IE83699B1 - Rapid onset formulation - Google Patents
Rapid onset formulationInfo
- Publication number
- IE83699B1 IE83699B1 IE2002/0488A IE20020488A IE83699B1 IE 83699 B1 IE83699 B1 IE 83699B1 IE 2002/0488 A IE2002/0488 A IE 2002/0488A IE 20020488 A IE20020488 A IE 20020488A IE 83699 B1 IE83699 B1 IE 83699B1
- Authority
- IE
- Ireland
- Prior art keywords
- rapid onset
- formulation
- minutes
- weight
- doxylamine succinate
- Prior art date
Links
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- 235000001727 glucose Nutrition 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 238000009499 grossing Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 201000010538 lactose intolerance Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 1
- 235000019645 odor Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002572 peristaltic Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 239000000770 propane-1,2-diol alginate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 230000008786 sensory perception of smell Effects 0.000 description 1
- 235000020374 simple syrup Nutrition 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- OKODKVMXHLUQSW-JITBQSAISA-M sodium;(E)-4-hydroxy-4-oxobut-2-enoate;octadecanoic acid Chemical compound [Na+].OC(=O)\C=C\C([O-])=O.CCCCCCCCCCCCCCCCCC(O)=O OKODKVMXHLUQSW-JITBQSAISA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229940114926 stearate Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000000152 swallowing Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000005019 zein Substances 0.000 description 1
Description
TITLE OF THE INVENTION
RAPID ONSET FORMULATION
BACKGROUND OF THE INVENTION
FIELD OF THE INVENTION
The present invention relates to a rapid onset formulation, preferably in
form of an enterically coated tablet, for a medicament comprising a
synergistic duo of active ingredients namely, doxylamine succinate and
pyridoxine HCI, hereinafter referred to as “DS-P”. DS-P is useful in the
treatment of nausea and vomiting, especially, but not limited to, during
pregnancy, hereinafter referred to as "NVP". Thus the present invention is
concerned with all known and future therapeutic indications of DS-P.
THE PRIOR ART
Pharmaceutical formulations of DS-P are known. The current formulation,
commercially available in Canada under the name Diclectin (Duchesnay
Inc.) comprises the following active ingredients: pyridoxine HCI and
Doxylamine succinate. lt additionally comprises the following excipients:
lactose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide
and magnesium stearate.
Diclectin is the world's most studied drug in regard to its safety during
pregnancy. Because of its excellent safety profile, Diclectin is the drug of
choice for the treatment of NVP. The current formulation is sugar coated
and suffers from drawbacks, one of which being its delayed onset of action.
However, the current formulation once ingested, can take more than 4
hours before the two active ingredients (pyridoxine HCI and doxylamine
succinate) reach nearly full dissolution in the small intestines, where it is
.699
absorbed. This delay is often considered too long for patients, such as
women suffering from NVP, who require urgent relief of symptoms.
Another drawback of the current formulation is related to patient
compliance. Women suffering from NVP often complain of hyper olfaction,
which means that various odors and tastes can trigger nausea or vomiting
problems. The smell and taste of sugar on the current sugar coated
formulation as well as the use of organic solvents and phthalates in the
preparation of the currently used enteric coating, bothers many pregnant
women to the point where the intake of the drug is essentially inhibited.
The size of the currently available tablet is also problematic. A smaller size
tablet would improve patient compliance since women suffering from NVP
often have problems swallowing. Furthermore, a smaller tablet looks less
harmful than a bigger one and patients will have the impression that they
are taking a lesser amount of drug. This will in turn significantly increase
patient compliance.
Finally, the current formulation contains lactose. This is objectionable for
those patients suffering from lactose intolerance.
Thus, it is desirable to provide patients suffering from nausea and vomiting
an improved rapid onset formulation overcoming the drawbacks of the prior
art.
However, since D8-P is orally delivered as an enteric coated tablet, the
novel oral formulation must transit through the stomach unscathed and
rapidly release both active ingredients once the dosage form reaches its
intended destination, namely the intestines.
