U.S. patent application number 14/212838 was filed with the patent office on 2014-09-18 for diclofenac parenteral compositions.
This patent application is currently assigned to DR. REDDY'S LABORATORIES, INC.. The applicant listed for this patent is DR. REDDY'S LABORATORIES, INC.. Invention is credited to Andrew Xian Chen, Hailiang Chen, Franklin Okumu.
Application Number | 20140275261 14/212838 |
Document ID | / |
Family ID | 50483604 |
Filed Date | 2014-09-18 |
United States Patent
Application |
20140275261 |
Kind Code |
A1 |
Okumu; Franklin ; et
al. |
September 18, 2014 |
DICLOFENAC PARENTERAL COMPOSITIONS
Abstract
The present application provides parenteral compositions of
diclofenac or its pharmaceutically acceptable salt and methods for
making and using such compositions. Some of the compositions of the
present application has one or more following properties: (1) ready
to be injectable, (2) in the form of an oil-water emulsion, (3)
stable under appropriate storage conditions, (4) containing
therapeutically effective amount of diclofenac or its
pharmaceutically acceptable salt, (5) sterilizable by filtration
(6) containing components acceptable by regulatory agencies (e.g.
the FDA), (7) containing low oil content and thus not exacerbating
hyperlipidemia, and (8) is neither hypoallergenic nor vein
irritating.
Inventors: |
Okumu; Franklin;
(Morristown, NJ) ; Chen; Andrew Xian; (San Diego,
CA) ; Chen; Hailiang; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DR. REDDY'S LABORATORIES, INC. |
Bridgewater |
NJ |
US |
|
|
Assignee: |
DR. REDDY'S LABORATORIES,
INC.
Bridgewater
NJ
|
Family ID: |
50483604 |
Appl. No.: |
14/212838 |
Filed: |
March 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61793356 |
Mar 15, 2013 |
|
|
|
Current U.S.
Class: |
514/567 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 31/196 20130101; A61K 47/26 20130101; A61K 9/1075 20130101;
A61K 47/24 20130101; A61K 31/196 20130101; A61K 2300/00 20130101;
A61K 47/44 20130101; A61K 45/06 20130101 |
Class at
Publication: |
514/567 |
International
Class: |
A61K 9/107 20060101
A61K009/107; A61K 31/196 20060101 A61K031/196 |
Claims
1. A parenteral composition in the form of oil-in-water emulsion
that comprises: (a) diclofenac or its pharmaceutically acceptable
salt, (b) an oil component, (c) a phospholipid component, and (d)
water.
2. The composition of claim 1, wherein the oil component comprises
a monoglyceride, a diglyceride, a triglyceride, or a mixture
thereof.
3. The composition of claim 2, wherein the triglyceride is medium
chain triglycerides.
4. The composition of claim 1, wherein the oil component comprises
combination of vegetable oil and a medium chain triglyceride.
5. The composition of claim 1, further comprises a
cryoprotectant.
6. The composition of claim 1, wherein the phospholipid component
comprises a phosphatidyl choline, lecithin,
phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid,
or a mixture thereof.
7. The composition of claim 6, wherein the lecithin comprises soy
lecithin and egg lecithin.
8. The composition of claim 1, wherein the composition optionally
comprise additives such as acidifying, alkalizing, antioxidant,
buffering, chelating, complexing and solubilizing agents,
antioxidants and antimicrobial preservatives, suspending and/or
viscosity modifying agents, tonicity modifying agents, and other
biocompatible materials or therapeutic agents.
9. The composition of any of the claims 1-8, wherein the
composition has an osmolality of at least 250 mOsm.
10. The composition of any of the claims 1-9, comprises at least
one tonicity modifying agent.
11. The composition of any of the claims 1-10, is vein
non-irritable.
12. The composition of any of the claims 1-11, is filter
sterilizable.
13. The composition of claim 5, wherein the cryoprotectant is
sucrose.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to parenteral composition
comprising diclofenac or its pharmaceutically acceptable salt. The
present invention also provides methods for preparing and using
such parenteral composition.
BACKGROUND
[0002] In postoperative pain management, health care professionals
generally are required to administer opioids, which is a potent
analgesic. Although opioids have proven pain management properties,
they also have a significant number of potential side effects,
including nausea, vomiting, constipation, pruritus, urinary
retention, respiratory depression, and sedation. On the other hand
nonsteroidal, anti-inflammatory drugs (NSAIDs) provide
anti-inflammatory and analgesic effects, but they are limited to
oral or rectal administrations greatly limiting the use of NSAIDs
under postoperative conditions. Currently, ketorolac tromethamine
is only NSAID that can be administered intravenously or
intramuscularly, but its chronic use is limited due to GI
toxicity.
[0003] Diclofenac, chemical name
o-(2,6-dichloroanilino)phenylacetic acid, is known as a potent
analgesic and antirheumatic and is described, in U.S. Pat. No.
3,558,690. Diclofenac is sold commercially as immediate release,
delayed release (enteric coated) and extended-release
(sustained-release) dosage forms. Due to the relatively large
"first-pass-effect" of the substance and for faster flooding it is
desirable to use injection solutions, in which an amount of 75 mg
should be used per injection. For intramuscular/intravenous
injections, the volume is to be kept as low as possible.
[0004] Due to the relatively poor solubility of diclofenac in water
an aqueous injection solution with a reasonable volume cannot be
obtained. Further, diclofenac is relatively instable in
solution.
[0005] Examples of Diclofenac injectable compositions known in the
art are:
[0006] U.S. Pat. No. 4,593,044 to Merckle GmbH describes a
ready-to-use injection solution with as high an active compound
content as possible in a small volume. The solubilization of
diclofenac is achieved by using lysinate salt form of diclofenac
and solubilizers such as propylene glycol, glycerol or
polyoxyalkylenes.
