NZ747690B2 - Compositions for the treatment of chronic vulval and perineal pain and symptoms and conditions associated therewith - Google Patents
Compositions for the treatment of chronic vulval and perineal pain and symptoms and conditions associated therewith Download PDFInfo
- Publication number
- NZ747690B2 NZ747690B2 NZ747690A NZ74769017A NZ747690B2 NZ 747690 B2 NZ747690 B2 NZ 747690B2 NZ 747690 A NZ747690 A NZ 747690A NZ 74769017 A NZ74769017 A NZ 74769017A NZ 747690 B2 NZ747690 B2 NZ 747690B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition
- vulval
- pain
- chronic
- amitriptyline
- Prior art date
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Abstract
Provides herein are compositions for the treatment of chronic vulval or perineal pain, and of symptoms or conditions associated therewith, comprising an estrogen, optionally estriol, and a tricyclic antidepressant, optionally amitriptyline, formulated for topical, transdermal or transmucosal administration. Also provided are methods for the production of said compositions and to uses thereof in the treatment of chronic vulval or perineal pain, and of symptoms or conditions associated therewith. tration. Also provided are methods for the production of said compositions and to uses thereof in the treatment of chronic vulval or perineal pain, and of symptoms or conditions associated therewith.
Description
ITIONS FOR THE TREATMENT OF CHRONIC VULVAL AND
PERINEAL PAIN AND SYMPTOMS AND CONDITIONS ASSOCIATED
THEREWITH
Technical field
The present invention relates generally to compositions and methods for the
ent of chronic vulval and al pain. Compositions of the invention are
formulated for topical, transdermal or transmucosal delivery and se an estrogen,
typically estriol, and a tricyclic antidepressant, lly amitriptyline.
Background of the invention
Vulvodynia is a complex gynaecological disorder characterised by chronic pain
localized to the vulva. It is a potentially debilitating condition that can last for years,
cause physical disability, sexual dysfunction, and psychological difficulties. Daily
activities and quality of life can be significantly impaired with many sufferers
experiencing difficulty walking or sitting for long periods, sensitivity to clothing touching
the vaginal area, and mild to intense pain typically described as burning, stinging or
itching. Although often difficult to diagnose, it is typically estimated that in excess of 15
percent of the adult female population in western countries may experience vulvodynia at
some point during their lifetime. It most ly affects women of child bearing age.
The most common form of vulvodynia is vulvar vestibulitis. Women with vulvar
vestibulitis lly experience pain ing and limited to the vestibule and only
during or after touch or pressure is applied. Vulvar vestibulitis is characterized by pain,
ness, vestibular erythema, itching, swelling and urethritis. The pain may be
described as sharp, g, or a sensation of rawness. Generalized vulvodynia is
terized by diffuse pain and/or a burning sensation on or around the vulva, the labia
majora, labia minor, and/or the vestibule. The pain can be constant or intermittent and the
symptoms, although not necessarily caused by touch or re to the vulva, can be
exacerbated by physical contact to the area.
The etiology of vulvodynia is unknown. However, it has been hypothesized that
viral, fungal and ial assaults, allergic reactions, neuropathic processes and an
autoimmune response may play a role. Irritation of the s that support the uterus,
bladder and rectum (pelvic floor muscle or levator ani myalgia) as well as irritation of the
nerves of the vulval tissue, known as pudendal neuralgia, may result in additional l
symptoms associated with ynia.
Pudendal neuralgia (or also known as chronic perineal pain) is a term referring to
chronic pain within the distribution of the pudendal nerve, which comprises the vulva as
well as the labia majora and the skin around the anus as well as part of the mons veneris.
The pudendal nerve also innervates the urethra and the anal mucosa. Thus the dysfunction
of the pudendal nerve extends not only to the sensory function of the perineal skin
ding the vulva) but also to voiding and defecation. Symptoms such as the nt
urge to void or the sensation of a foreign body in the rectum can occur. These symptoms
are not classified as pain per se but nevertheless contribute to the individual’s disability.
Because of the potential for multiple causes, chronic pain such as pudendal
neuralgia and vulvodynia can be difficult to treat. First-line therapy typically involves the
treatment of suspected causes by pharmacologic treatment of infections and the
discontinued use of suspected irritants and therapeutic agents that may contribute to the
problem. Oral medications such as antihistamines, and tricyclic antidepressants, oral
supplements such as calcium citrate, dietary changes and physical therapy, such as pelvic
floor muscle re-education, may provide some symptomatic relief. More invasive
treatments include interferon intra lesional injections, laser y and surgery, r
these options are costly and may be associated with complications such as hematoma,
wound dehiscence and uneven healing. There is no known cure as such for chronic pain
mes such as vulvodynia and al neuralgia.
There remains a need for the development of cost effective, simple to use
treatment options for the chronic vulval and perineal pain ated with conditions such
as vulvodynia and pudendal neuralgia.
