U.S. patent application number 15/328443 was filed with the patent office on 2017-07-27 for oral transmucosal compositions including aromatase inhibitors for low testosterone levels in men.
The applicant listed for this patent is Professional Compounding Centers of America. Invention is credited to BRUCE VINCENT BIUNDO, TSU-I CATHERINE WANG.
Application Number | 20170209366 15/328443 |
Document ID | / |
Family ID | 55163958 |
Filed Date | 2017-07-27 |
United States Patent
Application |
20170209366 |
Kind Code |
A1 |
WANG; TSU-I CATHERINE ; et
al. |
July 27, 2017 |
ORAL TRANSMUCOSAL COMPOSITIONS INCLUDING AROMATASE INHIBITORS FOR
LOW TESTOSTERONE LEVELS IN MEN
Abstract
Formulations for oral transmucosal compositions that include
aromatase inhibitors (AIs) in combination with transmucosal
absorption enhancers are disclosed. Disclosed oral transmucosal
compositions may be for immediate release or slow release, and may
be administered to increase bloodstream testosterone levels and
thereby reduce symptoms of testosterone deficiency. Disclosed oral
transmucosal compositions may include liquid dosage forms, solid
dosage forms, and chewing gums. Further dosage forms may include
mucoadhesive thin strips, thin films, tablets, patches, and tapes,
among others. Other dosage forms may be: mucoadhesive liquids such
as gel-forming liquid; gel-forming; semisolids; and gel-forming
powders, among other dosage forms that exhibit mucoadhesive
properties, and provide oral transmucosal delivery of AIs.
Disclosed oral transmucosal compositions may allow the delivery of
AIs directly into the patient's bloodstream, thus providing high
bioavailability of AIs; therefore, required dose may be lower.
Additionally, adjustments of AIs dosages may be achieved when using
disclosed oral transmucosal compositions.
Inventors: |
WANG; TSU-I CATHERINE;
(SUGAR LAND, TX) ; BIUNDO; BRUCE VINCENT;
(HOUSTON, TX) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Professional Compounding Centers of America |
Houston |
TX |
US |
|
|
Family ID: |
55163958 |
Appl. No.: |
15/328443 |
Filed: |
July 22, 2015 |
PCT Filed: |
July 22, 2015 |
PCT NO: |
PCT/US15/41560 |
371 Date: |
January 23, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/006 20130101;
A61K 9/06 20130101; A61K 47/36 20130101; A61K 47/10 20130101; A61K
47/42 20130101; A61K 31/4196 20130101; A61K 9/2018 20130101; A61K
9/0056 20130101; A61K 47/38 20130101; A61K 9/0058 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/68 20060101 A61K009/68; A61K 47/10 20060101
A61K047/10; A61K 47/36 20060101 A61K047/36; A61K 47/38 20060101
A61K047/38; A61K 31/4196 20060101 A61K031/4196; A61K 47/42 20060101
A61K047/42 |
Claims
1. A method of oral transmucosal delivery of aromatase inhibitors
into a patient's bloodstream comprising administering a composition
comprising at least one aromatase inhibitor and a transmucosal
absorption enhancer, wherein the aromatase inhibitor bypasses
hepatic metabolism, and wherein in the patient is a male with low
testosterone levels.
2. The method of claim 1, wherein the aromatase inhibitor is a
selective aromatase inhibitor.
3. The method of claim 2, wherein the selective aromatase inhibitor
is selected from the group consisting of anastrozole, letrozole,
exemestane, vorozole, formestane, fadrozole, and combinations
thereof.
4. The method of claim 1, wherein the aromatase inhibitor is a
non-selective aromatase inhibitor.
5. The method of claim 4, wherein the non-selective aromatase
inhibitor is selected from the group consisting of
aminoglutehimide, testolactone, and combinations thereof.