[0007] U.S. Pat. No. 5,283,067 to Ciba-Geigy Corporation describes
a lyophilized formulation comprising micronized diclofenac sodium,
which is meant for intramuscular injection. This lyophilized
formulation, after being suspended in an aqueous liquid vehicle, is
converted into a dosage form for parenteral administration.
[0008] U.S. Pat. No. 5,389,681 to Ciba-Geigy Corporation describes
a sterilizable parenteral solution comprising a diclofenac salt and
stabilizers, such as ethyl lactate combined with glutathione or
N-acetylcysteine.
[0009] U.S. Pat. No. 7,423,028 to IbsalnstitutBiochemique S.A.
discloses aqueous solution comprising a complex of diclofenac and
hydroxypropyl-.beta.-cyclodextrin in the molar ratio of 1:1 and
1:1.3. The composition further comprises polysorbate in lower
concentration.
[0010] Although several of above references disclose various
diclofenac injectable compositions, there exists a long felt need
to develop a stable composition that is ready-to-inject
intramuscularly or intravenously and does not cause any irritation
to the tissues at the site of the injection.
[0011] It has been challenging to design a stable diclofenac
parenteral composition that can be readily administered (without
dilution or forming suspension) to alleviate pain or inflammation,
especially in unconscious/unresponsive patients. Further the
composition should not be inducing GI ulceration or bleeding after
surgery, and other concurrent damage to the GI membranes or
layers.
[0012] The present inventors provided a composition meant for
parenteral administration comprising diclofenac or its
pharmaceutically acceptable salt to a subject that can be used in
postoperative pain management, with minimal or no side-effects.
SUMMARY
[0013] The present application provides parenteral compositions of
diclofenac or its pharmaceutically acceptable salt and methods for
making and using such compositions.
[0014] The compositions of the present application has one or more
following properties: (1) ready to be injectable, (2) in the form
of an oil-water emulsion, (3) stable under appropriate storage
conditions, (4) containing therapeutically effective amount of
diclofenac or its pharmaceutically acceptable salt, (5)
sterilizable by filtration (6) containing components acceptable by
regulatory agencies (e.g. the FDA), (7) containing low oil content
and thus not causing hyperlipidemia, and (8) not hypoallergenic or
vein irritating.
[0015] In one aspect, the present application provides a parenteral
composition in the form of oil-in-water emulsion that
comprises:
[0016] (a) diclofenac or its pharmaceutically acceptable salt,
[0017] (b) an oil component,
[0018] (c) a phospholipid component, and
[0019] (d) water.
[0020] In another aspect, the present application provides a method
of treating inflammation, pain and/or fever in a mammal, which
comprises parenterally administering the aforesaid parenteral
composition to the mammal
DETAILED DESCRIPTION
[0021] The present application will be described in more detail
below.
[0022] While the specification concludes with the claims
particularly pointing and distinctly claiming the invention, it is
believed that the present invention will be better understood from
the following description. The present invention can comprise (open
ended) or consist essentially of the components of the present
invention as well as other ingredients or elements described
herein. As used herein, "comprising" means the elements recited, or
their equivalent in structure or function, plus any other element
or elements which are not recited. The terms "having" and
"including" are also to be construed as open ended unless the
context suggests otherwise. All ranges recited herein include the
endpoints, including those that recite a range "between" two
values.
DEFINITIONS
[0023] The terms as used herein have the following meanings:
[0024] Diclofenac as used herein also encompasses pharmaceutically
acceptable salts. The solid state form of diclofenac used in the
composition of the present invention is not critical. For example,
diclofenac can be amorphous or crystalline.
[0025] The term "pharmaceutically acceptable salts" as used herein
includes those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, which are well known in the art. The salts
can be prepared in situ during the final isolation and purification
of the compounds of the invention, or separately by reacting the
pharmaceutically active substance having a free base function with
a suitable organic acid or inorganic acid.
[0026] Examples of pharmaceutically acceptable nontoxic acid
addition salts include, but not limited to, salts of an amino group
formed with inorganic acids such as hydrochloric acid, hydrobromic
acid, phosphoric acid, sulfuric acid and perchloric acid or with
organic acids such as acetic acid, maleic acid, tartaric acid,
citric acid, succinic acid lactobionic acid or malonic acid or by
using other methods used in the art such as ion exchange
techniques. Other pharmaceutically acceptable salts include, but
not limited to, adipate, alginate, ascorbate, aspartate,
benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, diethylamine, ethanesulfonate,
formate, fumarate, glucoheptonate, glycerophosphate, gluconate,
hemisulfate, heptanoate, hexanoate, hydroiodide,
2-hydroxy-ethanesulfonate, lactate, laurate, lauryl sulfate,
malate, maleate, malonate, methanesulfonate,
2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate,
palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, stearate, succinate,
sulfate, tartarate, thiocyanate, p-toluenesulfonate, undecanoate,
valerate salts, and the like. Representative alkali or alkaline
earth metal salts include sodium, lithium, potassium, calcium,
magnesium, and the like. Further pharmaceutically acceptable salts
include, when appropriate, nontoxic ammonium, quaternary ammonium,
and amine cations formed using counterions such as halide,
hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having
from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
[0027] The phrase `therapeutically effective amount` as used
herein, means an amount of diclofenac, sufficient to reduce the
pain, but low enough to avoid serious side effects (at a reasonable
benefit/risk ratio), within the scope of sound medical judgment.
The effective amount of the diclofenac will vary with the
particular condition being treated, the age and physical condition
of the patient being treated, the severity of the condition, the
duration of the treatment, the nature of concurrent therapy, and
like factors within the knowledge and expertise of the attending
physician.