Summary of the invention
A first aspect of the present invention provides a composition for the treatment of
chronic vulval or perineal pain, or of a symptom or condition ated ith, the
composition comprising an estrogen and a tricyclic antidepressant, n the
composition is formulated for topical, transdermal or transmucosal administration.
In particular embodiments the composition is a topical ition.
The composition may, for example, be in the form of a gel, cream, ointment or
lotion.
The en may be a natural or synthetic en. The estrogen may be
selected from the group consisting of estriol, estrone, 17 beta-estradiol, estradiol, estradiol
benzoate, estradiol 17 beta-cypionate, ethinyl estradiol, mestranol, moxestrol,
ienediol, polyestradiol phosphate, quinestradiol, quinestrol, and any combination
thereof.
Typically the estrogen displays weak estrogenic activity. In particular
embodiments the weak estrogen is estriol.
The tricyclic antidepressant may be ed from amitriptyline, nortriptyline and
desipramine. In particular embodiments the tricyclic antidepressant is amitriptyline. The
amitriptyline may be in the form of ptyline hydrochloride.
In ary embodiments the composition is a gel composition, optionally an
organogel. The gel composition may be produced using as two phase system comprising
an organic phase and an aqueous phase. In one embodiment the organic phase comprises
a mixture of lecithin and isopropyl palmitate. In one embodiment the aqueous phase
comprises a poloxamer.
Typically the en (more typically wherein the estrogen is estriol) is
dissolved or dispersed in the organic phase and the tricyclic pressant (more typically
wherein the tricyclic antidepressant is amitriptyline or amitriptyline hydrochloride) is
dissolved in the aqueous phase.
Optionally the composition, or at least the organic phase in a two phase gel
system, further comprises a solubilizing agent.
The condition associated with chronic vulval pain may be vulvodynia. The
vulvodynia may be zed or generalized vulvodynia. The condition may be selected
from vulval vestibulitis, localized provoked ulodynia (LPV), dysesthetic vulvodynia,
vulvar dermatoses, cyclic vulvovaginitis, or pelvic floor tension myalgia (levator ani
myalgia). The condition associated with chronic perineal pain may be pudendal neuralgia.
The symptom or associated condition may comprise urethritis, urinary ncy or
urgency or faecal frequency or urgency.
A second aspect of the invention provides a method for the treatment of c
vulval or perineal pain, or of a symptom or condition associated therewith, the method
comprising topically, ermally or transmucosally administering to a female subject in
need thereof a composition sing an estrogen and a tricyclic antidepressant.
Typically the method comprises the administration of a composition according to
the first aspect.
A third aspect of the invention provides the use of an estrogen and a tricyclic
antidepressant for the manufacture of a composition for the treatment of chronic vulval or
al pain, or of a symptom or condition associated therewith, wherein the ition
is formulated for topical, transdermal or transmucosal administration.
A fourth aspect of the invention provides a topical composition for the treatment
of chronic vulval or perineal pain, or of a m or condition associated therewith, the
composition comprising l and ptyline.
The composition may, for example, be in the form of a gel, cream, ointment or
lotion.
In exemplary embodiments the composition is a gel composition, optionally an
organogel. The gel composition may be produced using as two phase system comprising
an organic phase and an aqueous phase. In one embodiment the organic phase ses
a mixture of lecithin and isopropyl palmitate. In one embodiment the s phase
comprises a poloxamer.
Typically the estrogen (more typically wherein the estrogen is estriol) is
dissolved or dispersed in the organic phase and the tricyclic antidepressant (more typically
wherein the tricyclic antidepressant is amitriptyline or amitriptyline hydrochloride) is
ved in the aqueous phase.
Optionally the composition, or at least the organic phase in a two phase gel
system, further comprises a solubilizer.
A fifth aspect of the invention provides a method for the treatment of chronic
vulval or perineal pain, or of a m or condition associated therewith, the method
comprising lly administering to a female subject a composition comprising estriol
and amitriptyline.
lly the method comprises the stration of a composition according to
the fourth aspect.
A sixth aspect of the invention provides the use of estriol and amitriptyline for the
manufacture of a composition for the treatment of chronic vulval or perineal pain, or of a
m or condition associated therewith, wherein the composition is formulated for
topical administration.
Detailed description of the invention
In the context of the t specification, the terms "a" and "an" are used herein
to refer to one or to more than one (i.e. to at least one) of the grammatical object of the
article. By way of example, "an element" means one element or more than one element.
In the context of the present ication, the term "comprising" means
"including principally but not necessarily solely". Furthermore, variations of the word
"comprising", such as "comprise" and "comprises", have correspondingly varied
meanings.
In the context of the present specification, the term "about" is understood to refer
to a range of values that a person of skill in the art would consider lent to the recited
value in the context of achieving the same on or result.
The term “associated with” as used in the t of a condition associated with
chronic vulval pain means a condition that may have as an underlying cause c
vulval pain, or that may otherwise be associated, either directly or indirectly, with chronic
vulval pain.
