NZ763688B2 - Compositions and methods for the treatment of eye disorders - Google Patents
Compositions and methods for the treatment of eye disorders Download PDFInfo
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- NZ763688B2 NZ763688B2 NZ763688A NZ76368818A NZ763688B2 NZ 763688 B2 NZ763688 B2 NZ 763688B2 NZ 763688 A NZ763688 A NZ 763688A NZ 76368818 A NZ76368818 A NZ 76368818A NZ 763688 B2 NZ763688 B2 NZ 763688B2
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- pilocarpine
- eye
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
Aspects of the present disclosure provide compound of Formula (I) and pharmaceutically acceptable hydrates, solvates, crystals, co-crystals, enantiomers, stereoisomers, polymorphs and prodrugs thereof that can find utility in treatment of eye disorders and complications associated therewith. Aspects of the present disclosure also relate to methods of treating an eye disorder and/or complications thereof in a subject in need thereof by administering the compound of Formula (I) or a pharmaceutically acceptable hydrate, solvate, crystal, enantiomer, stereoisomer, polymorph or prodrug thereof. Formula (I) wherein, X+represents, Formula (II) or Formula (III). of the present disclosure also relate to methods of treating an eye disorder and/or complications thereof in a subject in need thereof by administering the compound of Formula (I) or a pharmaceutically acceptable hydrate, solvate, crystal, enantiomer, stereoisomer, polymorph or prodrug thereof. Formula (I) wherein, X+represents, Formula (II) or Formula (III).
Description
COMPOSITIONS AND METHODS FOR THE TREATMENT OF EYE DISORDERS
PRIORITY
The present application claims the benefit of Indian Provisional Application No.
IN201741041231 filed on 17 November 2017, the contents of which are incorporated in its
entirety herein by reference.
TECHNICAL FIELD
The present disclosure generally relates to compounds and compositions for the
treatment of eye disorders. More particularly, the present disclosure relates to new
compounds and crystals, solvates, enantiomers, stereoisomers, esters, polymorphs, co-crystals
and hydrates thereof that can find utility in management of eye disorders. Aspects of the
present disclosure also relates to treatment of subjects with a pharmaceutically acceptable
dose of compound(s), crystals, solvates, enantiomer, stereoisomer, esters, hydrates, or
mixtures thereof.
BACKGROUND
Background description includes information that may be useful in understanding
the present invention. It is not an admission that any of the information provided herein is
prior art or relevant to the presently claimed invention, or that any publication specifically or
implicitly referenced is prior art.
Age-related eye diseases, in many cases are not sudden but tend to develop slowly
as a person ages. Of many age-related eye diseases, there are four major diseases that are
recognized, which can be detected and treated if a comprehensive eye examination is
performed. These four age-related eye diseases - Macular Degeneration, Cataract, Glaucoma
and Diabetic Retinopathy are expected to dramatically increase if left untreated and can cause
vision loss and blindness. Population that is most at risk for developing eye disease is
unaware of the factors that make them susceptible. As the proportion of the elderly
population increases around the world, the prevalence and effects of age-related eye diseases
are also increasing. The leading causes of blindness and low vision are primarily age-related
eye diseases such as age-related macular degeneration, cataract, diabetic retinopathy, and
glaucoma. Age-related cataract will become an even larger percentage of the causes of
blindness worldwide, and glaucoma and age-related macular degeneration will emerge as
public health issues.
18029454_1 (GHMatters) P113464.NZ
Most common eye problems include Refractive errors, Cataracts - clouded lenses,
Optic nerve disorders, including glaucoma, Retinal disorders - problems with the nerve layer
at the back of the eye, Macular degeneration - a disease that destroys sharp, central vision,
Diabetic eye problems and Conjunctivitis - an infection also known as pinkeye. Presbyopia is
progressive loss of accommodation resulting in loss of visual ability to focus on objects
located at different distances. Accommodation in humans is performed by ciliary muscle and
iris sphincter contractions, convergence and changes in the shape and position of the lens.
The latter action is passive, meaning the lens changes are dependent on the ciliary muscle and
iris contractions. Also, when the centre of the accommodation is active, the ciliary muscle
contraction is stimulated and miosis and convergence occurs in normal binocular patients.
Published WO document WO2018065831 (Intl. Appl. No. )
discloses pilocarpine-(R)-lipoate for treatment of Xerostomia, Sjogrens Syndrome and Dry
Mouth, contents of which are incorporated in its entirety herein by reference. However, it
fails to suggest utility thereof in treatment of eye disorders and complications associated
therewith.
Managing acute pathology often relies on the addressing the underlying pathology
and symptoms of the disease. There is currently a need in the art for new compounds and
compositions that can find utility in the treatment of eye disorders and/or in delaying the
onset of eye disorders and complications associated therewith.
OBJECTS OF THE INVENTION
An object of the present disclosure is to provide compounds and crystals, co-
crystals, solvates, enantiomer, stereoisomer, esters, hydrates, or mixtures thereof that can find
utility in treatment of eye disorders.
Another object of the present disclosure is to provide a pharmaceutical
composition for treatment of eye disorders.
SUMMARY
The present disclosure generally relates to compounds and compositions for the
treatment of eye disorders. More particularly, the present disclosure relates to compounds and
pharmaceutically acceptable salts, hydrates, solvates, crystals, co-crystals, enantiomers,
stereoisomers, esters, polymorphs or prodrugs thereof that can find utility in treatment of eye
disorders. Aspects of the present disclosure also relates to treatment of subjects with a
18029454_1 (GHMatters) P113464.NZ
pharmaceutically acceptable dose of the compound or pharmaceutically acceptable salts,
crystals, solvates, enantiomer, stereoisomer, esters or hydrates thereof.
[0010a] In one aspect, there is provided a compound of formula I
Formula I
or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, polymorph or prodrug thereof,
wherein, X represents,
or .
[0010b] In another aspect, there is provided a pharmaceutical composition comprising at
least one compound as defined herein and a pharmaceutically acceptable excipient.
[0010c] In another aspect, there is provided a method of synthesis of a compound as
defined herein, the method comprising treating pilocarpine with lipoic acid.
[0010d] In another aspect, there is provided a medicament for treatment of an eye disorder
or complications associated therewith comprising a compound as defined herein.
[0010e] In another aspect, there is provided use of a compound of formula I
Formula I
18029454_1 (GHMatters) P113464.NZ
or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, or polymorph thereof,
wherein, X represents
or ,
for the manufacture of a medicament for treating an eye disorder or complications thereof.
An aspect of the present disclosure provides a compound of formula I,
Formula I
or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, polymorph or prodrug thereof,
wherein, X represents,
wherein said compound finds use in treatment of eye disorder or complications associated
therewith. The eye disorder that can be treated by the compound of formula I of the present
disclosure includes macular degeneration, cataract, glaucoma, diabetic retinopathy, dry eye,
ocular neuritis, retinitis pigmentosa and presbyopia.
18029454_1 (GHMatters) P113464.NZ
In an embodiment, the compound of formula I can be pilocarpine-RS-lipoate
which is selected from:
, and
In another embodiment, the compound of Formula I can be pilocarpine-(R)-
lipoate which is selected from:
, and
In another embodiment, the compound of Formula I can be pilocarpine-(S)-lipoate
which is selected from:
, and
18029454_1 (GHMatters) P113464.NZ
In an embodiment, the compound of Formula I comprises pilocarpine-(R)-lipoate
with an enantiomeric excess (ee) of at least 1%. In an embodiment, the compound of Formula
I comprises pilocarpine-(S)-lipoate with an enantiomeric excess (ee) of at least 1%.