6. The method of claim 1, wherein the transmucosal absorption
enhancer is selected from the group consisting of an enzyme
inhibitor; a chitosan or derivative thereof; a cylcodextrin; a bile
salt; a chelating agent; a fatty acid or derivatives thereof; a
lecithin; a phospholipid; a sulfoxide; urea or derivative thereof;
and a surfactant.
7. The method of claim 1, wherein the composition further comprises
a mucoadhesive polymer.
8. The method of claim 1, wherein the composition is administered
to a sublingual, buccal, gingival, or palatal site.
9. The method of claim 8, wherein the composition is administered
to a sublingual site in a dosage form selected from the group
consisting of a solution, emulsion, suspension, liquid spray and
tablet.
10. The method of claim 8, wherein the composition is administered
to a buccal site in a dosage form selected from the group
consisting of a buccal troche.
11. The method of claim 1, wherein the composition is formulated as
a chewing gum.
12. The method of claim 3, wherein the composition administered is
(a) about 0.05 mg/day to about 1.0 mg/day of anastrozole; (b) about
10 mg/day to about 50 mg/day of exemestane; or (c) about 0.025
mg/day to about 5.0 mg/day of letrozole.
13. The method of claim 1, wherein the composition further
comprises an additive selected from the group consisting of
diluents, binders, disintegrants, glidants, lubricants, thickening
agents, pH adjusters, preservatives, sweetners, flavors, colors,
effervescent agents, stabilizing agents, antioxidants, surfactants,
and combinations thereof.
14. A composition consisting of (a) at least one aromatase
inhibitor; (b) a transmucosal absorption enhancer; (c) a vehicle;
and (d) optionally, one or more additives.
15. The composition of claim 14, wherein the aromatase inhibitor is
a selective aromatase inhibitor.
16. The composition of claim 15, wherein the selective aromatase
inhibitor is selected from the group consisting of anastrozole,
letrozole, exemestane, vorozole, formestane, fadrozole, and
combinations thereof.
17. The composition of claim 14, wherein the aromatase inhibitor is
a non-selective aromatase inhibitor.
18. The composition of claim 17, wherein the non-selective
aromatase inhibitor is selected from the group consisting of
aminoglutehimide, testolactone, and combinations thereof.
19. The composition of claim 14 further consisting of a
mucoadhesive polymer.
20. A composition comprising: (a) about 0.25 to about 2.5 mg
letrozole; (b) about 1-5% gelatin; (c) about 1-5% pectin; (d) about
1-10% sodium carboxymethylcellulose; (e) about 0.1-5% xanthan gum;
(f) 1-10% polyethyleneglycol; (g) a penetration enhancer; and (h) a
plasticized base.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This Application is a 35 U.S.C. .sctn.371 National Stage
Entry of PCT/US2015/041560, filed on Jul. 22, 2015 which claims
priority to U.S. patent application Ser. No. 14/337,783, filed Jul.
22, 2014 entitled "Oral Transmucosal Compositions including
Aromatase Inhibitors for Low Testosterone Levels in Men", the
entirety of which is incorporated herein by reference as if set
forth herein in its entirety.
BACKGROUND
[0002] Field of the Disclosure
[0003] The present disclosure relates generally to pharmaceutical
compositions, and more particularly, to oral transmucosal
compositions including a plurality of aromatase inhibitors for
testosterone deficiency or high estradiol in men.
[0004] Background Information
[0005] Testosterone is the androgenic hormone primarily responsible
for normal growth and development of male sex and reproductive
organs, including the penis, testicles, scrotum, prostate, and
seminal vesicles. It facilitates the development of secondary male
sex characteristics such as musculature, bone mass, fat
distribution, hair patterns, laryngeal enlargement, and vocal cord
thickening, among others. Additionally, normal testosterone levels
maintain energy level, healthy mood, fertility, and sexual
desire.