The term “weak estrogenic activity” as used herein means that, compared to a
more potent estrogenic nd such as 17b-estradiol, the compound displaying weak
estrogenic activity does not ate the nuclear receptor effectively. For example,
estriol is an agonist as well as an nist of the beta estrogen receptor, and prevents
binding of iol, the more potent human estrogen, to the G protein-coupled estrogen
receptor. For use in accordance with the present invention, compounds with weak
estrogenic activity, will typically have a stimulatory effect on the mucosa without
significant effect on the nucleus, therefore only minimally stimulating the estrogen
receptor positive cells elsewhere in the body, namely breast and uterus. Thus, compounds
with weak estrogen activity, such as estriol, may have less unwanted systemic effects and
more pronounced, advantageous local effects than a more potent estrogen, making them
particularly suitable ents of compositions of the present invention.
As used herein the terms ing" and “treatment” refer to any and all uses
which remedy a condition or one or more symptoms, or otherwise hinder, retard, or
reverse the progression of a condition or one or more symptoms thereof in any way
whatsoever. Thus the terms "treating" and the like are to be considered in their broadest
context. For example, ent does not necessarily imply that a patient is d until
total ry.
The present ion provides compositions and s for treating chronic
vulval and perineal pain, and symptoms and conditions associated with such pain. More
particularly, provided herein are compositions comprising an estrogen and a tricyclic
pressant, wherein the composition is formulated for topical, transdermal or
transmucosal administration. Also provided herein are methods of treatment of pain and
associated symptoms and conditions as described herein, employing combinations of an
estrogen and a tricyclic antidepressant, by topical, transdermal or transmucosal
administration.
Methods and compositions of the invention are able the treatment of a
variety of conditions and symptoms associated with chronic vulval and perineal pain
including, but not d to, vulvodynia, pudendal neuralgia, pelvic floor tension myalgia,
the constant urge to void, or the sensation of a foreign body in the rectum, urethritis, and
the pain associated with any of these conditions or symptoms. The vulvodynia may be
localized or generalized vulvodynia. The condition may be selected from, for e,
vulval vestibulitis, localized provoked ulodynia (LPV), dysesthetic ynia,
vulvar dermatoses or cyclic vulvovaginitis.
The estrogen present in the composition may be a natural or tic estrogen.
The estrogen may be selected, for example, from the group consisting of estriol, estrone,
17 beta-estradiol, estradiol, estradiol benzoate, estradiol 17 beta-cypionate, ethinyl
estradiol, mestranol, moxestrol, mytatrienediol, polyestradiol phosphate, quinestradiol,
quinestrol, and any combination f. Typically the estrogen will display weak
estrogenic activity. Accordingly, in particular exemplary embodiments of the ion
the estrogen is estriol. Those skilled in the art will appreciate that other active compounds
having estrogenic activity, typically weak estrogenic activity, may be used as an
alternative or in addition. Estriol is a so-called weak estrogen which is predominantly
produced during pregnancy by the placenta and the fetal liver. Estriol is an agonist as well
as an antagonist of the beta estrogen receptor, and ts g of estradiol, the more
potent human estrogen, to the G protein-coupled estrogen receptor. Estriol has an
excellent stimulatory effect on l tissue, without significant effect on the nucleus.
Thus, the use of estriol is associated with less unwanted systemic effects and enhanced
beneficial local effects than a more potent estrogen.
The lic antidepressant present in the composition may be selected, for
example, from the group consisting of amitriptyline, nortriptyline and desipramine. In
particular exemplary embodiments of the invention the lic antidepressant is
amitriptyline. The amitriptyline may be in any form suitable for topical, transmucosal or
transdermal administration, such as amitriptyline hydrochloride. Those skilled in the art
will iate that other tricyclic antidepressants may be used as an alternative or in
addition. The amitriptyline (or equivalent) acts as a topical hetic when applied
directly to a tegument (skin, mucosa), reducing the sensitivity of the tegument to touch.
This is a pharmacological effect different from that obtained when the molecule is
introduced via the gastro-intestinal tract.
The estrogen and the tricyclic pressant may each be present in the
composition in an amount between about 0.0005% (w/w) and about 20% (w/w), between
about 0.0005% (w/w) and about 10% (w/w), between about 0.005% (w/w) and about 5%
(w/w), n about 0.005% (w/w) and about 3% (w/w), between about 0.005% (w/w)
and about 1% (w/w), or between about 0.005% (w/w) and about 0.5% (w/w).