In an embodiment, the compound of formula I is any of
, and
18029454_1 (GHMatters) P113464.NZ
Another aspect of the present disclosure is directed to a pharmaceutical
composition for treating an eye disorder or complications thereof, which comprises a
compound of formula I or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,
enantiomer, stereoisomer, polymorph or prodrug thereof and a pharmaceutically acceptable
excipient. In an embodiment, the pharmaceutical composition is formulated for oral, nasal,
topical, rectal, vaginal, aerosol or parenteral administration. In certain preferred
embodiments, the pharmaceutical composition is a topical ophthalmic formulation. In certain
preferred embodiments, the pharmaceutical composition is an ophthalmic drop formulation.
Another aspect of the present disclosure provides a method of synthesis of
pilocarpine-lipoate, the method comprising: treating pilocarpine HCl in acetone with
hydrogen carbonate to obtain the free base of pilocarpine, further the free base of pilocarpine
is reacted with lipoic acid. In an embodiment, the method further comprises a step of
contacting pilocarpine HCl with a base to obtain pilocarpine. In an embodiment, the method
comprises treating pilocarpine HCl in a solvent with a base to obtain pilocarpine. In an
embodiment, the method comprises treating pilocarpine HCl in acetone with sodium hydrogen
carbonate for about 18h at room temperature to obtain pilocarpine. In an embodiment, the
method effects yield of about 100%. In an embodiment, the method further comprises a step
of effecting recrystallization of the pilocarpine-lipoate. In an embodiment, the step of
effecting recrystallization comprises effecting recrystallization of pilocarpine-lipoate with
ethyl acetate (5 volumes) at 50-55°C to obtain crystalline pilocarpine-lipoate with yield of
about 80%.
Another aspect of the present disclosure provides a method of treating an eye
disorder or complications thereof in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of the compound of formula I
disclosed herein or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,
enantiomer, stereoisomer, polymorph or prodrug thereof. In an embodiment, the eye disorder
18029454_1 (GHMatters) P113464.NZ
that can be treated by the method disclosed herein can include macular degeneration, cataract,
glaucoma, diabetic retinopathy, dry eye, ocular neuritis, retinitis pigmentosa and presbyopia.
In yet another aspect, the present disclosure is directed to use of the compound of
formula I or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, polymorph or prodrug thereof for manufacture of a medicament for treatment
of an eye disorder or complications associated therewith.
Various objects, features, aspects and advantages of the inventive subject matter
will become more apparent from the following detailed description of preferred
embodiments, along with the accompanying drawing figures in which like numerals represent
like components.
DETAILED DESCRIPTION
The following is a detailed description of embodiments of the disclosure depicted
in the accompanying drawings. 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 as defined by the appended claims.
Each of the appended claims defines a separate invention, which for infringement
purposes is recognized as including equivalents to the various elements or limitations
specified in the claims. Depending on the context, all references below to the “invention”
may in some cases refer to certain specific embodiments only. In other cases it will be
recognized that references to the “invention” will refer to subject matter recited in one or
more, but not necessarily all, of the claims.
As used in the description herein and throughout the claims that follow, the
meaning of “a,” “an,” and “the” includes plural reference unless the context clearly dictates
otherwise. Also, as used in the description herein, the meaning of “in” includes “in” and “on”
unless the context clearly dictates otherwise.
All methods described herein can be performed in any suitable order unless
otherwise indicated herein or otherwise clearly contradicted by context. The use of any and
all examples, or exemplary language (e.g. “such as”) provided with respect to certain
embodiments herein is intended merely to better illuminate the invention and does not pose a
limitation on the scope of the invention otherwise claimed. No language in the specification
18029454_1 (GHMatters) P113464.NZ
should be construed as indicating any non-claimed element essential to the practice of the
invention.
Various terms as used herein are shown below. To the extent a term used in a
claim is not defined below, it should be given the broadest definition persons in the pertinent
art have given that term as reflected in printed publications and issued patents at the time of
filing.
The term "isomers" as used herein throughout the present disclosure encompasses
within its meaning, the compounds that have same molecular formula but differ in the nature
or sequence of bonding of their atoms or arrangement of their atoms in space.
The term "stereoisomer" as used herein throughout the present disclosure
encompasses within its meaning, isomers that differ in the arrangement of their atoms in
space.
The term "diastereomer" as used herein throughout the present disclosure
encompasses within its meaning, stereoisomers with opposite configuration at one or more
chiral centers, which are not enantiomers.
The term "enantiomer" as used herein throughout the present disclosure
encompasses within its meaning, stereoisomers bearing one or more asymmetric centers that
are non-superimposable mirror images of each other. When a compound has one asymmetric
center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers
is possible. An enantiomer can be characterized by the absolute configuration of its
asymmetric center or centers and is described by the R- and S-sequencing rules of Cahn,
lngold and Prelog (CIP), or by the manner in which the molecule rotates the plane of
polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers
respectively). A chiral compound can exist as either individual enantiomer or as a mixture
thereof. A mixture containing equal proportions of the enantiomers is called a "racemic
mixture".
The term "polymorph" as used herein is art-recognized and refers to a crystal
structure of a given compound.
The phrases “parenteral administration” and “administered parenterally” as used
herein refer to modes of administration other than enteral and topical administration, such as
injections, and include intravenous, intramuscular, intrapleural, intravascular, intrapericardial,
intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,
transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid,
intraspinal and intrastemal injection and infusion, but not limited thereto.
18029454_1 (GHMatters) P113464.NZ
A “patient,” “subject,” or “host” to be treated by the subject method may mean
either a human or non-human animal, such as primates, mammals, and vertebrates.
The phrase “pharmaceutically acceptable” is art-recognized. In certain
embodiments, the term includes compositions, polymers and other materials and/or dosage
forms which are, within the scope of sound medical judgment, suitable for use in contact with
the tissues of mammals, human beings and animals without excessive toxicity, irritation,
allergic response, or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
The phrase “pharmaceutically acceptable excipient” is art-recognized, and
includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such
as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or
transporting any subject composition, from one organ, or portion of the body, to another
organ, or portion of the body. Each carrier must be “acceptable” in the sense of being
compatible with the other ingredients of a subject composition and not injurious to the
patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic.
Some examples of materials which may serve as pharmaceutically acceptable carriers
include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and
potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl
cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8)
cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11)
polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as
ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide
and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18)
Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-
toxic compatible substances employed in pharmaceutical formulations.
The term “prodrug” is intended to encompass compounds that, under
physiological conditions, are converted into the therapeutically active agents of the present
disclosure. A common method for making a prodrug is to include selected moieties that are
hydrolyzed under physiological conditions to reveal the desired molecule. In other
embodiments, the prodrug is converted by an enzymatic activity of the host animal.
The term “prophylactic or therapeutic” treatment is art-recognized and includes
administration to the host of one or more of the compositions. If it is administered prior to
clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the
18029454_1 (GHMatters) P113464.NZ
host animal) then the treatment is prophylactic, i.e., it protects the host against developing the
unwanted condition, whereas if it is administered after manifestation of the unwanted
condition, the treatment is therapeutic, (i.e. it is intended to diminish, ameliorate, or stabilize
the existing unwanted condition or side effects thereof).
The term "treating" or “treatment” is art recognized and includes preventing a
disease, disorder or condition from occurring in a human being or an animal, which may be
predisposed to the disease, disorder and/or condition but has not yet been diagnosed as
having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and
relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder
and/or condition. Treating the disease or condition includes ameliorating at least one
symptom of the particular disease or condition, even if the underlying pathophysiology is not
affected, such as treating Disorders of eyelid, lacrimal system and orbit, Disorders of
conjunctiva, Disorders of sclera, cornea, iris and ciliary body, Disorders of lens, Disorders of
choroid and retina, Glaucoma, Disorders of vitreous body and globe, Disorders of optic nerve
and visual pathways, Visual disturbances and blindness, Presbyopia and other related
diseases or any other medical condition, is well understood in the art, and includes
administration of a composition which reduces the frequency of, or delays the onset of,
symptoms of a medical condition in a subject relative to a subject which does not receive
such composition.
