: LIPOIDAL DOSAGE FORMS OF ANIMALARIAL EXHIBITING FASTER RELEASE

Abstract

The present invention specifies linaclotide formulations like granules, powder, effervescent powder, powder for oral suspension/solution, liquid emulsion and liquid suspension which are presumed to be better formulations of Chloroquine which have advantage of overcoming absorption issues via GUT, especially in pediatric and geriatric formulations. These formulations with pharmaceutical acceptable excipients in each, contributing in improving patient efficacy and acceptability.

Specification

Description:FIELD OF INVENTION
[0001] The present disclosure relates to an orally ingested dosage form of Artemisinin,
Amodiaquine, Halofantrine and Chloroquine and/or a pharmaceutically acceptable salt thereof,
and a preparation method therefore and a use, thereof. The present invention relates to
pharmaceutical compositions comprising Artemisinin, Amodiaquine, Halofantrine and
Chloroquine or pharmaceutically acceptable salts thereof, as well as to various formulation
prototypes for the preparation and use of the compositions.
BACKGROUND OF THE INVENTION
[0002] Various formulation prototypes have been used to develop compositions for
pharmaceutically active agents. However, the specific components of these compositions vary
greatly and depend significantly on the pharmaceutically active agent and the desired properties
and dosage concentrations. For example, the formulation must be compatible with the
pharmaceutically active agent and provide formulations which are having superiors invitro drug
release.
[0003] Artemisinin, Amodiaquine, Halofantrine and Chloroquine are orally administered and has
been approved in the U.S. by the FDA for the treatment of malaria. In humans, Artemisinin,
Amodiaquine, Halofantrine and Chloroquine has been shown reduced absorption because of
limited solubility/drug release.
[0004] As approved by the FDA, Artemisinin, Amodiaquine, Halofantrine and Chloroquine are
administered in an oral, solid, capsule formulation. With respect to Artemisinin, Amodiaquine,
Halofantrine and Chloroquine, there is a need for developing a lipoidal formulation in-order to
overcome poor solubility challenge.
SUMMARY AND OBJECTIVES OF THE INVENTION
[0005] This present invention should not be construed as limited to the embodiments set forth
herein; rather, these embodiments are provided by way of illustration only and so that this
disclosure will be thorough, complete and will fully convey the full scope of the invention to
those skilled in the art. However, this invention focuses primarily to develop a formulation which
is presumed to be faster in drug release compared to powder in capsule dosage form.
Artemisinin, Amodiaquine, Halofantrine and Chloroquine oral suspension/solution, liquid
emulsion are presumed to be better when it is formulated in form of lipoidal nature and choice of
suitable lipid excipients.
DETAILED DESCRIPTION OF THE INVENTION
[0006] The following is a detailed description of embodiments of the present disclosure. The
embodiments are in such detail as to clearly communicate the disclosure. However, the amount
of detail offered is not intended to limit the anticipated variations of embodiments; on the
contrary, the intention is to cover all modifications, equivalents, and alternatives falling within
the spirit and scope of the present disclosure.
[0007] A method of preparing different lipoidal formulations of Artemisinin, Amodiaquine,
Halofantrine and Chloroquine and its related salts(if any), wherein the drug is mixed with
different acceptable pharmaceutical excipients especially in different categories but also, not
limited to like surfactants, cosurfactants, solvents, water, swellable polymers, lipids, bulking
agents, to formulate into liquid oral emulsion types.
EXAMPLES
Table 13 observations depict those formulations that comprise surfactants:co-surfactants ratio of
~3:1 and are most ideal concentrations for enhanced drug release in simulated lipid digestive
media. Hence, because of this reason, the percent drug release of all four drugs with a ration of
3:1 demonstrated complete drug release at 60 minutes; however the other ratio could not succeed
in extracting the drug in the dissolution media. On the same grounds similar observation trend
was also seen in all formulations of 1:1 ratio wherein the extent and rate were least among all
too. There also has been a uniform trend seen of percent drug release and ratio (from 3:1, 2:1 and
1:1) wherein the drug extent was maximum in 3:1 and least in 1:1. One more very important
observation was regarding the drug release of drug powder filled in empty hard gelatin capsules.
All capsules filled with only drug powder demonstrated the least drug release from the extent
and rate point of view. This also indicates that antimalarial drugs like artemisinin, Halofantrine,
amodiaquine and chloroquine, when formulated into conventional capsules, will face a lot of
challenges from oral bioavailability point of view. However, when emulsions of the same drugs
are prepared, the possibility of their oral bioavailability may also be overcome, which is