[0028] The terms such as `about`, `up to`, `generally`,
`substantially` and the like are to be construed as modifying a
term or value such that it is not an absolute. Such terms will be
defined by the circumstances and the terms that they modify as
those terms are understood by those of skill in the art. This
includes, at very least, the degree of expected experimental error,
technical error and instrumental error for a given experiment,
technique or an instrument used to measure a value.
[0029] The term "oil-in-water emulsion" as used herein, refers to a
colloidal dispersion system in which liquid oil is dispersed in
small droplets (the discrete phase, also referred to as "the oil
phase") in an aqueous medium (the continuous phase, also referred
to as "the aqueous phase"), wherein in excess of 80% of the drug is
dissolved and remains in the oil droplets. In certain embodiments,
greater than 85%, 90%, 95% or 99% of the drug is present in the oil
phase.
[0030] The term "oil" as used herein, means a general sense to
identify hydrocarbon derivatives, carbohydrate derivatives, or
similar organic compounds that are liquid at body temperatures,
e.g., about 37 C., and are pharmacologically acceptable in
injectable compositions. It includes glycerides or
non-glycerides.
[0031] The term "oil component" refers to an oil, or a combination
of multiple oils.
[0032] In certain embodiments, the oil component of the present
application comprises a monoglyceride, a diglyceride, a
triglyceride, or a mixture thereof. In certain embodiments, the oil
component comprises an ester formed between one or more fatty acids
and an alcohol other than glycerol.
[0033] In certain embodiments, the oil refers to a "vegetable oil".
Vegetable oil refers to oil derived from plant seeds or nuts.
Exemplary vegetable oils include, but are not limited to, almond
oil, borage oil, black currant seed oil, corn oil, safflower oil,
soybean oil, sesame oil, cottonseed oil, peanut oil, olive oil,
rapeseed oil, coconut oil, palm oil, canola oil, castor oil, etc.
Vegetable oils are typically "long-chain triglycerides," formed
when three fatty acids (usually about 14 to about 22 carbons in
length, with unsaturated bonds in varying numbers and locations,
depending on the source of the oil) form ester bonds with the three
hydroxyl groups on glycerol. In certain embodiments, vegetable oils
of highly purified grade (also called "super refined") are
generally used to ensure safety and stability of oil-in-water
emulsions. In certain embodiments, hydrogenated vegetable oils,
which are produced by controlled hydrogenation of the vegetable
oil.
[0034] In certain embodiments, the oil refers to "medium chain
triglycerides". Medium chain triglycerides (MCT's) are another
class of triglyceride oil that can be either naturally derived or
synthetic. MCT's are made from fatty acids that are usually about 8
to about 12 carbons in length. Like vegetable oils, MCT's have been
used extensively in emulsions designed for injection. Such oil is
commercially available as Miglyol 812 from SASOL GmbH, Germany,
CRODAMOL GTCC-PN from Croda Inc. of Parsippany, N.J., or Neobees
M-5 oil from PVO International, Inc., of Boonton, N.J. Other
low-melting medium chain oils may also be used in the present
invention.
[0035] In one aspect, the present application provides a parenteral
composition in the form of oil-in-water emulsion that
comprises:
[0036] (a) diclofenac or its pharmaceutically acceptable salt,
[0037] (b) an oil component,
[0038] (c) a phospholipid component, and
[0039] (d) water.
[0040] In one embodiment of the above aspect, the present
application relates to a parenteral composition in the form of
oil-in-water emulsion that comprises:
[0041] (a) diclofenac or its pharmaceutically acceptable salt,
[0042] (b) a medium chain triglyceride,
[0043] (c) one or more phospholipids, and
[0044] (d) water.
[0045] In another aspect, the present application provides a
parenteral composition in the form of oil-in-water emulsion that
comprises:
[0046] (a) diclofenac or its pharmaceutically acceptable salt,
[0047] (b) an oil component,
[0048] (c) a phospholipid component,
[0049] (d) at least one tonicity modifying agent, and
[0050] (e) water.
[0051] In another aspect, the present application provides a
parenteral composition in the form of oil-in-water emulsion that
comprises:
[0052] (a) diclofenac or its pharmaceutically acceptable salt,
[0053] (b) an oil component,
[0054] (c) a phospholipid component,
[0055] (d) at least one antioxidant, and
[0056] (e) water.
[0057] In another aspect, the present application provides a
parenteral composition in the form of oil-in-water emulsion that
comprises:
[0058] (a) diclofenac or its pharmaceutically acceptable salt,
[0059] (b) medium chain triglycerides
[0060] (c) a phospholipid component,
[0061] (d) acryoprotectant,
[0062] (d) at least one tonicity modifying agent, and
[0063] (e) water.
[0064] In one embodiment of the present application, medium chain
triglyceride is selected from Miglyol 812.
[0065] In another embodiment of the present application, a
phospholipid is selected from egg lecithin (such as LIPOID E-80) or
soy lecithin (such as LIPOID S-100).
[0066] In another embodiment the composition comprises an oil
component and is vegetable oil.
[0067] In another embodiment the composition is selected from
almond oil, borage oil, black currant seed oil, corn oil, safflower
oil, soybean oil, sesame oil, cotton seed oil, peanut oil, olive
oil, rapeseed oil, coconut oil, palm oil, canola oil, and castor
oil.
[0068] In another embodiment, vegetable oil is soybean oil.
[0069] In another aspect, the present application provides a
parenteral composition in the form of oil-in-water emulsion that
comprises:
[0070] (a) diclofenac sodium,
[0071] (b) MIGLYOL 812,
[0072] (c) Egg lecithin,
[0073] (d) EDTA disodium dehydrate USP, and
[0074] (e) water.
[0075] In one embodiment, the above composition comprises
cryoprotectant.
[0076] In another embodiment, the cryoprotectant is sucrose.
[0077] In one embodiment, the above composition comprises
antioxidant.