The phrase "therapeutically effective amount" is an art-recognized term. In certain
embodiments, the term refers to an amount of a solvate or hydrate or composition disclosed
herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any
medical treatment. In certain embodiments, the term refers to that amount necessary or
sufficient to eliminate or reduce medical symptoms for a period of time. The effective
amount may vary depending on such factors as the disease or condition being treated, the
particular targeted constructs being administered, the size of the subject, or the severity of the
disease or condition. One of ordinary skill in the art may empirically determine the effective
amount of a particular composition without necessitating undue experimentation.
As used herein, the term “ophthalmic composition” refers to a composition
intended for application to the eye or its related or surrounding tissues such as, for example,
the eyelid or onto the cornea. The term also includes compositions intended to therapeutically
treat conditions of the eye itself or the tissues surrounding the eye. The ophthalmic
composition can be applied topically or by other techniques, as known to or appreciated by
persons skilled in the pertinent art, such as injection to the eye. Examples of suitable topical
18029454_1 (GHMatters) P113464.NZ
administration to the eye include administration in form of eye drops and by spray
formulations. A further suitable topical administration route is by subconjunctival injection.
The compositions can also be provided to the eye periocularly or retro-orbitally.
In certain embodiments, the pharmaceutical compositions described herein are
formulated in a manner such that said compositions will be delivered to a patient in a
therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The
desired amount of the composition to be administered to a patient will depend on absorption,
inactivation, and excretion rates of the drug as well as the delivery rate of the hydrates or
solvates and compositions from the subject compositions. It is to be noted that dosage values
may also vary with the severity of the condition to be alleviated. It is to be further understood
that for any particular subject, specific dosage regimens should be adjusted over time
according to the individual need and the professional judgment of the person administering or
supervising the administration of the compositions. Typically, dosing will be determined
using techniques known to one skilled in the art.
Additionally, the optimal concentration and/or quantities or amounts of any
particular solvate or hydrate or composition may be adjusted to accommodate variations in
the treatment parameters. Such treatment parameters include the clinical use to which the
preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult
or child, and the nature of the disease or condition.
In certain embodiments, the dosage of the compounds of Formula I provided
herein may be determined by reference to the plasma concentrations of the therapeutic
composition or other encapsulated materials. For example, the maximum plasma
concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to
infinity may be used.
When used with respect to a pharmaceutical composition or other material, the
term “sustained release” is art-recognized. For example, a subject composition which releases
a substance over time may exhibit sustained release characteristics, in contrast to a bolus type
administration in which the entire amount of the substance is made biologically available at
one time. For example, in particular embodiments, upon contact with body fluids including
blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically
acceptable excipients may undergo gradual or delayed degradation (for example, through
hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic
and/or biologically active solvate or hydrate and/or composition, for a sustained or extended
period (as compared to the release from a bolus). This release may result in prolonged
18029454_1 (GHMatters) P113464.NZ
delivery of therapeutically effective amounts of any of the therapeutic agents (compounds)
disclosed herein.
The phrases “systemic administration,” “administered systemically,” “peripheral
administration” and “administered peripherally” are art-recognized, and include the
administration of a subject composition, therapeutic or other material at a site remote from
the disease being treated. Administration of an agent for the disease being treated, even if the
agent is subsequently distributed systemically, may be termed “local” or “topical” or
“regional” administration, other than directly into the central nervous system, e.g., by
subcutaneous administration, such that it enters the patient’s system and, thus, is subject to
metabolism and other like processes.
The present disclosure also contemplates prodrugs of the compositions disclosed
herein, as well as pharmaceutically acceptable hydrates or solvates of said prodrugs.
The present disclosure generally relates to compounds and compositions for the
treatment of eye disorders. More particularly, the present disclosure relates to compounds and
pharmaceutically acceptable crystals, co-crystals, solvates, enantiomers, stereoisomers,
prodrugs or hydrates thereof that can find utility in treatment of eye disorders. Aspects of the
present disclosure also relate to methods of treating an eye disorder and/or complications
thereof in a subject in need thereof.
An aspect of the present disclosure provides a compound of formula I,
Formula I
or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, polymorph or prodrug thereof,
wherein, X represents,
18029454_1 (GHMatters) P113464.NZ
wherein said compound finds use in treatment of eye disorder or complications associated
therewith. The eye disorder that can be treated by the compound of formula I of the present
disclosure includes macular degeneration, cataract, glaucoma, diabetic retinopathy, dry eye,
ocular neuritis, retinitis pigmentosa and presbyopia.
In an embodiment, the compound of formula I can be pilocarpine-RS-lipoate
which is selected from:
, and
In an embodiment, the compound of Formula I can be pilocarpine-(R)-lipoate
which is selected from:
, and
18029454_1 (GHMatters) P113464.NZ
In an embodiment, the compound of Formula I can be pilocarpine-(S)-lipoate
which is selected from:
, and
In an embodiment, the compound of Formula I comprises pilocarpine-(R)-lipoate
with an enantiomeric excess (ee) of at least 1%. In an embodiment, the compound of Formula
I comprises pilocarpine-(S)-lipoate with an enantiomeric excess (ee) of at least 1%.
In an embodiment, the compound of formula I is any of
18029454_1 (GHMatters) P113464.NZ
, and
Another aspect of the present disclosure is directed to a pharmaceutical
composition for treating an eye disorder or complications thereof, which comprises the
disclosed compound of formula I or a pharmaceutically acceptable hydrate, solvate, crystal,
co-crystal, enantiomer, stereoisomer, polymorph or prodrug thereof and a pharmaceutically
acceptable excipient. In an embodiment, the pharmaceutical composition is formulated for
oral, nasal, topical, rectal, vaginal, aerosol or parenteral administration. In certain preferred
embodiments, the pharmaceutical composition is a topical ophthalmic formulation. In certain
preferred embodiments, the pharmaceutical composition is an ophthalmic drop formulation.
Another aspect of the present disclosure provides a method of synthesis of
pilocarpine-lipoate, the method comprising: treating pilocarpine with lipoic acid at a suitable
temperature to obtain pilocarpine-lipoate. In an embodiment, the method further comprises a
step of contacting pilocarpine HCl with a base to obtain pilocarpine. In an embodiment, the
method comprises treating pilocarpine HCl in a solvent with a base to obtain pilocarpine. In
an embodiment, the method comprises treating pilocarpine HCl in acetone with sodium
hydrogen carbonate for about 18h at room temperature to obtain pilocarpine. In an
embodiment, the method effects yield of about 100%. In an embodiment, the method further
comprises a step of effecting recrystallization of the pilocarpine-lipoate. In an embodiment,
18029454_1 (GHMatters) P113464.NZ
the step of effecting recrystallization comprises effecting recrystallization of pilocarpine-
lipoate with ethyl acetate (5 volumes) at 50-55°C to obtain crystalline pilocarpine-lipoate
with yield of about 80%.
Another aspect of the present disclosure provides a method of synthesis of
pilocarpine-(R)-lipoate, the method comprising: contacting pilocarpine with (R)-lipoic acid at
a suitable temperature to obtain pilocarpine-(R)-lipoate. In an embodiment, the method
comprises contacting pilocarpine HCl with a base to obtain pilocarpine. In an embodiment,
the method comprises treating pilocarpine HCl in a solvent with a base to obtain pilocarpine.
In an embodiment, the method comprises treating pilocarpine HCl in acetone with sodium
hydrogen carbonate for about 18h at room temperature to obtain pilocarpine. In an
embodiment, the method effects yield of about 100%. However, a person skilled in the
pertinent art would appreciate that any other method of synthesis of pilocarpine-(R)-lipoate,
as known to or appreciated by a person skilled in the art, can be suitably employed to sub-
serve its intended purpose without departing from the scope and spirit of the present
disclosure.