The main challenge surmounted by the present invention was to arrive at a
dosage form capable of overcoming the drawbacks of the prior art while
simultaneously delivering the synergistic duo of active ingredients for rapid
onset. It was also important to provide a formulation exhibiting similar
dissolution curves for both active ingredients so as to avoid the dissolution
of one active ingredient to the detriment of the other. This was important in
view of the synergistic therapeutic effect of the duo of active ingredients.
SUMMARY OF THE INVENTION
In general terms, the invention provides a new aqueous enteric—coated
formulation comprising DS—P, the formulation exhibiting a dissolution profile
indicative of a rapid onset.
The invention also seeks to provide a pharmaceutical composition having
specific in-vitro dissolution profiles indicative of rapid onset of the active
ingredients. The pharmaceutical composition being suitable for simple and
reproducible manufacture,
Further scope of applicability will become apparent from the detailed
description given hereinafter. It should be understood however, that this
detailed description, while indicating preferred embodiments of the
invention, is given by way of illustration only, since various changes and
modifications within the spirit and scope of the invention will become
apparent to those skilled in the art.
DESCRIPTION OF THE DRAWINGS
Figure 1 depicts two examples of dissolution profiles in accordance to the
rapid onset formulation of the present invention in comparison to a
dissolution profile of the prior art formulation. The first dissolution profile
(example 1) corresponds to a rapid onset formulation from which nearly
100% of both active ingredients is released within 45 minutes. The second
dissolution profile (example 2) corresponds to a rapid onset formulation
from which approximately 95% of both active ingredients is released within
120 minutes. The last and comparative dissolution profile (prior art)
corresponds to from which
approximately 100% of the pyridoxine HCI and approximately 90% of the
doxylamine succinate is released within 240 minutes.
the currently available formulation
Figure 2 is a schematic flowchart of the preferred manufacturing process of
a preferred formulation in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Other objects and attendant features of the present invention will become
readily appreciated, as the same becomes better understood by reference
to the following detailed description of a preferred embodiment described
for the purpose of illustration.
In a broad sense, the invention provides a rapid onset formulation
comprising pyridoxine HCI and doxylamine succinate.
The formulation of the present invention may be used in the human and
veterinary fields of medicine whenever symptoms of nausea and/or
vomiting require medical intervention. Since the formulation of the present
invention is intended for medicinal purposes, then the formulation and its
components should be pharmaceutically acceptable. The preferred
formulation is in the form of an oral dosage form such as a tablet, pill or
encapsulated beads or solution. The most preferred formulation is a tablet.
The tablet of the present invention is preferably capable of transiting
through the stomach unscathed. To test this feature, the tablet of the
present invention was tested to resist disintegration in simulated gastric
fluid "SGF" for a minimum period of 1 hour.
In accordance with the present invention, the formulation will satisfy the
following dissolution profiles when measured in 1000 ml phosphate buffer
at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm; preferably
measured by high performance liquid chromatography:
(a) at least about 40% of the total amounts of each of pyridoxine HCl
and doxylamine succinate are dissolved after 30 minutes of
measurement;
(b) at least about 70% of the total amounts of each of pyridoxine HCl
and doxylamine succinate are dissolved after 60 minutes of
measurement;
(c) at least about 80% of the total amounts of each of pyridoxine HCl
and doxylamine succinate are dissolved after 90 minutes of
measurement;
(d) at least about 00% of the total amounts of each of pyridoxine HCl
and doxylamine succinate are dissolved after 120 minutes of
measurement;
in the present invention, any reference to dissolution profile should be
construed as referring to the results of a dissolution test in which the
amount of pyridoxine HCl and of doxylamine succinate released is
measured in 1000 ml phosphate buffer at pH 6.8 and 37°C using a USP
(United States Pharmacopoeia) type 2 dissolution apparatus at 100 rpm;
preferably measured by high performance liquid chromatography.
As used herein and in the claims, an "enteric coating" is understood to
mean a coating comprising one or more layers generally resistant to
disintegration in human gastric fluids, but which will disintegrate in human
intestinal fluids, as well as coatings which disintegrate very slowly in
human gastric fluids, but more rapidly in human intestinal fluids. In a broad
sense, "enteric coating" can encompass for example any seal coat placed
on the compressed core of a tablet prior to the enteric coating per se as
well as any finishing aesthetic coat placed on the enteric coating per se.