[0078] In another embodiment, the antioxidant is sodium sulfite,
sodium bisulfate, sodium metabisulfite, butylatedhydroxytoluene,
butylatedhydroxyanisole or a mixture thereof.
[0079] In another aspect, the present application provides a
parenteral composition in the form of oil-in-water emulsion that
comprises:
[0080] (a) diclofenac sodium,
[0081] (b) MIGLYOL 812,
[0082] (c) Soy lecithin,
[0083] (d) EDTA disodium dehydrate USP, and
[0084] (e) water.
[0085] In one embodiment, the above composition comprises
cryoprotectant.
[0086] In another embodiment, the cryoprotectant is Sucrose.
[0087] In another embodiment, the present application relates to a
parenteral composition in the form of oil-in-water emulsion that
comprises: [0088] (a) diclofenac or its pharmaceutically acceptable
salt, [0089] (b) an oil component comprising combination of
vegetable oil and a medium chain triglyceride, [0090] (c) one or
more phospholipids, and [0091] (d) water.
[0092] In certain embodiments, the combinations of vegetable oil
and MCT oil are used in the present application. Such combinations
generally have long record of safe use in combination in injectable
emulsions and provide the superior stability for the emulsion. The
specific type of vegetable oil used (i.e., soy bean oil, corn oil,
or safflower oil, etc.) is not critical, so long as it is safe,
well tolerated, pharmaceutically acceptable, chemically stable and
provides emulsion droplets having a desired size range.
[0093] In certain embodiments, the vegetable oil to medium chain
triglyceride ratio in an oil-in-water emulsion is within a range of
about 9:1 to about 1:1, by weight. In certain embodiments, the
ratio of the vegetable oil to MCT oil is about 9:1, 8:1, 7:1, 6:1,
5:1, 4:1, 3:1, 2:1 or 1:1.
[0094] The content of the total oil component may be within a range
of 1% to 50%, by weight. In certain embodiments, the total
concentration of the oil component is about at most about 5%, 10%,
15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% by weight. In certain
embodiments, the oil-in-water emulsions comprise oil in an amount
that does not result in hyperlipidemia when administered to a
subject.
[0095] In certain embodiments, the average diameter of the droplets
in the emulsions of the composition is from about 50 to about 250
nm. In certain embodiments, the average diameter of the oil
droplets may be within a range of about 50 to about 200 nm, or
about 50 nm to about 150 nm. In certain embodiments, the average
droplet diameter is about 50, 60, 70, 80, 90, 100, 110, 120, 130,
140, 150, 160, 170, 180, 190 or 200 nm.
[0096] In certain embodiments, the composition of the present
application may be filter sterilized using via 0.2 .mu.m
filters.
[0097] The term "filter sterilized" means a composition that has
passed through a filter having a pore size sufficiently small to
result the composition free or substantially free of bacterial
contaminants. Bacteria generally range in size from about 0.2 .mu.m
to about 600 .mu.m, with most bacteria having a size in the range
of about 1 .mu.m to about 10 .mu.m. Filters having pore size of
about 0.22 .mu.m or less are considered to produce sterile
filtrates and are sufficiently small to result in a filter
sterilized composition. Such filters and filter kits are available
from Millipore Corporate, as well as other manufacturers.
[0098] An "emulsifier" refers to a compound that prevents the
separation of the injectable emulsion into individual oil and
aqueous phases. Emulsifiers useful in the present invention
generally are (1) compatible with the other ingredients of the
oil-in-water emulsions of the present invention, (2) do not
interfere with the stability or efficacy of the diclofenac in the
emulsions, (3) are stable and does not deteriorate in the
preparation, and (4) are non-toxic.
[0099] Suitable emulsifiers include, but are not limited to,
propylene glycol mono- and di-fatty acid esters,
polyoxyethylenesorbitan fatty acid esters, polyoxyethylene fatty
acid esters, polyoxyethylene-polyoxypr-opylene co-polymers and
block co-polymers, salts of fatty alcohol sulphates, sorbitan fatty
acid esters, esters of polyethylene-glycol glycerol ethers, oil and
wax based emulsifiers, glycerol monostearate, glycerinesorbitan
fatty acid esters and phospholipids.
[0100] A "phospholipid" refers to a triester of glycerol with two
fatty acids and one phosphate ion. Exemplary phospholipids useful
in the present invention include, but are not limited to,
phosphatidyl choline, lecithin (a mixture of choline ester of
phosphorylated diacylglyceride), phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid with about 4 to about 22
carbon atoms, and more generally from about 10 to about 18 carbon
atoms and varying degrees of saturation. The "phospholipid
component" can be either a single phospholipid or a mixture of
several phospholipids. The phospholipids should be acceptable for
the chosen route of administration.
[0101] The `phospholipids` can be of natural origin or
synthesized.
[0102] Naturally occurring lecithin is a mixture of the
diglycerides of stearic, palmitic, and oleic acids, linked to the
choline ester of phosphoric acid, commonly called
phosphatidylcholine, and can be obtained from a variety of sources
such as eggs and soya beans. Soy lecithin and egg lecithin
(including hydrogenated versions of these compounds) have a long
history of safety, possess combined emulsification and
solubilization properties, and tend to be broken down into
innocuous substances more rapidly than most synthetic surfactants.
Commercially available soya phospholipids are the CENTROPHASE and
CENTROLEX products marketed and sold by Central Soya, PHOSPHOLIPON
from Phospholipid GmbH, Germany, LIPOID by Lipoid GmbH, Germany,
and EPIKURON by Degussa.