In an embodiment, the method further comprises a step of effecting
recrystallization of the pilocarpine-(R)-lipoate. In an embodiment, the step of effecting
recrystallization comprises effecting recrystallization of pilocarpine-(R)-lipoate with ethyl
acetate (5 volumes) at 50-55°C to obtain crystalline pilocarpine-(R)-lipoate with yield of
about 80%. However, it should be appreciated that recrystallization of the pilocarpine-(R)-
lipoate can be effected employing any other method as known to or appreciated by a person
skilled in the pertinent art without departing from the scope and spirit of the present
invention.
Although several embodiments of the present disclosure describes the method of
preparation and recrystallization of pilocarpine-(R)-lipoate, it should be appreciated by a
person skilled in the art, the substantially same or similar method can be used for synthesis of
pilocarpine-(R,S)-lipoate and/or pilocarpine-(S)-lipoate and the same has not been described
in detail for the sake of brevity.
Still further aspect of the present disclosure provides a method of treating an eye
disorder or complications thereof in a subject in need thereof, the method comprising
administering to the subject a therapeutically effective amount of the compound of formula I
or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer,
stereoisomer, polymorph or prodrug thereof. In an embodiment, the eye disorder that can be
treated by the method disclosed herein can include macular degeneration, cataract, glaucoma,
18029454_1 (GHMatters) P113464.NZ
diabetic retinopathy, dry eye, ocular neuritis, retinitis pigmentosa and presbyopia. In an
embodiment, the compound of formula I can be administered to said subject in combination
with a pharmaceutically acceptable excipient. In an embodiment, the therapeutically effective
amount of the compound of formula I that can be administered to said subject can range from
0.001mg to 1000mg. In an embodiment, the compound of formula I can be administered
topically to at least one eye of a subject in need of treatment for eye disorder or complications
associated therewith.
In an embodiment, the compound of formula I that can be used in the treatment
method of the present disclosure can be selected from one or more of:
18029454_1 (GHMatters) P113464.NZ
, and
The compounds of the present disclosure may be in the form of hydrates or
solvates of acid moiety - lipoic acid and the base component represented as X+ in which the
acid component is in partially ionic form and the base component represented as X+ is
protonated in the pharmaceutically acceptable salt. In some instances, however, for example
depending on the pH of the environment, the compounds may be in the form of a mixture of
X+ and lipoic acid.
Without wishing to bound by the theory, it is believed that pilocarpine aids in
lowering intraocular pressure, induces miosis and assists in accommodation in the eye, while
lipoic acid acts as an anti-oxidant, regenerates glutathione and improves lens activity in the
human eye.
Synthesis of Compounds of Formula I
Pilocarpine salt in a solvent can be treated with a base for a time period to get free
base of pilocapine, which upon contact with lipoic acid results in formation of compounds of
Formula I. Alternatively, pilocarpine can be contacted with lipoic acid to directly obtain
compounds of Formula I. A person skilled in the pertinent art would appreciate that choice of
solvent, base and process parameters like temperature, time and the likes can be suitably
amended/selected in order to sub-serve its intended purpose and the scope of the present
disclosure is not restricted to utilization of any specific solvent/base and/or the process
parameters.
In an embodiment, firstly, pilocarpine HCl in acetone is treated with sodium hydrogen
carbonate for 18 h at room temperature to get free base of Pilocarpine, which upon reaction with
(R)-Lipoic acid at room temperature for 1 h gives Pilocarpine-(R)-Lipoate in about 100% yield.
18029454_1 (GHMatters) P113464.NZ
Scheme 1: Synthesis of Pilocarpine-(R)-Lipoate
In an embodiment, the pilocarpine-lipoate is recrystallized using suitable solvent or a
combination of solvents to afford crystalline Pilocarpine-Lipoate. Such solvent or combination of
solvents are well known to a person skilled in the pertinent art and same has not been described in
detail for the sake of clarity. The technique of recrystallization is elaborately dealt with in
"Remington—The Science and Practice of Pharmacy", 20th. Ed., Lippincott Williams &
Wilkins, Baltimore, Md., 2000”, contents of which are incorporated herein in its entirety by
way of reference. In an embodiment, Pilocarpine-(R)-Lipoate is recrystallized from ethyl acetate
(5 volumes) at 50-55 °C to afford yellow crystalline Pilocarpine-(R)-Lipoate in about 80 % yield.
The present disclosure also discloses pharmaceutical compositions comprising a
pharmaceutically acceptable excipient and one or a combination of compounds of Formula I
that may be formulated for systemic or topical or oral administration. The pharmaceutical
composition may be also formulated for oral administration, oral solution, injection,
subdermal administration, or transdermal administration.
In many embodiments, the pharmaceutical compositions described herein
incorporate the disclosed compounds (Formula I) to be delivered in an amount sufficient to
deliver to a patient, a therapeutically effective amount of a compound of Formula I, as part of
a prophylactic or therapeutic treatment. The desired concentration of compound(s) of
Formula I or its pharmaceutical acceptable hydrates or solvates will depend on absorption,
inactivation, and excretion rates of the drug as well as the delivery rate of the hydrates or
solvates and compositions from the subject compositions. It is to be noted that dosage values
18029454_1 (GHMatters) P113464.NZ
may also vary with the severity of the condition to be alleviated. It is to be further understood
that for any particular subject, specific dosage regimens may need to be adjusted over time
according to the individual need and the professional judgment of the person administering or
supervising the administration of the compositions. Typically, dosing will be determined
using techniques known to one skilled in the art.
Additionally, the optimal concentration and/or quantities or amounts of any
particular compound of Formula I may be adjusted to accommodate variations in the
treatment parameters. Such treatment parameters may include the clinical use to which the
preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult
or child, and the nature of the disease or condition, but not limited thereto.
The concentration and/or amount of any compound of Formula I may be readily
identified by routine screening in animals, e.g., rats, by screening a range of concentration
and/or amounts of the material in question using appropriate assays. Known methods are also
available to assay local tissue concentrations, diffusion rates of the hydrates or solvates or
compositions, and local blood flow before and after administration of therapeutic
formulations disclosed herein. One such method is microdialysis, as reviewed by T. E.
Robinson et al., 1991, microdialysis in the neurosciences, Techniques, volume 7, Chapter 1.
The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis
loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When
compounds with Formula I such as those disclosed herein are injected adjacent to the loop,
released drugs are collected in the dialysate in proportion to their local tissue concentrations.
The progress of diffusion of the hydrates or solvates or compositions may be determined
thereby with suitable calibration procedures using known concentrations of hydrates or
solvates or compositions.
In certain embodiments, the dosage of the compounds of Formula I provided
herein may be determined by reference to the plasma concentrations of the composition or
other encapsulated materials. For example, the maximum plasma concentration (Cmax) and
the area under the plasma concentration-time curve from time 0 to infinity may be used.
Generally, in carrying out the methods detailed in the present disclosure, an
effective dosage for the compound of Formula I is in the range of about 0.01 mg/kg/day to
about 100 mg/kg/day in single or divided doses, for instance 0.01 mg/kg/day to about 50
mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a
dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 mg/kg/day,
mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compound of Formula I may
18029454_1 (GHMatters) P113464.NZ
also be administered to a human patient at a dose of, for example, between 0.001 mg and
1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300,
400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions
herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%,
%, 20%, or 10% of the compound of Formula I required for the same therapeutic benefit.