In embodiments in which the lic antidepressant is amitriptyline, the
amitriptyline may be present at about, for example, 0.05% (w/w), 0.1% (w/w), 0.2%
(w/w), 0.3% (w/w), 0.4% (w/w), 0.5% (w/w), 0.6% (w/w), 0.7% (w/w), 0.8% (w/w), 0.9%
(w/w), 1% (w/w), 1.1% (w/w), 1.2% (w/w), 1.3% (w/w), 1.4% (w/w), 1.5% (w/w), 1.6%
(w/w), 1.7% (w/w), 1.8% (w/w), 1.9% (w/w), 2% (w/w), 2.1% (w/w), 2.2% (w/w), 2.3%
(w/w), 2.4% (w/w), 2.5% (w/w), 2.6% (w/w), 2.7% (w/w), 2.8% (w/w), 2.9% (w/w), 3%
(w/w), 3.2% (w/w), 3.4% (w/w), 3.6%, 3.8% (w/w) or 4% (w/w). The skilled addressee
will appreciate that the amount of amitriptyline (or other tricyclic antidepressant) may be
varied depending on a variety of factors including, for example, the subject to be treated
(such as age, other conditions suffered, general health and wellbeing) and the nature and
ty of the pain or condition to be treated. Such variations are well within the skill of
the ordinary person skilled in the art and may be made without undue burden.
In embodiments in which the estrogen is estriol, the estriol may be present at
about, for example, 0.01% (w/w), 0.02% (w/w), 0.03% (w/w), 0.04% (w/w), 0.05%
(w/w), 0.06% (w/w), 0.07% (w/w), 0.08% (w/w), 0.09% (w/w), 0.1% (w/w), 0.2% (w/w),
0.3% (w/w), 0.4% (w/w), 0.5% (w/w), 0.6% (w/w), 0.7% (w/w), 0.8% (w/w), 0.9% (w/w),
1% (w/w), 1.2% (w/w), 1.4% (w/w), 1.6% (w/w), 1.8% (w/w), or 2% (w/w).
Alternatively, the l may be present at, for example, between about 100 mg/gm and
about 500 mg/gm based on the weight of the composition. For e the l may be
present at about 100 mg/gm, 125 mg/gm, 150 mg/gm, 175 mg/gm, 200 mg/gm, 225 mg/gm,
250 mg/gm, 275 mg/gm, 300 mg/gm, 325 mg/gm, 350 mg/gm, 375 mg/gm, 400 mg/gm, 425
mg/gm, 450 mg/gm, 475 mg/gm, or 500 mg/gm based on the weight of the composition.
The skilled addressee will appreciate that the amount of estriol (or other estrogen) may be
varied depending on a variety of factors including, for example, the subject to be treated
(such as age, other conditions suffered, general health and wellbeing) and the nature and
severity of the pain or ion to be d. Such variations are well within the skill of
the ordinary person skilled in the art and may be made without undue burden.
In an exemplary embodiment, a composition of the invention comprises
ptyline at about 0.5% (w/w) and l at about 300 mg/gm based on the weight of
the composition.
Compositions of the invention may further comprise one or more additional
agents or compounds such as anti-inflammatory agents, antioxidants, anti-erythema
actives, anti-microbial agents, ial oils, herbal extracts, vitamins, and the like.
Exemplary anti-inflammatory agents that may be employed e steroidal and
non-steroidal compounds such as those suitable for topical administration. Suitable
steroidal compounds include clobetasol propionate, betamethasone dipropionate,
halobetasol proprionate, diflorasone diacetate, fluocinonide, halcinonide, amcinonide,
desoximetasone, inolone acetonide, mometasone furoate, fluticasone propionate,
betamethasone dipropionate, fluocinolone acetonide, hydrocortisone te,
hydrocortisone butyrate, flurandrenolide, triamcinolone acetonide, mometasone furoate,
inolone acetonide, fluticasone propionate, desonide, fluocinolone acetonide,
hydrocortisone valerate, prednicarbate, triamcinolone acetonide, desonide, hydrocortisone
, hydrocortisone aceponate, hydrocortisone buteprate, methylprednisolone aceponate,
mometasone furoate and prednicarbate. Suitable non-steroidal nflammatory
compounds e indomethacin, ketoprofen, felbinac, diclofenac, ibuprofen, piroxicam,
benzydamin, acetylsalicylic acid, diflunisal, salsalate, naproxen, fenoprofen, ketoprofen,
flurbiprofen, oxaprozin, loxoprofen, indomethacin, sulindac, etodolac, ketorolac, enac
, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam,
mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, firocoxib, and
licofelone, semi-synthetic glycosaminoglycosan , flavanols, flavonoids, isoflavones
and derivatives. Other suitable anti-inflammatories include, for e, zinc cream or
lotion, and n E oil, cream or lotion.
Examples of antioxidants include, but are not limited to, water-soluble
antioxidants such as sulfhydryl compounds and their derivatives (for example sodium
metabisulfite and N-acetyl-cysteine), lipoic acid and dihydrolipoic acid, resveratrol and
lactoferrin. Oil-soluble antioxidants include, but are not limited to butylated
hydroxytoluene, retinoids, tocopherols, carotenoids, ubiquinone,
dimethylmethoxychromanol and rcetin.
es of anti-erythema actives include, but are not limited to Matricaria
recutita extract, Anthemis nobilis extract, Centella asiatica extract, um maritimum
extract, Gingko biloba extract, rea cyaneus extract, and extracts from Euphrasia
species.