[0006] The testes produce testosterone and are regulated by a
complex chain of signals that begins in the brain. This chain is
called the hypothalamic-pituitary-gonadal axis. The hypothalamus
secretes gonadotropin-releasing hormone (GnRH) to the pituitary
gland in pulses (bursts) which trigger the secretion of luteinizing
hormone (LH) from the pituitary gland. Luteinizing hormone
stimulates the Leydig cells of the testes to produce testosterone.
Normally, the testes produce approximately 4 mg to 7 mg of
testosterone per day.
[0007] Testosterone production declines naturally with age. Low
testosterone, or testosterone deficiency (TD), may result from
disease or damage to the hypothalamus, pituitary gland or testicles
that inhibits hormone secretion and testosterone production, and is
also known as hypogonadism. Depending on age, insufficient
testosterone production can lead to abnormalities in muscle and
bone development, underdeveloped genitalia and diminished
virility.
[0008] Testosterone deficiency can be treated by intramuscular
injections at intervals of 7 to 21 days, a testosterone patch worn
on the body, transdermal testosterone gels, mucoadhesive material
applied above the teeth twice a day, oral tablets, long-acting
subcutaneous implants, testosterone stick applicators (applied
similar to underarm deodorant), injectable pellets, and the
like.
[0009] Typically, testosterone therapy is administered orally,
parenterally, transdermally, or through buccal administration.
Additionally, testosterone therapy typically involves very high
doses of testosterone.
[0010] Oral therapy of testosterone lacks effectiveness because
testosterone is metabolized extensively during the first passage of
the liver before reaching the systemic blood circulation (i.e., the
first-pass effect). Intramuscular injections of testosterone esters
are widely used, but local pain, tolerability, and the
unphysiologically high levels of testosterone in the body during
the first days/weeks after injection are severe drawbacks to this
form of treatment. Local pain is attributed to the large volumes of
testosterone injected and the required help of health care
professionals makes injections inconvenient and expensive. These
same drawbacks also apply to implanted pellets.
[0011] Transdermal administration (e.g., patches, gels, etc.) has
the benefit that the first-pass effect is avoided and the treatment
is not painful. Unfortunately, transdermal compositions, excluding
patches, currently prescribed for hypogonadal men include from 40
mg to 120 mg (dosed daily) of which only a low percentage is
absorbed through the skin. Another drawback is that a large part of
the testosterone remains on the skin, with the potential risk of
transferring the medication to the skin of another person when
direct skin-to-skin contact is made. Additionally, the non-absorbed
portion of testosterone is lost to the surrounding environment
making these formulations non-environmentally-friendly.
Additionally, a common side effect of transdermal compositions is
local skin irritation. This is likely due to the very high ethanol
content of such formulations.
[0012] Oral transmucosal delivery is a particularly advantageous
delivery route. One of the advantages of oral transmucosal delivery
is that it is a non-invasive drug delivery method. Furthermore,
oral transmucosal delivery has better patient compliance, less risk
of infection, and lower cost than invasive procedures such as
injection and implantation. Oral transmucosal delivery also results
in much shorter onset time (i.e., the time from administration to
therapeutic effect) than oral delivery does. The active
pharmaceutical ingredient (API) absorbed when using oral
transmucosal delivery via the oral mucosa will also avoid
degradation in the gastrointestinal tract and first pass metabolism
in the liver. Oral transmucosal delivery is simple and can be
administered by a caregiver or the patient with minimal
discomfort.
[0013] Oral transmucosal administration involves the patient
holding the compositions in the oral cavity while the APIs
dissolves in the fluid available, diffuses through the mucosa
lining of the mouth, and is absorbed directly into the bloodstream
bypassing the gastrointestinal tract as well as hepatic
metabolism.
[0014] Recently, research studies have demonstrated that aromatase
inhibitors (AIs) as APIs may be used for male testosterone therapy.