A therapeutically effective amount of the compound of Formula I as described
herein refers to an amount of the compound of formula I which is sufficient to elicit the
desired biological response. An effective amount may be sufficient to prohibit, treat,
alleviate, ameliorate, halt, restrain, slow or reverse the progression, or reduce the severity of a
complication resulting from intraocular pressure, optic nerve complications, glaucoma, ocular
lens complications, cataracts, lens thickening and refractive index problems of the eye. As
such, these methods include both medical therapeutic (acute) and/or prophylactic
(prevention) administration as appropriate. The amount and timing of compositions
administered will, of course, be dependent on the subject being treated, on the severity of the
affliction, on the manner of administration and on the judgment of the prescribing physician.
Thus, because of patient-to-patient variability, the dosages given above are a guideline and
the physician may titrate doses of the drug to achieve the treatment that the physician
considers appropriate for the patient. In considering the degree of treatment desired, the
physician must balance a variety of factors such as age of the patient, presence of preexisting
disease, as well as presence of other diseases. In an exemplary embodiment, the
therapeutically effective amount of the compound of Formula I can range from 0.001mg to
1000mg.
The compositions disclosed herein may be administered to a subject in need of
treatment by a variety of conventional routes of administration, including orally, topically,
parenterally, e.g., intravenously, subcutaneously or intramedullary, but not limited thereto.
Further, the compositions may be administered intranasally, as a rectal suppository, or using a
"flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to
use water. Furthermore, the compositions may be administered to a subject in need of
treatment by controlled release dosage forms, site specific drug delivery, transdermal drug
delivery, patch (active/passive) mediated drug delivery, by stereotactic injection, or in
nanoparticles.
The compositions may be administered alone or in combination with
pharmaceutically acceptable carriers, vehicles or diluents (collectively, referred to herein as
excipients), in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and
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diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic
solvents. The pharmaceutical compositions formed by combining the compounds and the
pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a
variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and
the likes. These pharmaceutical compositions may, if desired, contain additional ingredients
such as flavorings, binders, excipients and the likes. Thus, for purposes of oral
administration, tablets containing various excipients such as L-arginine, sodium citrate,
calcium carbonate and calcium phosphate may be employed along with various disintegrating
agents such as starch, alginic acid and certain complex silicates, together with binding agents
such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents
such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting
purposes. Solid compositions of a similar type may also be employed as fillers in soft and
hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and
high molecular weight polyethylene glycols, but not limited thereto. When aqueous
suspensions or elixirs are desired for oral administration, the essential active ingredient may
be combined with various sweetening or flavoring agents, coloring matter or dyes and, if
desired, emulsifying or suspending agents, together with diluents such as water, ethanol,
propylene glycol, glycerin and combinations thereof. The compounds of Formula I may also
be formulated as enterically coated formulations including various excipients, as is well
known in the pharmaceutical art.
For parenteral administration, solutions (compositions) may be prepared using (for
example) sesame or peanut oil, aqueous propylene glycol, or sterile aqueous solutions. Such
solutions may be suitably buffered if necessary, and the liquid diluent is first rendered
isotonic with sufficient saline or glucose. These particular aqueous solutions are especially
suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In
this connection, the sterile aqueous media employed are all readily available by standard
techniques known to those skilled in the art.
The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150
to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the compounds of
Formula I disclosed herein, for instance, compounds of Formula I or pharmaceutical
acceptable hydrates or solvates of a compounds of Formula I.
Generally, a composition as described herein may be administered orally, or
parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical
administration may also be indicated, for example, where the patient is suffering from
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gastrointestinal disorder that prevent oral administration, or whenever the medication is best
applied to the surface of a tissue or organ as determined by the attending physician. Localized
administration may also be indicated, for example, when a high dose is desired at the target
tissue or organ. For buccal administration the active composition may take the form of tablets
or lozenges formulated in a conventional manner.
The dosage administered will be dependent upon the identity of the disease; the
type of host involved, including its age, health and weight; the kind of concurrent treatment,
if any; the frequency of treatment and therapeutic ratio, but not limited thereto. Illustratively,
dosage levels of the administered active ingredients are: ocular, 0.0001 to about 100mg/kg;
intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about
1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000
mg/kg of host body weight.
Expressed in terms of concentration, an active ingredient can be present in the
compositions of the present invention for localized use about the cutis, intranasally,
pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of
from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w
of the composition; and for parenteral use in a concentration of from about 0.05 to about 50%
w/v of the composition and preferably from about 5 to about 20% w/v.
The compositions of the present invention are preferably presented for
administration to humans and animals in unit dosage forms, such as tablets, capsules, pills,
powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-
parenteral solutions, suspensions, and oral solutions or suspensions and the like, containing
suitable quantities of an active ingredient. For oral administration either solid or fluid unit
dosage forms can be prepared.
As discussed above, the tablet core may contain one or more hydrophilic
polymers. Suitable hydrophilic polymers include, but are not limited to, water swellable
cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic
polymers, hydrocolloids, clays, gelling starches, swelling cross-linked polymers, and
mixtures thereof. Examples of suitable water swellable cellulose derivatives include, but are
not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose,
hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC),
hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose,
hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures thereof.
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Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene
glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited
to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited
to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-
molecular weight crosslinked acrylic acid homopolymers and copolymers such as those
commercially available from Noveon Chemicals under the tradename CARBOPOL .
Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum,
locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, tragacanth, pectin,
xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin,
chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to,
smectites such as bentonite, kaolin, and laponite; magnesium trisilicate; magnesium
aluminum silicate; and mixtures thereof. Examples of suitable gelling starches include, but
are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate
and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-linked
polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked
agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof.
The carrier may contain one or more suitable excipients for the formulation of
tablets. Examples of suitable excipients include, but are not limited to, fillers, adsorbents,
binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants,
antioxidants or mixtures thereof.
Suitable binders include, but are not limited to, dry binders such as polyvinyl
pyrrolidone and hydroxypropylmethylcellulose; wet binders such as water-soluble polymers,
including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan,
carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan,
zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose,
and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to,
sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof. Suitable
lubricants include, but are not limited to, long chain fatty acids and their hydrates or solvates,
such as magnesium stearate and stearic acid, talc, glycerides waxes, and mixtures thereof.
Suitable glidants include, but are not limited to, colloidal silicon dioxide. Suitable release-
18029454_1 (GHMatters) P113464.NZ
modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent
polymers, and mixtures thereof.
Suitable insoluble edible materials for use as release-modifying excipients
include, but are not limited to, water-insoluble polymers and low-melting hydrophobic
materials, copolymers thereof, and mixtures thereof. Examples of suitable water-insoluble
polymers include, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid
copolymers, copolymers thereof and mixtures thereof. Suitable low-melting hydrophobic
materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and
mixtures thereof. Examples of suitable fats include, but are not limited to, hydrogenated
vegetable oils such as for example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids
and their hydrates or solvates, and mixtures thereof. Examples of suitable fatty acid esters
include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl
behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryl
trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoyl
macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include
phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, and
mixtures thereof. Examples of suitable waxes include, but are not limited to, carnauba wax,
spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin
wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super
disintegrants include, but are not limited to, croscarmellose sodium, sodium starch glycolate
and cross-linked povidone (crospovidone). In one embodiment the tablet core contains up to
about 5 percent by weight of such super disintegrant.
Examples of antioxidants include, but are not limited to, tocopherols, ascorbic
acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and
edetate hydrates or solvates, and mixtures thereof. Examples of preservatives include, but are
not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, benzoic acid, and
sorbic acid, and mixtures thereof.
In one embodiment, the immediate release coating has an average thickness of at
least 50 microns, such as from about 50 microns to about 2500 microns; e.g., from about 250
microns to about 1000 microns. In embodiment, the immediate release coating is typically
compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume
of that specific layer.
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In one embodiment, the immediate release coating contains a first portion and a
second portion, wherein at least one of the portions contains the second pharmaceutically
active agent. In one embodiment, the portions contact each other at a center axis of the tablet.