Exemplary antimicrobial agents include anti-bacterial, iral, ungal and
anti-protozoal nds. Examples of anti-bacterial compounds include, but are not
d to antibiotics such as erythromycin, spiramycin, clarithromycin, clindamycin and
tretinoin. Examples of anti-viral compounds include, but are not d to acyclovir,
amantadine, valacyclovir and rimantadine. Examples of anti-fungal compounds include,
but are not limited to chlorphenesin, clioquinol, haloprogin, undecylenic acid, tolnaftate,
fluconazole, butoconazole, clotrimazole, econazole, miconazole, terconazole and
tioconazole. Examples of anti-protozoal nds include, but are not limited to antimalarial
drugs, spiramycin and clioquinol.
Essential oils may enhance the emollient and penetration properties of the
composition. Exemplary essential oils include, but are not limited to rass oil, tea
tree oil, thyme oil, and lavender oil.
Suitable vitamins include but are not limited to vitamin A, pro vitamin A, vitamin
B1, vitamin B2, vitamin B3, vitamin B4, vitamin B5, vitamin B6, vitamin B12, vitamin D,
vitamin D2, n D3, tocopherol (vitamin E), vitamin F and vitamin K1.
The compositions may comprise one or more ceutically acceptable
humectants, emollients or preservatives. The inclusion of humectants and ents
provide a moisturising effect to the topical compositions when applied repeatedly to the
skin thereby minimising any drying effect that the composition may impart when applied
to sensitive membranes such as around the .
A wide variety of suitable emollients are known to those skilled in the art. See
for example the ational ic Ingredient Dictionary and Handbook, Eds.
ger and McEwen, The Cosmetic, Toiletry, and Fragrance Assoc., Washington,
D.C., 7th Edition, 1997. Emollients useful in the present invention include, but are not
limited to: in, propylene glycol, sorbitol, an palmitate, n, lanolin
derivatives, polyethylene glycol (for example PEG300), aloe vera, glucamate DOE 120,
allantoin, alginates, monoester salts of sulfosuccinates, ceramides, and mixtures thereof.
Further exemplary moisturisers include, but are not limited to, cetyl palmitate, castor oil,
jojoba seed oil, grape seed oil, sunflower seed oil, wer seed oil, diglycerin, oleic
acid, dimethicone copolyol, dextrin, jojoba esters, panthenol, squalene, coconut oil, cocoa
butter, honey, hydrogenated in, pyl isostearate, hydrogenated vegetable oil,
glyceryl distearate, marine exopolysaccharides, polyfructol, hyaluronic acid, hydrolysed
hyaluronic acid, flavonoids from Salvia sclarea and Citrus aurantiaca, itol, seed
extract from Tamarindus indica, and Opuntia ficus-indica t.
Examples of humectants include, but are not limited to ol, sorbitol,
polyethylene glycol, mono- and oligomeric sugars, natural extracts such as quillaia, lactic
acid and urea.
Examples of preservatives include but are not d to benzyl alcohol and
parabens.
itions of the invention may be formulated for topical, transdermal or
transmucosal administration. Typically the compositions are formulated for l
administration. le ceutically acceptable carriers, diluents, excipients and
adjuvants suitable for topical compositions include demineralised or distilled water; saline
solution; vegetable based oils such as peanut oil, safflower oil, olive oil, cottonseed oil,
maize oil, sesame oil, arachis oil or coconut oil; silicone oils, including polysiloxanes,
such as methyl polysiloxane, phenyl polysiloxane and methylphenyl polysolpoxane;
volatile silicones; mineral oils such as liquid paraffin, soft paraffin or squalane; cellulose
derivatives such as methyl cellulose, ethyl cellulose, carboxymethylcellulose, sodium
carboxymethylcellulose or hydroxypropylmethylcellulose; lower alkanols, for example
ethanol or iso-propanol; lower aralkanols; lower polyalkylene glycols or lower alkylene
glycols, for example polyethylene glycol, polypropylene glycol, ethylene glycol,
propylene glycol, 1,3-butylene glycol or glycerin; fatty acid esters such as isopropyl
palmitate, isopropyl myristate or ethyl oleate; polyvinylpyrridone; agar; carrageenan; gum
tragacanth or gum acacia, and petroleum jelly. lly, the carrier or carriers will form
from 10% to 99.9% by weight of the compositions.
Compositions of the invention may be in any form suitable for topical,
transdermal or transmucosal administration. For example, the composition may be in the
form of a cream, ointment, lotion, gel, paste, on, spray or the like. Compositions
may prepared so as to contain liposomes, micelles, and/or microspheres.
Ointments, as is well known in the art, are semisolid preparations that are
lly based on petrolatum or other petroleum derivatives. The specific ointment base
to be used, as will be appreciated by those d in the art, is one that will provide for
optimum drug delivery, and, preferably, will provide for other desired characteristics as
well, e.g., emolliency or the like. Suitable ointment bases are typically grouped into four
classes: oleaginous bases; emulsifiable bases; on bases; and water-soluble bases.