AIs work by binding to the aromatase enzyme that converts
testosterone into estrogen. Estradiol serves as a major mediator of
sex steroid-gonadotropin feedback; hence, high estradiol levels
could contribute to low testosterone production through inhibition
of LH. However, high estradiol levels can exist independently of
testosterone levels. AIs effectively inhibit or block conversion of
testosterone into estrogen which leads to increased LH and
follicle-stimulating hormone (FSH) release from the pituitary.
Increased LH and FSH results in a subsequent increase in testicular
stimulation and serum testosterone levels without the increase in
estrogen levels, and thus could limit the likelihood of undesirable
effects such as gynecomastia. However, there are no AI products on
the market for treatment of either testosterone deficiency or high
estradiol in men.
[0015] For the aforementioned reasons, there is a need for oral
transmucosal dosage forms, including AIs, which can deliver AIs
directly into the patient's bloodstream with a high percentage of
bioavailability.
SUMMARY
[0016] The present disclosure refers to oral transmucosal
compositions that may include one or more aromatase inhibitors
(AIs) in order to increase testosterone levels in a patient's
bloodstream and reduce symptoms of testosterone deficiency.
According to some embodiments, the oral transmucosal compositions
may include different components, such as active pharmaceutical
ingredients (APIs), transmucosal absorption enhancers, suitable
vehicles, and suitable additives, among others.
[0017] According to one embodiment, APIs may include selective AIs
such as Anastrozole (Arimidex), Letrozole (Femara), Exemestane
(Aromasin), Vorozole (Rivizor), Formestane (Lentaron), and
Fadrozole (Afema). In another embodiment, APIs may include
non-selective AIs such as Aminoglutethimide, and Testolactone
(Teslac). In yet another embodiment, APIs may include any other
selective or non-selective chemical known to people skilled in the
art that inhibits the enzyme aromatase and may prevent estrogen
from being formed from its metabolic precursors.
[0018] In an example, the AI employed in oral transmucosal
compositions may be Anastrozole, Exemestane, or Letrozole.
[0019] In some embodiments, various additives may be included to
facilitate the preparation of suitable dosage forms. For example,
additives may include diluents, binders, disintegrants, lubricants,
glidants, mucoadhesive polymers, thickening agents, transmucosal
absorption enhancers, polymer plasticizers, pH adjusters,
preservatives, sweeteners, flavors, colors, effervescent agents,
stabilizing agents, antioxidants, and surfactants, among others.
Additives are known to those skilled in the art.
[0020] In some embodiments, transmucosal absorption enhancers
provide more efficient API skin and mucosal tissue penetration. In
these embodiments, the transmucosal absorption enhancers allow
lower API dosage requirements.
[0021] In some embodiments, oral transmucosal compositions allow
the delivery of AIs directly into the patient's bloodstream
bypassing the gastrointestinal tract and the hepatic metabolism. In
these embodiments, bypassing the gastrointestinal tract and the
hepatic metabolism results in a higher percentage of
bioavailability of AIs to the patient. Further to these
embodiments, adjustments of AIs dosages may be achieved when using
the disclosed oral transmucosal compositions.
[0022] In some embodiments, oral transmucosal compositions may
provide dosage regimens of AIs that are tailored for individual
patients. In an example, depending on the baseline serum
concentrations of testosterone and estradiol in a patient, a
medical doctor may prescribe an oral transmucosal composition with
a dosage regimen to more closely mimic the circadian rhythm and
physiological pulsatile secretion of testosterone thereby keeping
the testosterone and estradiol levels within suitable ranges.
[0023] Examples of oral transmucosal compositions that may be
administered include dosage ranges of: about 0.05 mg/day to about
1.0 mg/day of Anastrozole, preferably about 0.1 mg/day to about 0.5
mg/day; about 10 mg/day to about 50 mg/day of Exemestane,
preferably about 25 mg/day to about 50 mg/day; or about 0.025
mg/day to about 5.0 mg/day of Letrozole, preferably about 0.25
mg/day to about 2.5 mg/day.