In a most preferred embodiment, the formulation of the present invention
contains a core ‘coated with an aqueous enteric coating. The core
comprises the active ingredients pyridoxine HCl and doxylamine succinate
along with non-active excipients such as a filler or binder, a disintegrating
agent, a lubricant, a silica flow conditioner and a stabilizing agent.
Examples of fillers or binders include acacia, alginic acid, calcium
(dibasic),
hydroxyethylcellulose,
dextrin,
pregelatinized starch, calcium sulfate, amylose, glycine, bentonite,
phosphate carboxymethylcellulose, carboxymethylcellulose
sodium, hydroxypropylcellulose,
hydroxypropylmethylcellulose, dextrates, sucrose, tylose,
maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium
phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar
gum, liquid glucose, compressible sugar, magnesium aluminum silicate,
maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium
alginate, tragacanth microcrystalline cellulose, starch, and zein. A most
preferred filler or binder consists of microcrystalline cellulose.
Examples of disintegrating agents include alginic acid,
carboxymethylcellulose, carboxymethylcellulose sod ium,
hydroxypropylcellulose (low substituted),
powdered cellulose, colloidal silicon dioxide, sodium croscarmellose,
microcrystalline cellulose,
crospovidone, methylcellulose, polacrilin potassium, povidone, sodium
alginate, sodium starch glycolate, starch, disodium disulfite, disodium
edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA)
crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl
starch, sodium carboxymethyl starch, microcrystalline cellulose. A most
preferred disintegrating agent consists of sodium crosscarmelose.
Examples of lubricants include calcium stearate, canola oil, glyceryl
palmitostearate, hydrogenated vegetable oil (type I), magnesium oxide,
magnesium stearate, mineraloil, poloxamer, polyethylene glycol, sodium
lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc
stearate, glyceryl behapate, magnesium lauryl sulfate, boric acid, sodium
benzoate, sodium acetate,
sodium benzoate/sodium acetate (in
combination), DL leucine. A most preferred lubricant consists of
magnesium stearate,
Examples of silica flow conditioners include colloidal silicon dioxide,
magnesium aluminum silicate and guar gum. A most preferred silica flow
conditioner consists of silicon dioxide.
Examples of stabilizing agents include acacia, albumin, polyvinyl alcohol,
alginic acid, bentonite, dicalcium phosphate, carboxymethylcellulose,
hydroxypropylcellulose, colloidal silicon dioxide,.cyclodextrins, glyceryl
monostearate, hydroxypropyl methylcellulose, magnesium trisilicate,
magnesium aluminum silicate, propylene glycol, propylene glycol alginate,
sodium alginate, carnauba wax, xanthan gum, starch, stearate(s), stearic
acid, stearic monoglyceride and stearyl alcohol. A most preferred
stabilizing agent consists of magnesium trisilicate.
In a preferred embodiment, the core of the new rapid onset Diclectin
formulation will contain approximately about 4 to 10%, most preferably
about 7% by weight of pyridoxine HCl; about 4 to10%, most preferably
about 7% by weight of doxylamine succinate; about 40 to 80%, most
preferably about 62% by weight of microcrystalline cellulose; about 10 to
%, most preferably about 18% by weight of magnesium trisilicate; about
0.5 to 5%, most preferably about 1% by weight of silicon dioxide; 0.5 to 5%
most preferably about 3% by weight of sodium croscarmellose and about
.5 to 5%, most preferably about 3% by weight of magnesium stearate.
Examgle 1
The following is an example of a 145 mg Diclectin rapid onset core
formulation:
Table 1: Core Ingredients:
Doxylamine Succinate
Pyridoxine HCI 10.0 6.9 6.897
Magnesium trisilicate 26.4 18.2 18.207
Microcrystalline 90.0 62.1 62.069
Cellulose PH 102
Sodium 3.6 2.5 2.483
Croscarmellose Type A
Magnesium Stearate 4.0 2.8 2.759
Silicon Dioxide NF 1.0 0.7 0.690
The core can then be enterically coated with an aqueous enteric coating
which will allow the formulation to transit through the stomach relatively
unscathed while allowing rapid dissolution in the intestines.