Oleaginous ointment bases e, for example, vegetable oils, fats obtained from
animals, and lid hydrocarbons obtained from petroleum. Emulsifiable ointment
bases contain little or no water and include, for example, hydroxystearin sulfate,
anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either waterin-oil
(W/O) ons or oil-in-water (O/W) emulsions, and include, for example, cetyl
alcohol, glyceryl monostearate, lanolin and stearic acid. Water-soluble ointment bases are
prepared from polyethylene glycols of varying molecular weight.
Creams, as also well known in the art, are viscous liquids or semisolid emulsions,
either oil-in-water or water-in-oil. Cream bases are typically washable, and contain
an oil phase, an emulsifier and an aqueous phase. The oil phase may be comprised of
petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase may
exceed the oil phase in volume, and generally contains a humectant. The fier in a
cream formulation is generally a nonionic, anionic, cationic or amphoteric tant.
Methods for the ation of suitable ointments and creams are well known to
those skilled in the art, as are methods for the preparation of lotions, gels, ,
solutions, sprays and the like, for example with reference to any one of numerous texts
well known in the field (such as Remington: The Science and Practice of Pharmacy).
In particular embodiments, the composition may be in the form of a water-based
gel wherein the gel includes at least one gelling agent, a solubilising agent and water.
Gelling agents that may be used in the compositions of the invention include, but
are not limited to: algal extracts, gums, polysaccharides, starches, s, hydrolysed
ns, cellulose tives and polymers comprising pendant carboxylic acid groups,
or esters thereof, polymers comprising pendant anhydrides of dicarboxylic acid groups
and block ymers, ing poloxomers, based on ethylene oxide and/or propylene
oxide.
Algal extracts that may be used include, but are not limited to alginates and
carrageenans. Cellulose derivatives that may be used include, but are not limited to
methylcelluloses, ethylcelluloses hydroxypropylmethylcelluloses, hydroxyethylcelluloses
and carboxymethylcelluloses, which may or may not be cross-linked. Hydrolysed ns
include but are not limited to gelatin.
Polymers comprising pendant carboxylic acid groups may be homopolymers,
copolymers or olymers comprising an acrylic acid backbone, for example
carbomers. In one embodiment, the gelling agent is a polymer of acrylic acid cross-linked
with polyalkenyl ethers or divinyl glycol. In an alternative embodiment, the gelling agent
is a copolymer of acrylic acid and long-chain alkyl acrylates crosslinked with polyalkenyl
ethers, for example allyl pentaerythritol.
Carbomers suitable for use in the present invention include, but are not limited to,
those commercially available under the trade names ol® (Lubrizol Advanced
Materials, Inc.), Pemulen® (Lubrizol Advanced Mater ials, Inc.), Noveon® (Lubrizol
Advanced Materials, Inc.), Synthalen® (3V Sigma) an d Hivis Wako® (Wako Pure
Chemicals Co.). Carbomers used in the present invention may be ers having
Brookfield viscosities in the range of about 40,000 to 70,000 mPa.s at 25 °C. In one
ment, the carbomer may be Carbopol® 980.
Block co-polymers based on ethylene oxide and/or propylene oxide that are
suitable for use in the present invention include those commercially available under the
trade name Pluronic®.
The amount of gelling agent present in the composition will depend on the
particular gelling agent being used. Typically the amount of gelling agent t in the
composition is between about between about 0.01% (w/w) and about 50% (w/w), or
between about 0.05% (w/w) and about 40% (w/w), or between about 0.05% (w/w) and
about 30% (w/w), or between about 0.05% (w/w) and about 20% (w/w), or between about
0.05% (w/w) and about 10% (w/w), or between about 0.05% (w/w) and about 5% (w/w),
or between about 0.05% (w/w) and about 3% (w/w), or between about 0.1% (w/w) and
about 2% (w/w). Where a gelling agent sold under the trade name Carbopol® is
employed, the amount used may be in the range of between about 0.05% (w/w) and about
% (w/w). Where a gelling agent sold under the trade name Pluronic® is employed, the
amount used may be in the range of between about 1% (w/w) and about 30% (w/w).
In ary embodiments the composition is a gel ition, optionally an
organogel. The gel ition may be produced using as two phase system comprising
an organic phase and an aqueous phase. Typically, as will be understood by those skilled
in the art, blending or mixing of the organic phase and the aqueous phase until high shear
may be required to produce the organogel. The ratio of the organic phase to the aqueous
phase may be between about 1:5 and about 5:1, such as about 1:5, 1:4, 1:3, 1:2, 1:1, 2:1,
3:1, 4:1 or 5:1. In an ary embodiment the ratio of the organic phase and the
aqueous phase may be about 1:2.