[0024] In some embodiments, oral transmucosal compositions may
include liquid dosage forms such as sublingual solutions,
emulsions, suspensions, and liquid sprays, among others. In other
embodiments, oral transmucosal compositions may include solid
dosage forms such as sublingual tablets, and buccal troches, among
others. In yet other embodiments, oral transmucosal dosage forms
may include chewing gums.
[0025] In some embodiments, oral transmucosal dosage forms include
mucoadhesive polymers as part of the compositions. Examples of
dosage forms include mucoadhesive thin strips, thin films, tablets,
patches, and tapes, among others. In other embodiments, dosage
forms include: mucoadhesive liquids such as gel-forming liquid;
semisolids such as gels, gel-forming ointments, and gel-forming
pastes; gel-forming powders, or any other dosage forms that exhibit
mucoadhesive properties and provide oral transmucosal delivery of
AIs.
[0026] Absorption sites, within the oral cavity, for oral
transmucosal dosage forms may be sublingual, buccal, gingival,
palatal, or the like.
[0027] In some embodiments, providing low dose formulations in any
of the above identified methodologies will result in acceptable
testosterone levels in the patient. This contrasts with current
popular topical treatment options, which use very high dosages of
testosterone to get a few milligrams of testosterone absorbed into
the bloodstream.
[0028] In some embodiments, dosage forms are designed for immediate
release and transmucosal absorption of AIs. In other embodiments,
AIs may be released and absorbed over a prolonged period of time
for systemic effects.
[0029] Numerous other aspects, features, and benefits of the
present disclosure may be made apparent from the following detailed
description.
DETAILED DESCRIPTION
[0030] The present disclosure is here described in detail. Other
embodiments may be used and/or other changes may be made without
departing from the spirit or scope of the present disclosure. The
illustrative embodiments described in the detailed description are
not meant to be limiting of the subject matter presented here.
Definitions
[0031] As used here, the following terms may have the following
definitions:
[0032] "Active Pharmaceutical Ingredient (API)" refers to a
chemical compound that induces a desired effect, and includes
agents that are therapeutically effective, prophylactically
effective, or cosmeceutically effective.
[0033] "Adsorption Enhancer" or, equivalently, "Penetration
Enhancer" refers to a substance used to modify, generally to
increase, the rate of permeation through skin or other body tissue
of one or more substances (e.g., APIs) in a formulation.
[0034] "Aromatase Inhibitor (Al)" refers to a chemical compound
that blocks or inhibits the activity of aromatase which is an
enzyme that converts androgens to estrogens. As such, an aromatase
inhibitor acts to reduce estrogen levels in the body.
[0035] "Treating" and "Treatment" refers to reduction in severity
and/or frequency of symptoms, elimination of symptoms and/or
underlying cause, prevention of the occurrence of symptoms and/or
their underlying cause, and improvement or remediation of
damage.
[0036] "Vehicle" refers to a substance of no therapeutic value that
is used to convey at least one API for administration.
Description of the Disclosure
[0037] Embodiments of the present disclosure are directed towards
oral transmucosal delivery of active pharmaceutical ingredient
(APIs). Oral transmucosal compositions that include one or more
aromatase inhibitors (AIs) as APIs are described. The present
disclosure including AIs is proposed to increase testosterone
levels in a patient's bloodstream and reduce symptoms of
testosterone deficiency.
[0038] Estradiol serves as a major mediator of sex
steroid-gonadotropin feedback; hence, high estradiol levels could
contribute to low testosterone production through inhibition of
luteinizing hormone (LH). Aromatase inhibitors block the formation
of estradiol and can limit the inhibition of LH. High estradiol
levels can exist independently of testosterone levels and AIs may
limit the likelihood of undesirable effects from estradiol such as
gynecomastia.