The coating formulation can be as follows:
Table 2: Coating Formulation
Opadry Clear YS7472 3.33
Purified Water USP
Total:
.33
Estacryl ' sop Enericl 0 58 27.29 27.29
Coating Solution*
Talc USP 200 Mesh 2.85 1.97 1.968
Polyethylene Glycol 400 USP 1.20 0.83 0.826
Antifoam 1520 0.12 0.08 0.081
Purified Water USP
Total: 30.17 30.17
.04
Opadry White YS—1—7003
.108‘
.61 ' H
Purified Water USP
Total: 1.61 1.11
*Estacryl 30D Enteric Coating Solution contains 30% of solids. Therefore,
the total actual enteric coating amounts to 11.07%.
Total coated tablet weight 167.47 mg.
The purpose of the seal coat is to provide a smooth surface for the enteric
coating, thereby avoiding mounds, pits or crevasses wherein uneven
amounts of enteric coating would be applied.
Dissolution Data
The rapid onset formulation of the previous example has exhibited in-vitro
dissolution profiles as shown in Table 3 below, when measured in 1000 ml
phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at
100 rpm. The numerical values are expressed as percentages of dissolved
active ingredient in relation to starting quantities.
Table 3: Dissolution profiles
minutes 20 2 0 77 79 79 43
minutes 91 90 90 91 94 95 92
minutes 96 96 94 94 95 96 95
minutes 95 98 96 95 98 96 96
45 minutes 97 96 97 94 99 98 97
It
minutes 90 87 89 89 97 96 91
minutes 98 97 96 92 98 97 96
minutes 97 98 96 94 99 97 97
45 minutes 98 96 98 92 100 99 97
The extremely low dissolution values obtained after 5 minutes for runs 1 to
3, can be explained by the non-disintegration of the core formulation at the
minute interval.
Example of method of manufacture
The formulation of the present invention was prepared using the
ingredients shown in Table 1, above. Doxylamine succinate and silicon
dioxide NF are pre—blended in a 2 cu. Ft. V-Blender. The resulting pre-
blend is then milled through a Quadro Co Mill, Model 1968, equipped with
a 40 mesh screen.
Pyridoxine HCI is also milled through a Quadro Co Mill, Model 1968,
equipped with a 40 mesh screen. The milled pyridoxine HCI is then
combined with the doxylamine / silicon dioxide NF pre—blend and the
combined mixture blended.
Microcrystalline Cellulose is milled through a 40 mesh screen and split into
two approximately equal portions. One portion is subsequently combined
in a 65OL Gallay Bin with the previously formed pre—blend containing both
the active ingredients, followed by the addition of the second portion. The
loaded material is then blended followed by the addition of magnesium
trisilicate and sodium croscarmellose. The newly formed mixture is
blended. The addition of magnesium stearate followed by an additional
blending completes the preparation of the core formulation.
The final blend is‘ compressed in tablet form and is subsequently seal
coated, enteric coated using a suitable commercially available aqueous
enteric coating and top coated for aesthetics. The overall manufacturing
process is depicted in Figure 2.
All coating steps using the ingredients of Table 2, namely, the seal coat on
the core, the enteric coating and the opadry white (color coat) are
advantageously performed in a Vector Hi (trade-mark) coater pan equipped
with a peristaltic pump.
Example 2
The following is another example of a 146 mg Diclectin rapid onset core
formulation. The formulation was manufactured along the same
manufacturing methods as described above in example 1. This example
demonstrates that the rapid onset feature of the formulation of the present
invention was obtained with a different group of excipients.
Table 4: Core ingredients:
oxylamine Succate I A I if M if H 7.‘
Pyridoxine HCl 10.5 7.2
Magnesium trisilicate 30.0 20.6
Microcrystalline 65.0 44.5
Cellulose PH 102
Calcium Phosphate (Dibasic) 25.0 17.1
Magnesium Stearate 4.0 2.7
Colloidal Silicon Dioxide 1.0 0.7
The coating formulation can be as follows:
Table 5: Coating Formulation
Opadry s——7o 4.3
Antifoam AF Emulsion 0.07
Sureteric YAE18107 16.06
Purified Water USP
opadry'“ Clear vs7472 0.73
Total coated tablet weight 167.24 mg.