[0103] Phospholipids can also be synthesized. Exemplary common
synthetic phospholipids include, but not limited to Diacylglycerols
such as 1,2-Dilauroyl-sn-glycerol (DLG),
1,2-Dimyristoyl-sn-glycerol (DMG), 1,2-Dipalmitoyl-sn-glycerol
(DPG), 1,2-Distearoyl-sn-glycerol (DSG); Phosphatidic Acids such as
1,2-Dimyristoyl-sn-glycero-3-phosphatidic acid, sodium salt
(DMPA,Na), 1,2-Dipalmitoyl-sn-glycero-3-phosphatidic acid, sodium
salt (DPPA,Na), 1,2-Distearoyl-sn-glycero-3-phosphatidic acid,
sodium salt-(DSPA,Na); Phosphocholines such as
1,2-Dilauroyl-sn-glycero-3-phosphocholine (DLPC),
1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC),
1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),
1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC),
1,2-Distearoyl-sn-glycero-3-phosphocholine (DSPC);
Phosphoethanolamines such as
1,2-Dilauroyl-sn-glycero-3-phosphoethanolamine (DLPE),
1,2-Dimyristoyl-sn-glycero-3-phosphoethanolamine (DMPE),
1,2-Dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE),
1,2-Distearoyl-sn-glycero-3-phosphoethanolamine (DSPE);
Phosphoglycerols such as
1,2-Dilauroyl-sn-glycero-3-phosphoglycerol, sodium salt (DLPG),
1,2-Dimyristoyl-sn-glycero-3-phosphoglycerol, sodium salt (DMPG),
1,2-Dimyristoyl-sn-glycero-3-phospho-sn-1-glycerol, ammonium salt
(DMP-sn-1-G,NH.sub.4),
1,2-Dipalmitoyl-sn-glycero-3-phosphoglycerol, sodium salt
(DPPG,Na), 1,2-Distearoyl-sn-glycero-3-phosphoglycerol, sodium salt
(DSPG,Na), 1,2-Distearoyl-sn-glycero-3-phospho-sn-1-glycerol,
sodium salt (DSP-sn-1G,Na); Phosphoserines such as
1,2-Dipalmitoyl-sn-glycero-3-phospho-L-serine, sodium salt
(DPPS,Na); Mixed Chain Phospholipids such as
1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC),
1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol, sodium salt
(POPG,Na), 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol,
ammonium salt
[0104] POPG,NH.sub.4); Lysophospholipids such as
1-Palmitoyl-2-lyso-sn-glycero-3-phosphocholine (P-lyso-PC),
1-Stearoyl-2-lyso-sn-glycero-3-phosphocholine (S-lyso-PC);
Pegylated Phospholipids such as
N-(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DPPE,
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt,
N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DSPE,
1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt,
N-(Carbonyl-methoxypolyethyleneglycol 5000)-MPEG-5000-DPPE,
1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine, sodium salt,
N--(Carbonyl-methoxypolyethyleneglycol 750)-MPEG-750-DSPE,
1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt,
N--(Carbonyl-methoxypolyethyleneglycol 2000)-MPEG-2000-DSPE,
1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt.
[0105] The amount of phospholipids, by weight may be within a range
of about 0.5% to about 6%. In certain embodiments, the
phospholipids in the emulsions are at a concentration, by weight,
about 0.5%, 1.0%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5% or 6% by
weight.
[0106] In certain embodiments, the ratio of the oil component to
phospholipid in the emulsions may range from about 1:20 to about
20:1 (w/w).
[0107] The compositions of the present invention may optionally
contain additives such as acidifying, alkalizing, buffering,
chelating, complexing and solubilizing agents, antioxidants and
antimicrobial preservatives, suspending and/or viscosity modifying
agents, tonicity modifying agents, and other biocompatible
materials or therapeutic agents. Such agents generally are present
in the aqueous phase of the emulsion. In certain embodiments, such
additives assist in stabilizing the emulsion or the drug in the
emulsion and in rendering the composition biocompatible.
[0108] The aqueous phase generally has an osmolality of
approximately 300 mOsm and may include potassium or sodium
chloride, trehalose, sucrose, sorbitol, glycerol, mannitol,
polyethylene glycol, propylene glycol, albumin, amino acid and
mixtures thereof. In certain embodiments, a tonicity of at least
250 mOsm is achieved with an agent that also increases viscosity,
such as sorbitol or sucrose. The compounds useful for modifying
osmolality of the emulsions of the present invention are referred
to "tonicity modifiers" or "osmolality modifiers."
[0109] In certain embodiments, the concentration of the tonicity
modifying agent is sufficient for providing tonicity of at least
250 mOsm and may be present in the range of about 1% to about 40%
w/w, about 2% to about 30% w/w and about 5% to about 20% w/w.
[0110] "Antioxidants" used in this invention refers primarily to
metal ion chelators and/or reducing agents that are safe to use in
an injectable product. A metal ion chelator functions as an
antioxidant by binding to metal ions and thereby reduces the
catalytic effect of metal ion on the oxidation reaction of the
drug, oil or phospholipid components. Metal chelators useful in
this invention include, but are not limited to, EDTA, glycine and
citric acid or salts thereof.
[0111] In another embodiment, the reducing agent useful in this
invention include, but are not limited tosulfite, bisulfite,
metabisulfite, butylatedhydroxytoluene (BHT),
butylatedhydroxyanisole (BHT) or a mixture thereof. A reducing
agent inhibits oxidation reaction of the drug, oil or phospholipid
components and prevents discoloration of the emulsions.
[0112] In certain embodiments, the concentration of antioxidant in
the emulsion can be from about 0.0001% to about 1% w/v. In certain
embodiments, the concentration is from about 0.001% to about 0.1%
w/v, or from about 0.001% to about 0.005% w/v.
[0113] In certain embodiments, the concentration of EDTA in the
emulsion can be from about 0.0001% to about 0.01% w/v.
[0114] In certain embodiments, the sulfite, bisulfite, or
metabisulfiteis a sodium or potassium salt.