[0039] Formulation
[0040] Oral transmucosal compositions may include one or more AIs
as APIs, transmucosal absorption enhancers, vehicles, and
additives, among other suitable ingredients.
[0041] According to one embodiment, APIs may include selective AIs
such as Anastrozole (Arimidex), Letrozole (Femara), Exemestane
(Aromasin), Vorozole (Rivizor), Formestane (Lentaron), and
Fadrozole (Afema). In another embodiment, APIs may include
non-selective AIs such as Aminoglutethimide, and Testolactone
(Teslac). In yet another embodiment, APIs may include any other
selective or non-selective chemical known to people skilled in the
art that inhibits the enzyme aromatase and may prevent estrogen
from being formed from its metabolic precursors.
[0042] The list of AIs above is not exhaustive; other compounds
described in the art that meet the set requirements may also be
considered.
[0043] In an example, the AI employed in oral transmucosal
compositions may be Anastrozole, Exemestane, or Letrozole.
[0044] In some embodiments, various additives may be included to
facilitate the preparation of suitable dosage forms. For example,
additives may include diluents, binders, disintegrants, lubricants,
glidants, mucoadhesive polymers, thickening agents, transmucosal
absorption enhancers, polymer plasticizers, pH adjusters,
preservatives, sweeteners, flavors, colors, effervescent agents,
stabilizing agents, antioxidants, and surfactants, among others.
Additives are known to those skilled in the art.
[0045] In some embodiments, transmucosal absorption enhancers
provide more efficient API skin and mucosal tissue penetration. In
these embodiments, the transmucosal absorption enhancers allow
lower API dosage requirements.
[0046] In some embodiments, diluents for solid dosage forms may
include calcium carbonate, dibasic calcium phosphate, tribasic
calcium phosphate, calcium sulfate, kaolin, microcrystalline
cellulose, and other cellulose derivates, sodium chloride, starch
and starch derivates, sucrose, dextrose, lactose, and sorbitol,
among others.
[0047] Binders for solid dosage forms may include starch and starch
derivatives, gelatin, sucrose, glucose, dextrose, molasses,
lactose, natural and synthetic gums, acacia, sodium alginate,
extract of Irish Moss, panwar gum, ghatti gum, mucilage of isapol
husks, carboxymethylcellulose, methylcellulose, cellulose
derivatives, Veegum, polyvinylpyrolidone, and polyethylene glycols,
among others.
[0048] Disintegrants for solid dosage forms may include veegum,
agar, bentonite, alginic acid and alginic acid derivatives, guar
gum, starch, sodium starch glycolate, other starch derivatives,
clays, cellulose, and cellulose derivatives, among others.
[0049] Lubricants for solid dosage forms may include stearic acid,
stearic acid derivatives, stearic acid salts such as magnesium
stearate and calcium stearate, talc, hydrogenated vegetables oils,
polyethylene glycols, surfactants, and waxes, among others.
[0050] Additionally, solid dosage forms of oral transmucosal
compositions may include: a glidant, such as colloidal silicon
dioxide and talc, among others; a sweetening agent, such as sucrose
or saccharin, among others; natural or artificial flavors, such as
peppermint, methyl salicylate, or orange flavor, among others.
[0051] The pH adjusting agents may include sodium bicarbonate,
magnesium hydroxide, calcium carbonate, dibasic calcium phosphate,
tribasic calcium phosphate, sodium bicarbonate, magnesium
hydroxide, potassium hydroxide, citric acid, lactic acid,
hydrochloric acid, sulfuric acid, phosphoric acid, sodium phosphate
monobasic, and sodium phosphate dibasic, among others.
[0052] Surfactants may include: polysorbates such as polysorbate
20, 40, 60, and 80, among others; sorbitan esters such as sorbitan
monolaurate, and sorbitan monopalmitate, sorbitan monooleate, among
others; and sodium lauryl sulfate, among others.