In one embodiment, the first portion includes the first pharmaceutically active agent and the
second portion includes the second pharmaceutically active agent.
In one embodiment, the first portion contains the first pharmaceutically active
agent and the second portion contains the second pharmaceutically active agent. In one
embodiment, one of the portions contains a third pharmaceutically active agent. In one
embodiment one of the portions contains a second immediate release portion of the same
pharmaceutically active agent as that contained in the tablet core.
In one embodiment, the outer coating portion is prepared as a dry blend of
materials prior to addition to the coated tablet core. In another embodiment the outer coating
portion is included of a dried granulation including the pharmaceutically active agent.
Formulations with different drug release mechanisms described above could be
combined in a final dosage form containing single or multiple units. Examples of multiple
units include multilayer tablets, capsules containing tablets, beads, or granules in a solid or
liquid form. Typical, immediate release formulations include compressed tablets, gels, films,
coatings, liquids and particles that can be encapsulated, for example, in a gelatin capsule.
Many methods for preparing coatings, covering or incorporating drugs, are known in the art.
The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of
drug-containing beads, granules or particles, or an outer layer of a coated core dosage form,
contains a therapeutically effective quantity of the active agent with conventional
pharmaceutical excipients. The immediate release dosage unit may or may not be coated, and
may or may not be admixed with the delayed release dosage unit or units (as in an
encapsulated mixture of immediate release drug-containing granules, particles or beads and
delayed release drug-containing granules or beads).
Extended release formulations are generally prepared as diffusion or osmotic
systems, for example, as described in "Remington—The Science and Practice of Pharmacy",
20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000. A diffusion system
typically consists of one of two types of devices, reservoir and matrix, which are well known
and described in the art. The matrix devices are generally prepared by compressing the drug
with a slowly dissolving polymer carrier into a tablet form.
An immediate release portion can be added to the extended release system by
means of either applying an immediate release layer on top of the extended release core;
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using coating or compression processes or in a multiple unit system such as a capsule
containing extended and immediate release beads.
Delayed release dosage formulations are created by coating a solid dosage form
with a film of a polymer, which is insoluble in the acid environment of the stomach, but
soluble in the neutral or slightly basic environment of small intestine. The delayed release
dosage units can be prepared, for example, by coating a drug or a drug-containing
composition with a selected coating material. The drug-containing composition may be a
tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core"
dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation
into either a tablet or capsule.
A pulsed release dosage form is one that mimics a multiple dosing profile without
repeated dosing and typically allows at least a twofold reduction in dosing frequency as
compared to the drug presented as a conventional dosage form (e.g., as a solution or prompt
drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by
a time period of no release (lag time) or reduced release followed by rapid drug release.
Each dosage form contains a therapeutically effective amount of active agent
(compound of formula I). In one embodiment of dosage forms that mimic a twice daily
dosing profile, approximately 30 wt. % to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the
total amount of active agent in the dosage form is released in the initial pulse, and,
correspondingly approximately 70 wt. % to 30 wt. %, preferably 60 wt. % to 40 wt. %, of the
total amount of active agent in the dosage form is released in the second pulse. For dosage
forms mimicking the twice daily dosing profile, the second pulse is preferably released
approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12
hours, following administration.
Another dosage form contains a compressed tablet or a capsule having a drug-
containing immediate release dosage unit, a delayed release dosage unit and an optional
second delayed release dosage unit. In this dosage form, the immediate release dosage unit
contains a plurality of beads, granules particles that release drug substantially immediately
following oral administration to provide an initial dose. The delayed release dosage unit
contains a plurality of coated beads or granules, which release drug approximately 3 hours to
14 hours following oral administration to provide a second dose.
For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous
or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar
to the above parenteral solutions, may be prepared.
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Methods of preparing various pharmaceutical compositions with a certain amount
of one or more compounds of Formula I and/or other active agents are known, or will be
apparent in light of this disclosure, to those skilled in this art. For examples of methods of
preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack
Publishing Company, Easton, Pa., 19th Edition (1995).
In addition, in certain embodiments, subject compositions of the present
application maybe lyophilized or subjected to another appropriate drying technique such as
spray drying. The subject compositions may be administered once, or may be divided into a
number of smaller doses to be administered at varying intervals of time, depending in part on
the release rate of the compositions and the desired dosage.
Formulations useful in the methods provided herein include those suitable for oral,
nasal, topical (including ophthalmic, buccal and sublingual), rectal, vaginal, aerosol and/or
parenteral administration. The formulations may conveniently be presented in unit dosage
form and may be prepared by any methods well known in the art of pharmacy. The amount of
the compound that may be combined with a carrier material/excipient to produce a single
dose may vary depending upon the subject being treated, and the particular mode of
administration.
Methods of preparing these formulations or compositions include the step of
bringing into association compound with the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are prepared by uniformly and intimately bringing
into association a compound with liquid carriers, or finely divided solid carriers, or both, and
then, if necessary, shaping the product.
The compounds of Formula I described herein may be administered in inhalant or
aerosol formulations. The inhalant or aerosol formulations may comprise one or more agents,
such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in
inhalation therapy. The final aerosol formulation may for example contain 0.005-90% w/w,
for instance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to the
total weight of the formulation.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees,
powders, granules and the like), the subject composition is mixed with one or more
pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such
as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for
example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or
acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium
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carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5)
solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary
ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol
monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc,
calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the
pharmaceutical compositions may also comprise buffering agents. Solid compositions of a
similar type may also be employed as fillers in soft and hard-filled gelatin capsules using
lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the
subject compositions, the liquid dosage forms may contain inert diluents commonly used in
the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers,
such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut,
sunflower, soybean, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Suspensions, in addition to the active ingredient, may contain suspending agents
such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and
tragacanth, or mixtures thereof.
Dosage forms for transdermal administration include powders, sprays, ointments,
pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be
mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any
preservatives, buffers, or propellants that may be required. For transdermal administration,
the complexes may include lipophilic and hydrophilic groups to achieve the desired water
solubility and transport properties.
The ointments, pastes, creams and gels may contain, in addition to subject
compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc
and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium
silicates and polyamide powder, or mixtures of such substances. Sprays may additionally
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contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such as butane and propane.
Methods of delivering a composition or compositions via a transdermal patch are
known in the art. Exemplary patches and methods of patch delivery are described in US
Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and
6,103,275.
In another embodiment, a transdermal patch may include: a substrate sheet
comprising a composite film formed of a resin composition comprising 100 parts by weight
of a polyvinyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-
ethylene-butylene-styrene copolymer, a first adhesive layer on the one side of the composite
film, and a polyalkylene terephthalate film adhered to the one side of the composite film by
means of the first adhesive layer, a primer layer which comprises a saturated polyester resin
and is formed on the surface of the polyalkylene terephthalate film; and a second adhesive
layer comprising a styrene-diene-styrene block copolymer containing a pharmaceutical agent
layered on the primer layer. A method for the manufacture of the above-mentioned substrate
sheet comprises preparing the above resin composition molding the resin composition into a
composite film by a calendar process, and then adhering a polyalkylene terephthalate film on
one side of the composite film by means of an adhesive layer thereby forming the substrate
sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface
of the polyalkylene terephthalate film.
Another type of patch comprises incorporating the drug directly in a
pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a
suitable backing member, e.g. a polyester backing membrane. The drug should be present at a
concentration which will not affect the adhesive properties, and at the same time deliver the
required clinical dose.
Transdermal patches may be passive or active. Passive transdermal drug delivery
systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver
small-molecule drugs. Many of the other drugs are too large to be delivered through passive
transdermal patches and may be delivered using technology such as electrical assist
(iontophoresis) for large-molecule drugs.