indicated by the above results from tablet 13. Anjana et al., in a research study in the year 2017,
studied numerous natural ingredients and formulated in a unique liquid carrier system called
"phytosome," which demonstrated several folds increases in oral bioavailability.23 Rao YS et
al., in their review paper, also expressed that research on drug delivery via microemulsions is a
promising field that holds very high potential for regulated release, enables medication targeting
to different body locations and with improved bioavailability
Antimalarial drugs are well known for limited oral bioavailability and most of these exhibits
limited bioavailability because of poor absorption due to very less aqueous solubility and higher
C Log p-value(s). Artemisinin, halofantrine, amodiaquine and chloroquine area also among those
antimalarials, which exhibit similar limited oral bioavailability. Microemulsions formed by
varied concentrations of surfactant and co-surfactants in this study demonstrated that as the
concentration ratio of surfactant to co-surfactant increases, the drug release from the oil droplets
also increases. And since these oil droplets that contain the drug are in size of 250 nm in size, the
surface area being very high is primarily responsible for higher (rate and extent) drug release in
dissolution media when compared to formulation wherein drug powder was filled in empty hard
gelatin capsules. This indicates that such microemulsions, when formulated, is anticipated to
demonstrate more oral bioavailability compared to conventional solid oral tablets and capsules.
The reason for enhanced oral bioavailability is because of the reason that such higher
concentrations of surfactants and co-surfactants in emulsions impart a self-emulsifying property
depicted by higher thermodynamic stability, more resistance to acid and alkali of GUT,
resistance against proteolytic enzymes and all the harsh peristaltic movement of GUT. Even
though with all such harsh GUT environmental conditions, these self-emulsifying
microemulsions retain their O/W emulsion (droplet size) nature and the oil droplets migrate
through the enterocytes of the intestinal wall and form "Drug Chylomicrons Conjugates,"
which later transports through "lacteals" (i.e. lymphatic vessels") present in the intestinal villi.
Drug-chylomicron conjugates enter lacteals through these open, button-like junctions between
lymphatic endothelial cells. There are two reasons for why the drug-chylomicrons conjugates
don't enter the blood circulation and enter only the lymphatic vessels. The first reason is; that the
drug-chylomicron conjugates are so big in size that their uptake from the wall of blood
capillaries is not possible and secondly, they lack the desired lipophilic and hydrophilic balance
which is needed for absorption via blood capillaries exclusively. However, the drug-chylomicron
conjugates exocytosis to permeate through lymphatic vessels easily. Once drug-chylomicrons are
poured in the lymphatic system, they finally drain into the central systemic circulatory system
after bypassing metabolism in the liver. Self-emulsifying microemulsions are advantageous over
conventional emulsions and formulations because they have the extra edge of being highly
thermodynamically stable in-situ and withstand all the GUT stress to remain in sub microns
size, wherein they provide the highest surface area for the drug to get solubilized in-situ and
absorbs through the lymphatic circulatory system. The microemulsion of four test antimalarial,
i.e., artemisinin, halofantrine, amodiaquine and chloroquine, exhibited self-emulsifying
characteristics, too
SIGNATURE :
1. LNCT UNIVERSITY, BHOPAL 18-Nov-24
2. NILESH JAISWAL 18-Nov-24
3. DR PARULBEN DURGASHANKER 18-Nov-24
LIPOIDAL DOSAGE FORMS OF ANIMALARIAL EXHIBITING FASTER RELEASE
, Claims:1. A lipid formulation of pharmaceutically acceptable salt thereof of Artemisinin, Halofantrine,
Amodiaquine and Chloroquine.
2. A lipid formulation as per claim 1, a surfactant and cosurfactant, in a ration of 1:1, 2:1 and 3:1
3. The lipid formulation of claim 2, comprising surfactant from the group of Labrasol, tween 80,
span, glyceryl monooleate and likewise.
4. The lipid formulation of claim 2, wherein the cosurfactants are from Transcutol-P,
Cremophor, lauroglycol-90, PEG 400, propylene glycol , Capryol 90 and likewise.
5. The lipid formulation of claim 2, wherein solvents like ethanol, water.
6. The lipid formulation of claim 2,3,4 and 5 wherein the formulation exhibits invitro drug
release in simulated fasted gastric fluid of not less than 80% in 120 min.
7. The lipid formulation of claim 2,3,4 and 5 wherein the formulation exhibits invitro drug
release in simulated fed gastric fluid of not less than 80% in 120 min.
8. The lipid formulation of claim 2,3,4 and 5 wherein the formulation exhibits invitro drug
release in simulated fasted intestinal fluid of not less than 70% in 120 min.
9. The lipid formulation of claim 2,3,4 and 5 wherein the formulation exhibits invitro drug
release in simulated fed intestinal fluid of not less than 70% in 120 min.

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