[0053] Effervescent agents are usually a combination of one or more
acids with one or more bases. Acids may be selected from citric
acid, tartaric acid, and the like. Bases may be sodium bicarbonate
or other suitable agents that may react with acids, and produce
gas.
[0054] In some embodiments, a stabilizing agent may be used to
stabilize the API for a specific dosage form. In these embodiments,
the stabilizing agent used will depend on the API used as well as
the other additive ingredients. Any suitable chemical substance may
be used as a stabilizing agent. Stabilizing agents are known in the
art and will not be discussed further.
[0055] Mucoadhesive polymers may include: gums such as acacia,
agarose, alginic acid, sodium alginate and other alginic acid
derivatives, carrageenan, gelatin, gellan, guar gum, hakea gum,
karaya gum, and locust bean gum, among others; chitosan and
chitosan derivatives; hyaluronic acid, pectin, and other
polysaccharides; gelatin, polyisoprene, polyisobutylene,
polyetherurethane, polyvinylalcohol, polyvinylpyrrolidone,
polycarbophil, polyethylene oxide polymers, and pullulan, among
others. Mucoadhesive polymers may also include cellulose
derivatives such as ethyl cellulose, cellulose acetate,
hydroxyethyl cellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, methylcellulose,
methylhydroxyethylcellulose, and sodium carboxymethyl cellulose,
among others; poly(acrylic acid)-based polymers such as
polyacrylates, poly (methylvinylether-co-methacrylic acid),
poly(acrylic acid-co-ethylhexylacrylate), poly(acrylic
acid-co-acrylamide), poly(acrylic acid-co-butylacrylate),
poly(acrylic acid-co-methyl methacrylate), poly (2-hydroxyethyl
methacrylate), polymethacrylates , poly(alkylcyanoacrylate) and
other cyanoacrylates, poly (isohexycyanoacrylate), poly
(isobutylcyanoacrylate), and hydroxyethyl methacrylate, and any
other polymer known to a person skilled in the art that exhibits
mucoadhesive characters.
[0056] Plasticizers for mucoadhesive polymeric dosage forms may
include pullulan, hydroxypropyl methylcellulose, propylene glycol,
glycerol, sorbitol, mannitol, polyethylene glycols (PEG 200, 400,
600, 1000, 1500, 2000), tartaric acid, malic acid, lactic acid,
citric acid, and yonkenafil, and any other chemical known to a
person skilled in the art that can increase the plasticity of any
mucoadhesive polymer.
[0057] Oral transmucosal absorption enhancers may include: enzyme
inhibitors such as aprotinin and puromycin, among others; chitosan
and chitosan derivatives such as chitosan glutamate, trimethyl
chitosan, chitosan-4-thioglycolic acid, 5-methyl-pyrrolidine
chitosan, and chitosan-4-thio-butylamidine, among others; alpha,
beta, and gama cyclodextrins such as dimethyl cyclodextrin,
sulfobutyl cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin,
poly-beta-cyclodextin, and methylated beta-cyclodextrin, among
others; bile salts such as sodium deoxycholate, sodium
glycocholate, sodium glycodeoxycholate, sodium
glycodihydrofusidate, sodium taurocholate, sodium
taurodeoxycholate, sodium tauroglycocholate,sodium
taurodihydrofusidate, and sodium ursocholate, among others;
chelating agents such as sodium EDTA, citric acid, sodium citrate,
sodium salicylate, methylsalicylate, methoxysalicylate, and
polyacrylates, among others; alcohols such as ethanol and
isopropanol, among others; fatty acids and derivatives such as
oleic acid, methyloleate, capric acid, neodecanoic acid, elaidic
acid, lauric acid, palmitoylearnitine, cod liver oil extract, mono
glycerides and diglycerides of oleic acid andcapric acid, lauric
acid, sodium laurate, linoleic acid, sodium fusidate, sodium