Iontophoresis is a technique employed for enhancing the flux of ionized
substances through membranes by application of electric current. One example of an
iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal
mechanisms by which iontophoresis enhances molecular transport across the skin are (a)
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repelling a charged ion from an electrode of the same charge, (b) electroosmosis, the
convective movement of solvent that occurs through a charged pore in response the
preferential passage of counter-ions when an electric field is applied or (c) increase skin
permeability due to application of electrical current.
Ocular formulations include, but are not limited to, liquid formulations (e.g.,
solutions, suspensions) for topical administration as well as formulation for injection or
ocular insert administration. Preferably, the ocular formulation is formulated for topical
administration such as an eye drop, swab, ointment, gel, or mist (for example, an aerosol or
spray). In one embodiment, the formulation is an eye drop. For ocular formulations, the
pharmaceutically acceptable excipients are selected to be compatible with, and suitable for,
ocular use. Such excipients are well known in the art. In one embodiment, excipients may be
selected to improve the solubility of the agent. Exemplary excipients include, but are not
limited to, buffers, tonicity agents, viscosity agents, preservatives, emulsifiers, salts,
lubricants, polymers, solvents, and other known excipients for ocular pharmaceutical
formulations. Appropriate amounts can be determined by one of ordinary skill in the art, but
non-limiting exemplary amounts (in % by weight) are also provided below.
In one embodiment, the pharmaceutical composition includes one or more buffers
to adjust or maintain the pH of the formulation. In one embodiment, the pH is near
physiological pH (pH of tears is about 7). Thus, the pH of the formulation can be about 6 to
about 8, about 6.5 to about 7.5, about 6.8 to about 7.2, about 7.1 to about 7.5, or about 7. In
another embodiment, the pH is about 5.5. Thus, the pH of the formulation can be about 4 to
about 7, about 4.5 to about 6, about 4.5 to about 5.5, about 5.5 to about 6.5, about 5 to about
6, about 5.25 to about 5.75, or about 5.5. Exemplary buffers include, but are not limited to,
phosphate buffers (e.g., sodium phosphate monobasic monohydrate, sodium phosphate
dibasic anhydrous), borate buffers, and HBSS (Hank's Balanced Salt Solution). In one
embodiment, the buffer is a phosphate buffer. In another embodiment, the buffer is sodium
phosphate monobasic monohydrate and/or sodium phosphate dibasic anhydrous. The buffer
amount (amount of either total buffer or a single buffer excipient) can be 0.1% to about 1.0%,
about 0.2% to about 0.6%, about 0.05% to about 0.5%, about 0.25% to about 0.45%, or about
0.25%, about 0.43%, or about 0.7%. In one embodiment, the buffer is about 0.05% to about
0.5% (e.g., about 0.27%) sodium phosphate monobasic monohydrate and about 0.2% to about
0.6% (e.g., about 0.43%) sodium phosphate dibasic anhydrous.
In one embodiment, the pharmaceutical composition includes one or more tonicity
agents. Although the formulation may be hypertonic or hypotonic, isotonic formulations are
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preferred (260-320 mOsm). Exemplary tonicity agents include, but are not limited to, sodium
chloride. The tonicity agent amount can be about 0.1% to about 5%, about 0.1% to about 2%,
about 0.1% to about 1%, about 0.25% to about 0.75%, about 0.2% to about 0.6%, or about
0.5%. In one embodiment, the tonicity agent is about 0.2% to about 0.6% (e.g., about 0.5%)
sodium chloride.
In one embodiment the pharmaceutical composition includes one or more
viscosity agents to increase the viscosity of the formulation. Exemplary viscosity agents
include, but are not limited to, cellulosic agents (e.g., hydroxypropyl methylcellulose),
polycarbophil, polyvinyl alcohol. In one embodiment, the viscosity agent is a cellulosic
agent, e.g., hydroxypropyl methylcellulose. The viscosity agent amount can be about 0.1% to
about 5%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.1% to about 0.4%, or
about 0.2%. In one embodiment, the viscosity agent is about 0.1% to about 0.4% (e.g., about
0.2%) hydroxypropyl methylcellulose.
In one embodiment, the pharmaceutical composition includes one or more
preservatives to minimize microbial contamination or to enhance shelf life. Exemplary
preservatives include, but are not limited to, benzalkonium chloride (BAK), cetrimonium,
chlorobutanol, edetate disodium (EDTA), polyquaternium-1 (Polyquad®),
polyhexamethylene biguanide (PHMB), stabilized oxychloro complex (PURITE®), sodium
perborate, and SofZia®. The preservative amount may be, e.g., less than about 0.02%, about
0.004% or less, or about 0.005% to about 0.01%.
In one embodiment, the pharmaceutical composition includes one or more
stabilizers. Exemplary stabilizers include, but are not limited to amino acids such as alanine.
The stabilizer amount can be about 0.1% to about 5%, about 0.1% to about 2%, about 0.1%
to about 1%, about 0.25% to about 0.75%, about 0.2% to about 0.6%, or about 0.5%. In one
embodiment, the stabilizer is about 0.2% to about 0.6% (e.g., about 0.5%) alanine.
In one embodiment, the pharmaceutical composition includes one or more
emulsifiers. Exemplary emulsifiers include, but are not limited to, Polysorbate 80.
The compounds described herein can be used in combination with one another,
with other active agents known to be useful in ocular disease, or with adjunctive agents that
may not be effective alone, but may contribute to the efficacy of the active agent. For
example, adjunctive agents might include one or more amino acids or choline (separate from
the lipoic acid compound) to enhance the efficacy of the active agent. The combinations can
be advantageous, e.g., in reducing metabolic degradation.
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The term “co-administer” means to administer more than one active agent, such
that the duration of physiological effect of one active agent overlaps with the physiological
effect of a second active agent. In some embodiments, co-administration includes
administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second
active agent. Co-administration includes administering two active agents simultaneously,
approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each
other), or sequentially in any order. In some embodiments, co-administration can be
accomplished by co-formulation, i.e., preparing a single pharmaceutical composition
including both active agents. In other embodiments, the active agents can be formulated
separately. In another embodiment, the active and/or adjunctive agents may be linked or
conjugated to one another. In one embodiment, one or more pharmaceutical excipients are
selected from the group consisting of buffers, tonicity agents, and viscosity agents.
The pharmaceutical formulation may be packaged for administration by any
means known in the art including, but not limited to, individual dose units or multi-dose
units, e.g., dropper bottles. Multi-dose units may include, for example, about 1 mL to about
100 mL, about 1 mL to about 50 mL, about 1 mL to about 10 mL, about 2 mL to about 7 mL,
or about 5 mL. An individual dose may be, e.g., 1-10 drops, 1-5 drops, or 2-3 drops, wherein
each drop is about 5 to about 50 μl, about 10 to about 30 μl, or about 20 μl. Depending on the
active agent concentration and the condition of the patient, doses may be administered.
EQUIVALENTS
The present disclosure provides among other things compositions and methods for
treating neurological diseases and their complications. While specific embodiments of the
subject disclosure have been discussed, the above specification is illustrative and not
restrictive. Many variations of the systems and methods herein will become apparent to those
skilled in the art upon review of this specification. The full scope of the claimed systems and
methods should be determined by reference to the claims, along with their full scope of
equivalents, and the specification, along with such variations.
INCORPORATION BY REFERENCE
All publications and patents mentioned herein, including those items listed above,
are hereby incorporated by reference in their entirety as if each individual publication or
patent was specifically and individually indicated to be incorporated by reference. In case of
conflict, the present application, including any definitions herein, will control.