[0115] In certain embodiments, the concentration of sulfite,
bisulfite, or metabisulfiteis from about 0.001% to about 0.2% w/v,
or from about 0.01% to about 0.1% w/v.
[0116] In certain embodiments, the concentration of
butylatedhydroxytoluene (BHT), butylatedhydroxyanisole (BHT) is
from about 0.0001% to about 0.002% w/v.
[0117] As used herein, the term "preservatives" refers to agents
that can prevent microbial growth in the emulsion formulation of
this invention. The oil-in-water emulsions of the present
application may be conducive for microbial growth or contamination.
Therefore, a preservative may be desirable in the composition,
especially for a vialed product that is intended to provide
multiple doses where multiple punctures of the vial stopper by
syringe needles are needed. The preservatives useful for this
invention include, but are not limited to, sodium edetate (EDTA),
sodium metabisulfite, sodium benzoate, benzyl alcohol, bronopol,
parabens, cresol, phenol, phenoxyethanol, phenylmercuric acetate,
phenylmercuric borate, phenylmercuric nitrate, sorbate, benzoate,
sorbic acid thimerosal, cetrimide, chlorhexidine, chlorobutanol,
chlorocresol, benzalkonium chloride and benzethonium chloride or a
mixture thereof.
[0118] The aqueous phase of an oil-in-water emulsion of the present
composition is usually at a concentration of at least about 70% by
weight of the emulsion composition. In certain embodiments, the
aqueous phase is at a concentration of at least about 75%, 80%,
85%, 90% or 95%, by weight of the emulsion composition.
[0119] In certain embodiments, the components of the oil-in-water
emulsion (e.g., the drug, an oil component, a phospholipid
component, a stabilizer, and a tonicity modifier) are safe, well
tolerated, and acceptable by the FDA for intravenous/intramuscular
injection.
[0120] A component of oil-in-water emulsions is regarded as "safe"
if it does not cause undesired systemic or local reactions (e.g.,
anaphylactic shock) in patients. A component of oil-in-water
emulsions is regarded as "well tolerated" if it does not result in
substantially adverse effects at the injection site, such as
phlebitis, vein inflammation or vein irritation.
[0121] In certain embodiments, the oil-in-water emulsions of the
present composition are vein non-irritable. "Vein non-irritable"
refers to the property of a compound or composition, when
administered intravenously, does not cause substantial irritation
at the injection site, as evident by, for example, thickened skin,
necrotic skin, local redness, local swelling, venous dilation with
blood clog formation, or venous embolism with subcutaneous
inflammation.
[0122] In certain embodiments, the present compositions are both
chemically and physically stable. A composition is "chemically
stable" if thediclofenac or its pharmaceutically acceptable salt in
the composition is not substantially chemically degraded after
storage under appropriate conditions for at least 1 month. In
certain embodiments, the concentration of the intact diclofenac or
its pharmaceutically acceptable salt in the composition is reduced
by less than about 1%, 3%, 5%, 8%, or 10% under appropriate storage
conditions (e.g., at 2-8.degree. C. or room temperature) for at
least 1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.
[0123] An emulsion composition is "physically stable" if it may be
stored under appropriate conditions for at least 1 month without
increase in its average droplet size by more than 100%, or evidence
of phase separation, creaming, or particle aggregation. In certain
embodiments, the average size of particles of a composition of the
present invention does not increase by more than about 10%, 20%,
25%, 30%, 40%, 50%, 75%, or 100% under appropriate storage
conditions (e.g., 2-8.degree. C. or room temperature) for at least
1, 2, 3, 4, 5, 6, 9, 12, 15, 18, or 24 months.
[0124] In still another aspect, the composition of the present
application relates to emulsions that are ready-to-use for
intravenous injection/infusion/intramuscular injection. The term
"ready to use" means that the pharmaceutical compositions can be
used as is or without a need for further dilution, mixing, or other
alteration of its composition prior to use.
[0125] In certain embodiments, the present emulsions may be
parenterally administered to a subject. "Parenteral" includes any
mode of administration that does not go through the digestive
tract, but excludes trans-membrane delivery such as skin
patches.
[0126] In certain embodiments, the mode of administration of the
present emulsions is by intravenous, intra-arterial, intrathecal,
intraperitoneal, intraocular, intra-articular, intramuscular or
subcutaneous injection.
[0127] Besides being ready-to-use oil-in-water emulsions, the
compositions of the present application can also be prepared with a
cryoprotectant(s) as-a lyophilized solid, i.e., "an oil-in-solid
dispersion system" that can be reconstituted at a later date and
diluted with water to reform the oil-in-water emulsion before
injection.
[0128] As used herein, the term "an oil-in-solid dispersion system"
refers to a solid matrix prepared by freeze-drying (lyophilizing)
an oil-in-water emulsion, which can reform an oil-in-water emulsion
of similar droplet size upon mixing with water (reconstitution). In
certain embodiments, the average droplet size of the reformed
emulsion is no more than about 500%, 400%, 300%, 200%, or 150% of
the average droplet size of the emulsion before the freeze-drying.
An oil-in-solid dispersion system of this invention may be
optionally prepared by spray drying.
[0129] "Cryoprotectants" refers to those ingredients which are
added to maintain the discrete and submicron droplets of the
emulsion during the freeze-drying process and, upon the removal of
water of the emulsion, to provide a solid matrix for the droplets
to form the oil-in-solid dispersion system. Exemplary
cryoprotectants include, but not limited to, polyols,
monosaccharides, disaccharides, polysaccharides, amino acids,
peptides, proteins, and hydrophilic polymers, or mixtures thereof.
Examples of polyols include glycerin, mannitol, erythritol,
maltitol, xylitol, sorbitol, polyglycitol or mixtures thereof.