In one embodiment the organic phase comprises a mixture of lecithin and
isopropyl palmitate. The ratio of the lecithin to isopropyl palmitate in the organic phase
may be between about 1:5 and 5:1, between 1:4 and 4:1, between 1:3 to 3:1, between 1:2
and 2:1, or about 1:1. In one embodiment the aqueous phase comprises a poloxamer, such
as, for example Pluronic® F-127. Those d in the art will appreciate that a range of
other poloxamers may be used without departing from the scope of the ion. The
appropriate constituents of the organic phase and the aqueous phase can be determined by
those skilled in the art without experimentation.
Thus, an exemplary two phase system is the Pluronic® Lecithin Organogel
(PLO) system.
In an exemplary embodiment the estriol is typically first dissolved (either fully
dissolved or at least partially dissolved) or dispersed in a suitable solvent, such as
propylene glycol prior to the addition of the c phase such as the lecithin / isopropyl
palmitate mixture. The ratio of propylene glycol to the lecithin / isopropyl palmitate
mixture may be between about 1:10 and about 10:1, such as about 1:10, 1:9, 1:8, 1:7, 1:6,
1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1. In an ary
embodiment, the ratio of propylene glycol to the lecithin / isopropyl palmitate mixture
may be about 4:10.
In such two phase s, typically the estrogen (more typically wherein the
estrogen is estriol) is dissolved or dispersed in the organic phase and the tricyclic
antidepressant (more typically wherein the tricyclic antidepressant is amitriptyline or
amitriptyline hydrochloride) is ved in the aqueous phase.
Accordingly, also ed herein is a method for producing a composition
comprising an estrogen and a tricyclic antidepressant, optionally estriol and amitriptyline,
comprising: incorporating the estrogen, optionally estriol, in an organic phase, wherein the
organic phase optionally comprises a mixture of lecithin and isopropyl palmitate;
incorporating the tricyclic antidepressant, optionally amitriptyline, in an aqueous phase,
wherein the aqueous phase optionally comprises a poloxamer such as a Pluronic®
poloxamer, and mixing the organic phase and the aqueous phase, optionally under
conditions of high shear, to produce a gel composition.
ally the composition, or at least the organic phase in a two phase gel
system, further comprises a solubilizing agent.
The solubilising agent may be ed from the group consisting of: pyrrolidone
or a derivative thereof, castor oil, polyethoxylated castor oil, diethylene glycol monoethyl
ether, propylene glycol ate, propylene glycol mono caprylate, medium chain
glycerides, 2-methacryloxyethylphosphonylcholine, cyclodextrins and derivatives thereof,
lecithin, rbates, ospholipids, phospholipids, cholesterol-PEG, saturated
polyglycolised C8-C10 glycerides. In one exemplary embodiment, the solubilising agent is
a coholic solubilising agent, for example idone or a derivative thereof. As
used herein, a non-alcoholic solubilising agent means an agent which is free or
substantially free of alcohols, including polyhydric alcohols. “Substantially free" will be
tood to mean less than about 0.01%, or less than about 0.005%, or less than about
0.001% of the d component. In another exemplary embodiment the solubilising
agent is diethylene glycol monoethyl ether.
The solubilising agent may be present in an amount between about 1% (w/w) and
about 30% (w/w), or between about 1% (w/w) and about 20% (w/w), or between about
1% (w/w) and about 15% (w/w), or between about 1% (w/w) and about 10% (w/w).
Those skilled in the art will, by routine trial and experimentation, be able to ine the
amount of solubilising agent required to either dissolve or substantially solubilise the
active agents.
The compositions may comprise water in an amount between about 50% (w/w)
and about 90% (w/w), or between about 60% (w/w) and about 80% (w/w).
It will be iated by persons skilled in the art that numerous variations and/or
modifications may be made to the invention without departing from the spirit or scope of
the invention as broadly described. The present embodiments are, therefore, to be
considered in all respects as illustrative and not restrictive.
The invention will now be bed in more detail, by way of illustration only,
with respect to the following examples. The es are intended to serve to illustrate
this invention and should not be construed as limiting the generality of the disclosure of
the description throughout this ication.
Examples
Example 1 – Exemplary compositions comprising estriol and amitriptyline
An exemplary composition contains the following ingredients:
Amitriptyline
Estriol
Ethylhexyl stearate
Emulsifying wax
Tocopheryl acetate
Aloe barbadensis leaf juice
Disodium EDTA
Sorbitol
entasiloxane
Methylchloroisothiazolinone (and) Methylisothiazolinone
Water
The amitriptyline and estriol may be provided in the form of powders, mixed with
a base formulation comprising the remaining ingredients.
Example 2 – Preparation of a high bioavailability gel composition comprising estriol and
ptyline
l is essentially insoluble in water (27mg per litre), slightly soluble in
alcohol (10 mg /ml in ethanol) and e in pyridine (50mg / ml). Amitriptyline HCL is
soluble in water but the solubility decreases as pH increases (0.9 mg / ml at pH 6.8, and
1000 mg / ml at pH 1.2).
