-55
[0260] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking gum tragacanth in
place of levan and freezing the blisters at the rate of
0.1-2.degree. C./minute in step 6.
TABLE-US-00056 Component Amount/unit % w/w Gum tragacanth 25 mg 100
Purified water q.s 250 .mu.l --
Example-56
[0261] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking gum tragacanth in
place of levan and freezing the blisters at the rate of
20-160.degree. C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00057 Component Amount/unit % w/w Gum tragacanth 25 mg 100
Purified water q.s 250 .mu.l --
Example-57
[0262] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking Fish gelatin in
place of levan and freezing the blisters at the rate of
0.1-2.degree. C./minute in step 6.
TABLE-US-00058 Component Amount/unit % w/w Fish gelatin 25 mg 100
Purified water q.s 250 .mu.l --
[0263] The lyophilisates obtained were very fragile and were broken
into smaller pieces. No further analysis could be carried out.
Example-58
[0264] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking Fish gelatin in
place of levan and freezing the blisters at the rate of
20-160.degree. C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00059 Component Amount/unit % w/w Fish gelatin 25 mg 100
Purified water q.s 250 .mu.l --
Example-59
[0265] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking Fish gelatin in
place of levan and freezing the blisters at the rate of
0.1-2.degree. C./minute in step 6.
TABLE-US-00060 Component Amount/unit % w/w Fish gelatin 12.5 mg 50
Mannitol 12.5 mg 50 Purified water q.s 250 .mu.l --
Example-60
[0266] Comparative lyophilisates were prepared according to the
method described in "B" herein above, but taking fish gelatin in
place of levan and freezing the blisters at the rate of
20-160.degree. C./minute in .ltoreq.4 minutes in step 6.
TABLE-US-00061 Component Amount/unit % w/w Fish gelatin 12.5 mg 50
Mannitol 12.5 mg 50 Purified water q.s 250 .mu.l --
O. Disintegration Tests
[0267] Oa. Disintegration Test in Petri Dish
[0268] This test measures the expected disintegration time of a
composition of the invention in an aqueous medium which is an
indication of its disintegration time in saliva.
[0269] The disintegration rate of all the lyophilisates on a wet
filter paper was determined according to the method described in
PCT application WO2009002084, page 12 paragraph 129, wherein the
test was performed at a temperature of about 25.+-.2.degree. C.
Ob. Measurement of Oral Dissolving Time (ODT) of Placebos
[0270] The dissolving time of the placebo lyophilisates in the oral
cavity was determined according to the method described in PCT
application WO2009002084, page 12 paragraph 132, wherein the
lyophilisate was placed on the tongue of a healthy human adult and
then measuring the time for it to completely dissolve while rubbing
the lyophilisates between the tongue and the upper palate. The mean
ODT was calculated from the data obtained from 5 healthy human
adults.
P. Method for Testing Disintegration Time (In Vitro DT)
[0271] This test measures the disintegration time of the
compositions of the invention in aqueous medium which is an
indication of their disintegration time in saliva.
[0272] Equipment: Electrolab, Model: ED2 SAPO
[0273] Procedure: The method was followed as per USP 31-NF 26
(General Chapters, <701> Disintegration) and Ph Eur. 1997
(2.9.1. Disintegration of tablets and capsules). Water was filled
into the beaker and maintained at 37.degree. C..+-.0.5.degree. C.
using water bath. The lyophilisates were placed in sinker made up
of copper wire with diameter of about 0.5 mm (.+-.0.05 mm) and
length of about 15 mm. The lyophilisates were then placed into the
basket of basket rack assembly and instrument was set on. The
disintegration time was noted in seconds.
Q. Method Testing Tensile Strength for
[0274] Equipment: Engineering Systems (NOTTM) Ltd, Model: 5 kN
Testing Machine
[0275] Procedure: The method for determining tensile strength was
fed into the instrument.
[0276] The parameters test speed (15 mm/min), fracture mode, unit
(Newton, [N]), fracture percentage (80%), low limit (0.1), and
distance between the supporting edges (4.5 mm) were set into the
instrument. A load cell of 10 kg was used and the tensile strength
was calculated using the following formula:
N / mm 2 = 3 .times. Mean ( N ) .times. Distance between two
supporting axis in mm 2 .times. ( Thickness in mm ) 2 .times. (
Diameter in mm ) ##EQU00001##
[0277] Thickness and diameter were determined using vernier
calliper.
[0278] Tensile strength of commercially available Nimulid-MD, an
orodispersible tablet of Nimesulide prepared by conventional
compression technique was found to be 1.14 N/mm.sup.2.
R. Dissolution Method
[0279] This test measures the dissolution (%) of an active
ingredient from a composition of the invention in aqueous medium
which is an indication of the release rate of the active ingredient
from the composition.