Examples of monosaccharides include glucose, mannose, fructose,
lactulose, allose, altrose, gulose, idose, galactose, talose,
ribose, arabinose, xylose, lyxose or mixtures thereof. Examples of
disaccharides include sucrose, lactose, maltose, isomaltose,
trehalose, cellubiose or mixtures thereof. Examples of
polysaccharides include cellulose, amylose, inulin, chitin,
chitosan, amylopectin, glycogen, pectin, hyaruronic acid or
mixtures thereof. Examples of amino acids include alanine,
arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic
acid, glycine, histidine, isoleucine, leucine, lysine, methionine,
phenylalanine, proline, serine, threonine, tryptophan, tyrosine,
valine or mixtures thereof. Examples of peptides include diglycine
and triglycine. Examples of proteins include albumin, collagen,
casein, and gelatin Examples of hydrophilic polymers include, but
are not limited to, polyethylene glycols, povidones, poloxamers,
polyvinyl alcohols or mixtures thereof.
[0130] In certain embodiments, the concentration of a
cryoprotectant sufficient for stabilizing the oil droplets of an
emulsion and may be present in the range of about 2% to about 40%
w/w, about 5% to about 25% w/w and about 10% to about 20% w/w.
[0131] In one aspect the present application also provides methods
for preparing parenteral composition in the form of oil-in-water
emulsions for delivering diclofenac or its pharmaceutically
acceptable salt as described herein.
[0132] Such emulsion may be prepared by the process comprising the
steps of: [0133] (a) forming a mixture that comprises appropriate
amounts of [0134] (i) diclofenac or its pharmaceutically acceptable
salt, (ii) an oil component (e.g., a vegetable oil, or a
combination of a vegetable oil and a medium chain triglyceride),
and [0135] (iii) a phospholipid component, and [0136] (b) forming
an oil-in-water emulsion with the mixture of step (a) and an
aqueous solution.
[0137] In certain embodiments, step (b) may be performed by adding
the aqueous solution to the mixture of step (a) to form a primary
emulsion. The aqueous solution may be water or a buffer solution,
and may contain antioxidant(s), preservative(s), cryoprotectant(s),
additive(s) and/or tonicity modifier(s). The formation of the
primary emulsion may be performed or facilitated by the use of
mechanical homogenization (e.g., high shear mixing, high pressure
extrusion, and microfluidization) or other suitable techniques.
[0138] The methods may further comprise one or more of the
following steps: (A) adjusting the pH of the emulsion to a
desirable range, (B) homogenizing with high shear the emulsion to
provide an emulsion with an average droplet diameter less than
about 200 nm, and (C) sterilizing the emulsion by filtration using
a 0.2 .mu.m filter.
[0139] In certain embodiments, the composition of present
application may be sterilized by autoclave methods.
[0140] The composition of present application provides methods of
treating spinal cord injuries, traumatic brain injuries, strokes,
injuries to the peripheral nerves system, injuries to the central
nerves systems or injuries to other systems having nerve tissue,
preferably the injury has associated with it inflammation, where
the methods include the step of administering a composition of this
invention to an mammal including a human or directly to the site of
injury or into the blood or other bodily fluid of the mammal
including a human.
[0141] The composition of present application provides methods of
treating field injuries such as combat injuries or accident
injuries, where the methods include the steps of administering an
amount of a composition of this invention directly to the injury or
to the surrounding tissue to reduce inflammation while preventing
ulceration of the injury or while maintaining the integrity of
hydrophobic membranes and/or layers that may be associated with the
injured site, where the amount of the composition administered is
sufficient to cause a desired pharmacological effect.
[0142] The term "mammal" is defined as any class of warm-blooded
higher vertebrates that includes humans.
[0143] In certain embodiments, the compositions of present
application are used in pain management. The composition can be
used in postoperative pain management, battle field pain
management, accident pain management, or other pain management
under emergency conditions without the significant side effects of
alternative pain management medications such as opiates.
[0144] In another embodiment, the present application also provides
an injection apparatus including a reservoir including a volume of
a composition of this invention sufficient to cause a desired
pharmacological effect, a plunger operably connected to the
reservoir and a needle operably connected to an other end of the
reservoir, where the volume is injected through the needle when the
plunger is depressed.
[0145] The present application also provides a kit for emergency
administration of a sterile injectable pain relieving diclofenac
compositions, where the kit includes an injector apparatus
including a manual or electrically powered syringe, a needleless
injection system or other apparatus that can inject the composition
into a body of a mammal including a human. The kit also includes
containers including doses of at least one diclofenac composition
sufficient to cause desired pharmacologic effects.
[0146] The present invention is illustrated below by reference to
the following example. However, one skilled in the art will
appreciate that the specific methods and results discussed are
merely illustrative of the invention, and not to be construed as
limiting the invention.
EXAMPLES
Examples 1-6
TABLE-US-00001 [0147] Example 1 Example 2 Example 3 Example 4
Example 5 Example 6 Composition (%) (%) (%) (%) (%) (%) Diclofenac
sodium 3.75 3.75 3.75 3.75 3.75 3.75 Medium chain 0 2.5 5 0 0 0
triglycerides (MIGLYOL 812) Soybean oil, super 5 2.5 0 5 5 5
refined Egg lecithin (LIPOID 10 10 10 15 0 0 E-80) Soy lecithin
(LIPOID 0 0 0 0 10 15 S-100) EDTA disodium 0.0055 0.0055 0.0055
0.0055 0.0055 0.0055 dehydrate USP Purified water q.s. q.s. q.s.
q.s. q.s. q.s. pH 7.4 7.65 7.52 7.47 7.83 7.82
Procedure:
[0148] i. All the components are weighed in a clean container and
mixed well with a high shear mixer. [0149] ii. The mixture of step
i. is subjected to microfluidzation homogenization. [0150] iii. The
pH of the mixture step ii. is adjusted to the required pH. [0151]
iv. The mixture of step iii. is passed through a 0.22.mu.
filter.