EXAMPLES
SYNTHESIS OF COMPOUND OF FORMULA I
18029454_1 (GHMatters) P113464.NZ
Stage 1: Pilocarpine HCl in acetone was treated with sodium hydrogen carbonate
for 18 h at room temperature to get free base of Pilocarpine which upon reaction with (R)-
Lipoic acid at room temperature for 1 h gave Pilocarpine-(R)-Lipoate [5-(((3R,4S)ethyl
oxotetrahydro furanyl)methyl)-l-methyl-lH-imidazolium (R)(l,2-dithiolan
yl)pentanoate] in ~100% yield.
Stage 2: Stage 1 product was recrystallized from ethyl acetate (5 volumes) at 50-
55°C to afford yellow crystalline Pilocarpine-(R)-Lipoate n ~ 80 % yield.
CHARACTERIZATION OF PILOCARPINE-(R)-LIPOATE BY NMR
1H-NMR of Pilocarpine-(R)-Lipoate in DMSO-d6 solvent was obtained, and the
chemical shift value for corresponding protons are provided in the Table 1 hereinbelow.
Table 1: Chemical shift value of 1H-NMR of Pilocarpine-(R)-Lipoate
Chemical shift
Position of the protons
(in δ ppm with multiplicity)
δ 0.99 – 1.02 (3H, t)
δ 1.34 – 1.40 (2H, m)
δ 1.47 – 1.57 (4H, m)
δ 1.62 – 1.71 (2H, m)
δ 1.84 – 1.90 (1H, m)
δ 2.18 – 2.22 (2H, t)
27 Protons corresponding to
δ 2.31 – 2.43 (2H, m)
aliphatic carbons
δ 2.63 – 2.85 (3H, m)
δ 3.08– 3.21 (2H, m)
δ 3.53 (3H, s)
δ 3.59 - 3.63 (1H, m)
δ 3.94 – 3.97 (1H, m)
δ 4.18 – 4.22 (1H, m)
δ 6.71 (1H, s)
2 Protons corresponding to aromatic
carbons of the imidazole ring
δ 7.51 (1H, s)
1 Proton corresponding to
δ 12.02 (1H, bs)
quaternary NH
18029454_1 (GHMatters) P113464.NZ
OCULAR PHARMACOKINETIC STUDY
A pharmacokinetics study was conducted on male New Zealand white rabbits to
evaluate the ocular pharmacokinetics of CLX-156 (Pilocarpine-(R)-Lipoate) formulation.
Animals were topically administered with 50 μL of CLX-156 in each eye, and the aqueous
humour and blood samples were collected followed by sacrifice of the animals for collection
of lens, cornea and iris region at a pre-determined time.
Composition Per microlitre
Pilocarpine-(R)-Lipoate 29.4 mg*
Glycerin 27 mg
L-Alanine 5 mg
Water for Injection….qs 1 mL
*Approximate equivalent to 14.7 mg of R-lipoate
The aqueous humour and tissue concentration of Pilocarpine and (R)-Lipoic acid
were measured at 0.5h, 1h, 2h, 4h and 8h in 3 animals/time point/group (as provided in Table
2 and Table 3 hereinbelow). Further, (R)-Lipoic acid concentration was measured in the lens
region, and Pilocarpine concentration was measured in iris region of each of the treated
animals (as provided in Table 2 and Table 3). All the samples were analyzed using LCMS-
MS by a fit for purpose method.
Table 2: Concentration of (R)-Lipoic acid in aqueous humour and lens region, observed
during the pharmacokinetics study.
Concentration of (R)-Lipoic acid Concentration of (R)-
Parameters
in aqueous humour Lipoic acid in lens region
21.067 0.122
(μg/mL) (μg/g)
0.50 0.50
(h) (h)
17.271 0.364
last
(μg*h/mL) (μg*h/g)
Table 3: Concentration of Pilocarpine in aqueous humour and iris region, observed
during the pharmacokinetics study.
18029454_1 (GHMatters) P113464.NZ
Concentration of
Concentration of Pilocarpine in
Pilocarpine in
Parameters
aqueous humour
iris region
6.48 1.962
(μg/mL) (μg/g)
0.50 0.50
(h) (h)
6.359 1.491
last
(μg*h/mL) (μg*h/g)
From the aforesaid study and results obtained therefrom, following observations
were made – (a) maximum concentration of (R)-Lipoic acid, present in the aqueous humour
and lens region was 21.067 μg/mL and 0.122 μg/g, respectively; (b) the (R)-Lipoic acid was
detectable up to 2 to 4h in the aqueous humor, however, sustained level of (R)-Lipoic acid
was observed from 2 to 8h in the lens region, in animals treated with CLX-156 formulation;
(c) maximum concentration of pilocarpine present in the aqueous humour and iris region
were found to be 6.48 μg/mL and 1.962 μg/g, respectively; (d) pilocarpine was detectable up
to 4h and 2h in aqueous humour and iris region in animals treated with CLX-156 formulation.
The present disclosure provides compounds that provide better therapeutic benefit
to patients and individuals suffering from eye disorders. The compound(s) of Formula I of the
present disclosure aid(s) in reduction of elevated intraocular pressure (IOP) in patients with
open-angle glaucoma or ocular hypertension, in management of acute angle-closure
glaucoma, in prevention of postoperative elevated IOP associated with laser surgery, and
induction of miosis, and improves lens elasticity and enhances accommodation of the eye in
Presbyopics. The compound(s) of Formula I advantageously effects stabilization of lipoic
acid and improves bioavailability thereof in ocular tissues. Accordingly, compositions of the
present disclosure, including one or more compounds of Formula I, exhibits enhanced
therapeutic activity and efficacy including superior safety and tolerability.
While the foregoing describes various embodiments of the invention, other and
further embodiments of the invention may be devised without departing from the basic scope
thereof. The scope of the invention is determined by the claims that follow. The invention is
not limited to the described embodiments, versions or examples, which are included to enable
a person having ordinary skill in the art to make and use the invention when combined with
information and knowledge available to the person having ordinary skill in the art.
18029454_1 (GHMatters) P113464.NZ
Claims (9)
1. Use of a compound of formula I Formula I or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer, or polymorph thereof, wherein, X represents or , for the manufacture of a medicament for treating an eye disorder or complications thereof.
2. The use of claim 1, wherein said compound of formula I is selected from: 18029454_1 (GHMatters) P113464.NZ , and
3. The use of claim 1 or 2, wherein said compound is formulated for oral, nasal, topical, rectal, vaginal, aerosol or parenteral administration of said compound.
4. The use of any of claims 1 to 3, wherein said compound is formulated with a pharmaceutically acceptable excipient. 18141522_1 (GHMatters) P113464.NZ
5. The use of any of claims 1 to 4, wherein said compound is formulated for topical use in a form of an eye drop, a swab, an ointment, a gel or a mist.
6. The use as claimed in any of claims 1 to 5, wherein said compound is formulated for topical use in the eye.
7. The use as claimed in any of claims 1 to 6, wherein the medicament comprises a therapeutically effective amount of said compound in the range of from 0.001mg to 1000mg.
8. The use as claimed in any of claims 1 to 7, wherein said eye disorder is selected from the group consisting of macular degeneration, cataract, glaucoma, diabetic retinopathy, dry eye, ocular neuritis, retinitis pigmentosa and presbyopia.
9. A method of synthesis of the compound as defined in claim 1 or 2, the method comprising treating pilocarpine HCl in acetone with hydrogen carbonate to obtain free base of pilocarpine, further the free base of pilocarpine is reacted with lipoic acid. 18141522_1 (GHMatters) P113464.NZ
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN201741041231 | 2017-11-17 | ||
IN201741041231 | 2017-11-17 | ||
PCT/IB2018/057342 WO2019097318A1 (en) | 2017-11-17 | 2018-09-22 | Compositions and methods for the treatment of eye disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ763688A NZ763688A (en) | 2021-10-29 |
NZ763688B2 true NZ763688B2 (en) | 2022-02-01 |
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