The rapid onset formulation of the previous example has exhibited in-vitro
dissolution profiles as shown in Table 6 below, when measured in 1000 ml
phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at
rpm. The numerical values are expressed as percentages of dissolved
active ingredient.
Table 6: Dissolution profiles:
minutes
minutes 31 28 60 63 36 43 43
45 minutes 51 45 78 80 55 60 61
60 minutes 69 64 88 89 67 72 75
75 minutes 79 76 94 94 77 81 83
90 minutes 84 84 97 97 83 87 89
minutes 88 89 98 99 87 90 92
minutes 91 93 98 98 89 92 93
minutes 16 14 22 31 47 61 32
minutes 31 27 64 637 38 40 44
45 minutes 47 44 75 79 58 61 61
60 minutes 71 61 90 85 68 74 75
75 minutes 76 71 96 89 81 82 82
90 minutes 85 80 101 88 83 81 86
105 minutes 92 86 103 95 93 92 93
120 minutes 93 88 101 96 96 95 95
It follows from these results that the novel formulation demonstrates a rapid
onset as shown by its dissolution profile. Pyridoxine HCI presents an
average dissolution profile of over 90% within 120 minutes of starting the
measurements. Similarly, Doxylamine succinate displays an average
dissolution profile of over 90% within 120 minutes of starting the
measurements.
Example 3 (Comparative example using prior art formulation)
The following is an example of the prior art Diclectin formulation. An
example for a 146.2 mg tablet is provided. This example demonstrates a
strikingly slower onset of dissolution in comparison to the present
invention.
Table 7: Core Ingredients:
Pyridoxine HCI 11.0 7.5 A
Doxylamine Succinate 10.2 7.0
Lactose NF 25.0 17.1
Microcrystalline 65.0 44.4
Cellulose NF
Magnesium Trisilicate 30.0 20.6
Silicon Dioxide 1.0 0.7
Magnesium Stearate 4.0 2.7
Total: 146.2 1
The coating formulation is as follows:
Table 8: Coating Formulation
Coating Solution No. 714
Coating Powder No. 303
C.A.P. solution 10%
C.A.P. solution 5%
Gelatin Solution No. 105
Dusting Powder No. 755
White Smoothing Syrup
Sugar Syrup No. 111
Opalux AS-7000«B white
Wax Solution No. 723
The current formulation of the previous example has exhibited in—vitro
dissolution profiles as shown in Table 9 below, when measured in 1000 ml
phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at
rpm. The numerical values are expressed as percentages of dissolved
active ingredient.
Table 9: Dissolution profiles:
inutes H 7 9 11 it 11 16 7 13
minutes 22 23 32 25 28 23 25
45 minutes 37 34 45 39 42 34 38
60 minutes 50 44 56 49 51 44 49
90 minutes 69 63 73 69 67 63 67
120 minutes 83 76 84 82 80 76 80
150 minutes 94 86 91 91 86 86 89
180 minutes 99 94 98 96 93 92 95
minutes 93 93 100 100 99 101 98
minutes 12 15 17 8 18 16 14
minutes 17 21 31 18 27 30 24
45 minutes 24 32 45 25 38 38 34
60 minutes 34 41 56 36 46 49 44
90 minutes 52 55 69 55 62 66 60
minutes 69 65 75 68 71 75 71
150 minutes 80 74 80 78 79 82 79
180 minutes 82 78 86 82 80 84 82
240 minutes 95 89 89 82 .80 87 87
It follows from these results that the prior art formulation, exhibits a
noticeably slower dissolution pattern when compared with the novel
formulations. Indeed, after 90 minutes averages of only 60% doxylamine
and 67% pyridoxine HCI are dissolved. A slower in—vivo dissolution profile
is indicative of a delayed onset of action. The novel formulations, as
depicted by examples 1 and 2, show markedly faster onset dissolution
_1g_
profiles resulting in a rapid onset of action. The new formulations overcome
most, if not all of the drawbacks associated with the prior art.
The terms and descriptions used herein are preferred embodiments set
forth by way of illustration only, and are not intended as limitations on the
many variations which those of skill in the art will recognize to be possible
in practicing the present invention. It is the intention that all variants
whether presently known or unknown, that do not have a direct effect upon
the way the invention works, are to be covered by the following claims.