[0280] Equipment: Varian, Model: VK7025
[0281] Procedure: The dissolution time of the lyophilisates
containing an active ingredient was measured as follows: The method
was followed as per USP 32-NF 27 (General Chapters, <711>
Dissolution). Dissolution media (0. N HCl, Phosphate buffer pH 6.8,
Acetate buffer pH 4.5, or 0.5% SLS in water) was selected on the
basis of the active ingredient in the composition. Dissolution
bowls were filled with appropriate media volume (500 mL or 900 mL)
on the basis of the active ingredient in the composition and the
temperature of the media was maintained at 37.degree.
C..+-.0.5.degree. C. using water bath. The apparatus used was USP
type II (Paddle) and set at the required rpm (50 rpm) as per the
test procedure. Samples were withdrawn as per the time point (5
min, 10 min, 15 min, and 30 min) defined in the test procedure.
Samples were analyzed chromatographically or by UV as per the test
procedure and % release was calculated.
[0282] The disintegration rates, ODT, in-vitro DT, tensile strength
and Dissolution data for the lyophilisates prepared according to
examples 1 to 37, and comparative examples 38 to 48 are presented
in table 1.
TABLE-US-00062 TABLE 1 Disintegration Oral Dissolution test in
petri dissolving In-vitro Tensile (5/15 Example dish time DT
strength minutes) No (sec) (sec) (sec) (N/mm.sup.2) (%) 1 7 5 5
1.07 NA 2 4 6 2 1.58 NA 3 5 6 4 1.41 NA 4 8 7 5 1.38 NA 5 3 5 4
0.61 NA 6 2 2 3 0.22 NA 7 4 5 3 0.64 NA 8 5 5 3 0.73 NA 9 2 3 4
0.22 NA 10 2 4 4 0.21 NA 11 2 4 5 0.18 NA 12 3 4 3 0.44 NA 13 5 4 2
0.23 NA 14 2 4 3 0.32 NA 15 4 6 2 0.27 NA 16 2 4 4 0.09 NA 17 3 3 3
0.07 NA 18 4 3 3 0.09 NA 19 5 4 3 0.07 NA 20 2 4 4 0.16 NA 21 2 2 2
0.16 NA 22 2 3 4 0.10 NA 23 2 NA 3 0.32 98/99 24 6 NA 4 0.78 85/96
25 6 NA 3 0.64 99/99 26 4 NA 3 0.10 76/92 27 4 NA 3 0.84 87/95 28 4
NA 3 0.53 102/102 29 3 NA 3 0.09 102/92 30 3 NA 2 0.15 99/101 31 3
NA 2 0.13 93/95 32 3 NA 2 0.17 103/103 33 6 NA 7 0.68 102/103 34 3
NA 6 0.37 100/101 35 2 NA 3 0.19 100/102 36 6 NA 8 0.34 69/89 37 5
NA 2 0.34 68/85 38 6 NA 2 0.38 61/92 39 5 NA 9 0.19 51/75 40 6 NA 9
0.28 97/100 41 5 NA 6 0.12 93/92 42 4 NA 4 0.08 97/97 43 4 NA 2
0.14 97/97 44 5 NA 2 0.16 97/97 45 3 NA 2 0.08 97/98 46 4 NA 2 0.12
99/98 47 3 NA 2 0.20 96/96 48 2 NA 2 0.09 101/12 49 2 NA 2 0.10
101/19 50 32 30 196 0.80 NA 51 150 39 124 0.97 NA 52 35 51 128 0.27
NA 53 >300 190 >30 minutes <0.05 NA 54 >300 192 >30
minutes <0.05 NA 55 25 22 40 <0.05 NA 56 36 30 20 <0.05 NA
58 2 5 <2 <0.05 NA 59 2 3 <2 0.15 NA 60 2 4 <2 0.06 NA
NA--Not Applicable for column 3 as the oral dissolving time was
measured for placebo lyophilisates only. NA--Not applicable for
column 6 as the dissolution time was measured for lyophilisatc
containing drug substances only.
S. Pharmacokinetic Test
[0283] A comparative test was carried out to evaluate the
pharmacokinetic profile of the composition of Example 26 (240 .mu.g
desmopressin acetate, levan and mannitol) (the test composition)
with a reference composition comprising 240 .mu.g desmopressin
acctatc, fish gelatin and mannitol (Minirin Melt.RTM.). The test
was carried out in parallel design by single sublingual
administration of the respective compositions to eight New Zealand
rabbits in each treatment group. Blood samples were taken at
specified time intervals from each treatment group and analyzed for
Desmopressin content.
[0284] The pharmacokinetic parameters were calculated for
individual rabbits using non-compartmental analysis. The rate and
extent of absorption of Desmopressin were similar in test and
reference compositions, and the test by reference ratio of
C.sub.max (peak or maximum concentration) and AUC.sub.last (Area
Under Curve computed up to last sampling time) were within 20% of
reference composition. Further, C.sub.max for the test composition
was higher in comparison to the reference composition.
* * * * *