Examples 7-10
TABLE-US-00002 [0152] Example Example Example Example 7 8 9 10
Composition (%) (%) (%) (%) Diclofenac sodium 3.75 3.75 3.75 3.75
Medium chain tri- 5 5 5 5 glycerides (MIGLYOL 812) Egg lecithin 10
10 10 10 (LIPOID E-80) EDTA disodium 0.0055 0.0055 0.0055 0.0055
dehydrate USP Sucrose, USP/NF 15 15 15 15 Purified water q.s. q.s.
q.s. q.s. pH 7.5 8.5 8.0 7.0
Procedure:
[0153] The compositions are prepared as per the procedure mentioned
earlier.
Examples 11-15
TABLE-US-00003 [0154] Example Example Example Example Example 11 12
13 14 15 Composition (%) (%) (%) (%) (%) Diclofenac 3.75 3.75 3.75
3.75 3.75 sodium Medium chain 5 5 5 5 5 triglycerides (MIGLYOL 812)
Egg lecithin 10 10 10 10 10 (LIPOID E-80) EDTA disodium 0.0055
0.0055 0.0055 0.0055 0.0055 dehydrate USP Sucrose, 10 5 10 5 6
USP/NF Purified water q.s. q.s. q.s. q.s. q.s. pH 7.5 7.5 8.1 7.9
7.9
Procedure:
[0155] The compositions are prepared as per the procedure mentioned
earlier.
Examples 16-20
TABLE-US-00004 [0156] Example Example Example Example Example 16 17
18 19 20 Composition (%) (%) (%) (%) (%) Diclofenac 3.75 3.75 3.75
3.75 3.75 sodium Medium chain 5 5 5 5 5 triglycerides (MIGLYOL 812)
Egg lecithin 10 10 10 10 10 (LIPOID E-80) EDTA disodium 0.0055
0.0055 0.0055 0.0055 0.0055 dehydrate USP Sucrose, 7 8 8 10 8
USP/NF Purified water q.s. q.s. q.s. q.s. q.s. pH 7.9 7.9 7.9 7.9
8.0
Procedure:
[0157] The compositions are prepared as per the procedure mentioned
earlier.
Examples 21-25
TABLE-US-00005 [0158] Example Example Example Example Example 21 22
23 24 25 Composition (%) (%) (%) (%) (%) Diclofenac 3.75 3.75 3.75
3.75 3.75 sodium Medium chain 5 5 4 3 2 triglycerides (MIGLYOL 812)
Egg lecithin 10 10 10 10 10 (LIPOID E-80) Sodium oleate 0 0.03 0 0
0 EDTA disodium 0.0055 0.0055 0.0055 0.0055 0.0055 dehydrate USP
Sucrose, 5 8 8 8 8 USP/NF Purified water q.s. q.s. q.s. q.s. q.s.
pH 8.0 8.0 8.0 8.0 8.0
Procedure:
[0159] The compositions are prepared as per the procedure mentioned
earlier.
Examples 26-29
TABLE-US-00006 [0160] Example Example Example Example 26 27 28 29
Composition (%) (%) (%) (%) Diclofenac sodium 3.75 3.75 3.75 3.75
Medium chain triglycerides 1 7.5 2.5 1 (MIGLYOL 812) Egg lecithin
(LIPOID E-80) 10 7.5 12.5 14 Sodium oleate 0 0.03 0 0 EDTA disodium
dehydrate 0.0055 0.0055 0.0055 0.0055 USP Sucrose, USP/NF 8 8 8 8
Purified water q.s. q.s. q.s. q.s. pH 8.0 8.0 8.0 8.0
Procedure:
[0161] The compositions are prepared as per the procedure mentioned
earlier.
Examples 30 to 35
TABLE-US-00007 [0162] Example Example Example Example Example 30 31
32 33 34 Composition (%) (%) (%) (%) (%) Diclofenac 3.61 3.75 3.75
3.61 3.61 sodium Medium chain 5 5 5 5 5 triglycerides (MIGLYOL 812)
Egg lecithin 10 10 10 10 10 (LIPOID E-80) EDTA disodium 0.0055
0.0055 0.0055 0.0055 0.0055 dehydrate USP Sodium 0 0.2 0 0 0
bisulfate Ascorbic acid 0 0 0.2 0 0 L-cysteine 0 0 0 0.1 0
L-Methionine 0 0 0 0 0.3 Sucrose, 5 5 5 5 5 USP/NF Purified water
q.s. q.s. q.s. q.s. q.s. pH 8.0 8.0 8.0 8.0 8.0
Procedure:
[0163] The compositions are prepared as per the procedure mentioned
earlier.
Examples 35-38
TABLE-US-00008 [0164] Example Example Example Example 35 36 37 38
Composition (%) (%) (%) (%) Diclofenac sodium 3.61 3.75 3.75 3.61
Medium chain 5 5 5 5 triglycerides (MIGLYOL 812) Egg lecithin 10 10
10 10 (LIPOID E-80) EDTA disodium 0.0055 0.0055 0.0055 0.0055
dehydrate USP DL, .alpha.-tocopherol 0.075 0 0 0 Butylatedhydroxy-
0 0.0003 0 0.0003 anisol (BHA) Butylatedhydroxy- 0 0 0.002 0.002
toluene (BHT) Sucrose, USP/NF 5 5 5 5 Purified water q.s. q.s. q.s.
q.s. pH 8.0 8.0 8.0 8.0
[0165] Although the invention has been illustrated by certain of
the preceding examples, it is not to be construed as being limited
thereby; but rather, the invention encompasses the generic area as
hereinbefore disclosed. Various modifications and embodiments can
be made without departing from the spirit and scope thereof.
* * * * *