Claims (1)
- CLAIMS 1. An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating agent such that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: at least about 40% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 30 minutes of measurement; at least about 70% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 60 minutes of measurement; at least about 80% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 90 minutes of measurement; at least about 90% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 120 minutes of measurement. An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation as in claim 1, wherein the following dissolution characteristics are also satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: (a) at least about 20% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 15 minutes of measurement; (b) at least about 60% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 45 minutes of measurement; (c) at least about 80% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 75 minutes of measurement. 3. The rapid onset formulation of claims 1 or 2, wherein at least about 40% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved within 5 minutes when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. V 4. The rapid onset formulation of claims 1 or 2, wherein said formulation contains a core coated with at least one enteric coating, said core comprising pyridoxine HCI, doxylamine succinate and the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent. 5. The rapid onset formulation of claim 4, wherein said filler or binder consists of microcrystalline cellulose. 8. The rapid onset formulation of claim 4, wherein said disintegrating agent consists of sodium crosscarmellose. 7. The rapid onset formulation of claim 4, wherein said lubricant consists of magnesium stearate. 8. The rapid onset formulation of claim 4, wherein said silica flow conditioner consists of silicon dioxide. The rapid onset formulation of claim 4. wherein said stabilizing agent consists of magnesium trisilicate. 10. said core comprises: 11. core comprises: The rapid onset formulation of claims 1 or 2, wherein about 4—10% by weight of pyridoxine HCI; about 4-10% by weight of doxylamine succinate; about 40-80% by weight of microcrystalline cellulose; about 10-30% by weight of magnesium trisilicate; about 0.5-5% by weight of silicon dioxide; about 0.5-5% by weight of sodium croscarmellose; and about 0.5—5% by weight of magnesium stearate. The rapid onset formulation of claim 10, wherein said about 7% by weight of pyridoxine HCI; about 7% by weight of doxylamine succinate; about 62% by weight of microcrystalline cellulose; about 18% by weight of magnesium trisilicate; about 0.7% by weight of silicon dioxide; about 2.5% by weight of sodium croscarmellose; and about 2.8% by weight ofmagnesium stearate. The rapid onset formulation of claim 4, wherein said at least one enteric coating is aqueous based. 13. The rapid onset formulation of claim 12, wherein said enteric coating consists of a seal coat applied to the core, an enteric coating per se applied on the seal coat and an aesthetic top coat applied on the enteric coating per se. 14. Use of the rapid onset formation of claims 1 or 2 in the manufacture of a medicament for use in alleviating the symptoms of nausea and vomiting in a mammal. 15. Use of the rapid onset formulation of claims 1 or 2 in the manufacture of a medicament for use in alleviating the symptoms of nausea and vomiting during human pregnancy. 16. A medicament for attenuating the symptoms associated with nausea and vomiting consisting essentially of the formulation of claim 4. 17. A process for preparing the rapid onset formulation of claim 4, said process comprising the steps of: o blending said doxylamine succinale and said silica flow conditioner to obtain a pre-blend; o mixing said preblend with said pyridoxine HCI to obtain an active ingredient blend; o mixing said active ingredient blend with said remaining non-active excipients, namely: a filler or binder, a disintegrating agent, a lubricant, and a stabilizing agent to obtain a final blend; and o tabletting and coating said final blend. 18. A process in accordance with claim 17 wherein said final tabletting and coating step comprises compression of said final into a tablet shape, seal coating of said tablet shape, followed by enteric coating, followed by colour coating. ANNE RYAN & CO.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CACANADA21/06/20012,350,195 | |||
CA002350195A CA2350195C (en) | 2000-12-20 | 2000-12-20 | Rapid onset formulation of pyridoxine hydrochloride and doxylamine succinate |
US09/885,051 US6340695B1 (en) | 2000-12-20 | 2001-06-21 | Rapid onset formulation |
PCT/CA2001/000951 WO2003000263A1 (en) | 2000-12-20 | 2001-06-21 | Rapid onset formulation |
Publications (2)
Publication Number | Publication Date |
---|---|
IE20020488A1 IE20020488A1 (en) | 2003-04-30 |
IE83699B1 true IE83699B1 (en) | 2004-12-01 |
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