In an effort to produce a gel composition comprising estriol and amitriptyline the
inventors selected a Carbopol® polymer as the gelli ng agent. Estriol was dissolved in an
alcohol / solubiliser mix (comprising n-butanol, is o propanol, propylene glycol and
lene glycol monoethyl ether) sufficient to hold the estriol in an aqueous solution
(first solution) before adding Carbopol® 980. The second solution contained amitriptyline
HCL in a weak phosphate buffer to control the pH at 5.7. Both solutions were prepared
successfully however when mixed, no gel formed. Gel formation of the Carbomer range
is affected by salt content and Carbopol® Ultrez 21 is more resistant to salt than
Carbopol® 980. However this substitution did not r esult in gel formation. y the
phosphate buffer was removed to reduce the salt t and triethanolamine was used to
neutralise, but this also did not result in gel formation.
Pluronic® F-127 is a difunctional block copolymer s urfactant terminating in
primary hydroxyl groups. At higher concentrations (20%+) it is very fluid at low
temperatures (about 5oC) but when warmed to about 30oC, becomes a non fluid clear gel.
As it was determined that amitriptyline reduces the gelling properties of Pluronic® F-127,
it was decided that a two phase organic/aqueous gel system was appropriate, specifically a
pluronic in organogel (PLO) system. The PLO system uses Pluronic solution as the
aqueous phase and a in / isopropyl palmitate (LIP; in a 1:1 ratio) as the c
phase. These two phases, when blended under relatively high shear, produce an
organogel.
For the organic phase, estriol was dissolved/ dispersed (did not produce a clear
on) in propylene glycol then mixed with LIP. The ratio of propylene glycol to LIP
was 4 : 10. For the aqueos phase, amitriptyline HC L was dissolved in water, then
Pluronic® F-127 was added to give a 20% Pluronic so lution. The two phases were mixed
using a syringe to syringe transfer method which produce a relatively high shear mixing.
The ratio of c to aqueous phases was 1:2. This produced a stable organogel with
final concentrations of 300 mcg / g l and 0.5% w/w amitriptyline. Stability may be
increased by the addition of potassium sorbate.
To increase the dissolution of the estriol in the c phase, and thereby
e bioavailability, a combination of solubiliser (diethylene glycol hyl ether)
and propylene glycol was employed. A 50/50 mix of diethylene glycol monoethyl ether
and propylene glycol resulted in complete dissolution of the estriol. This was then
blended with the LIP to produce the organic phase. Mixing the organic phase with the
aqueous phase again resulted in a stable organogel.
Claims (11)
1. A composition for the treatment of chronic vulval or perineal pain, the composition comprising an en and a tricyclic antidepressant, wherein the composition is in the form of an organogel formulated for topical, transdermal or transmucosal administration, and n the estrogen is estriol and the tricyclic antidepressant is selected from amitriptyline and ptyline.
2. A composition according to claim 1, wherein the lic antidepressant is amitriptyline.
3. A ition according to claim 1 or 2, wherein the composition is a topical composition.
4. A composition according to any one of claims 1 to 3, wherein the chronic vulval or al pain is associated with ynia, pudendal neuralgia, or pelvic floor tension myalgia (levator ani myalgia).
5. A composition according to any one of claims 1 to 4, wherein the chronic vulval or perineal pain is associated with vulval vestibulitis, localized provoked vestibulodynia (LPV), hetic vulvodynia, vulvar dermatoses or cyclic vulvovaginitis.
6. A composition according to any one of claims 1 to 5, wherein the chronic vulval or perineal pain is associated with urethritis, urinary frequency or urgency, or faecal frequency or urgency.
7. Use of estriol and a tricyclic antidepressant selected from amitriptyline and nortriptyline in the manufacture of a composition for the treatment of chronic vulval or perineal pain, wherein the ition is in the form of an organogel ated for topical, transdermal or transmucosal administration.
8. Use according to claim 7, wherein the chronic vulval or perineal pain is associated with vulvodynia, pudendal neuralgia, or pelvic floor tension myalgia (levator ani myalgia).
9. Use according to claim 7 or 8, wherein the chronic vulval or perineal pain is associated with vulval ulitis, localized provoked vestibulodynia (LPV), dysesthetic vulvodynia, vulvar oses or cyclic vulvovaginitis.
10. Use according to any one of claims 7 to 9, wherein the chronic vulval or perineal pain is associated with urethritis, urinary frequency or urgency, or faecal frequency or urgency.
11. Use according to any one of claims 7 to 10, wherein the composition is a topical composition.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2016901605 | 2016-05-02 | ||
AU2016901605A AU2016901605A0 (en) | 2016-05-02 | Compositions for the treatment of chronic vulval and perineal pain and symptoms and conditions associated therewith | |
PCT/AU2017/050398 WO2017190183A1 (en) | 2016-05-02 | 2017-05-01 | Compositions for the treatment of chronic vulval and perineal pain and symptoms and conditions associated therewith |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ747690A NZ747690A (en) | 2021-11-26 |
NZ747690B2 true NZ747690B2 (en) | 2022-03-01 |
Family
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