caprate, lyceryl monolaurate, glyceryl monooleate, glyceryl
monostearate, sucrose fatty acid esters, and diethylene glycol
monoethyl ether, among others; lecithins and phospholipids such as
phodphatidylcholine, lysophosphatidyl choline, and
didecanoylphophatidylcholine, among others; sulfoxides such as
dimethylsulfoxide and decylmethyl sulfoxide, among others; polyols
such as glycerin, propylene glycol, propanediol, and polyethylene
glycols of various molecular weights, among others; urea and
derivatives such as unsaturated cyclic urea, among others;
surfactants such as sodium dodecyl sulfate, sodium lauryl sulfate,
dioctyl sodium sulfosuccinate, nonylphenoxypolyoxyethylene,
polyoxyethylene alkyl ethers, polyoxyethylene-9-lauryl ether,
polyoxyethylene 23 lauryl ether, polyoxyethylene-20-cetyl ether,
polyethyleneglycol dodecyl ether, polyethylene glycol-8 laurate,
glyceryl monolaurate, polyoxyethylene stearates, polysorbates,
sorbitan fatty acid esters, polyoxyethylene castor oil derivatives,
benzalkonium chloride, cetylpyridinium chloride, and
cetyltrimethylammonium bromide, among others. Other oral
transmucosal absorption enhancers may include alkylglycosides,
azone, hyaluronic acid, sodium Hyaluronate, glycine
chenodeoxycholate, lauroyl macroglycerides, isopropyl myristate,
isopropyl palmitate, glutathione, witepsol, menthol, capsaicin,
taurine, tocopheryl acetate, lauroyl macroglycerides, lionoleoyl
polyoxyl-6 glycerides; diethylene glycol monoethyl ether, dextran
sulfate, various saponins, poly-1-arginine, and 1-lysine, and any
other chemical known to a person skilled in the art that exhibits
penetration enhancing effect on transmucosal absorption.
[0058] Bases for chewing gum may include cellulosic polymer, and
acrylic polymer, among others.
[0059] In some embodiments, oral transmucosal compositions may
include pharmaceutical solvents to produce sprays, solutions,
emulsions, suspensions, gels, gel-forming liquids, ointments and
pastes, among others.
[0060] In some embodiments, pharmaceutical solvents for liquid
dosage forms of oral transmucosal compositions may include water,
liquid polyethylene glycols of various molecular weights, ethyl
oleate, medium chain triglycerides, isopropyl myristate, isopropyl
palmitate, isopropyl stearate, other pharmaceutically acceptable
esters of C8-C22 fatty acids and C2-C6 alcohols, mineral oil, and
vegetable oils, among others.
[0061] C8-C22 fatty acids may include fatty acids having from 8 to
22 carbon atoms, such as myristic acid, palmitic acid, stearic
acid, arachidic acid, or oleic acid, among others.
[0062] C2-C6 alcohols may include alcohols having from 2 to 6
carbon atoms, in particular the C2-C5 alcohols as well as the
homologues with 6 carbon atoms including diols and triols such as
ethanol, propylene glycol, and glycerol, among others.
[0063] Examples of vegetable oils may include almond oil, peanut
oil, sesame oil, sunflower oil, safflower oil, canola oil, corn
oil, and olive oil, among others.
[0064] In some embodiments, oral transmucosal ointments and pastes
may include petrolatum, PCCA plasticized base, paraffin wax,
various synthetic wax, lanolin, beeswax, carnauba wax, candelila
wax, silicones, isopropylesters, polyols, cellulose ethers, among
other suitable bases. In addition, ointment bases may also include
suitable pharmaceutical solvents, such as water, liquid
polyethylene glycols of various molecular weights, ethyl oleate,
medium chain triglycerides, isopropyl myristate, isopropyl
palmitate, isopropyl stearate, and other pharmaceutically
acceptable esters of C8-C22 fatty acids and C2-C6 alcohols, mineral
oil, and vegetable oils, among others.
[0065] Administration
[0066] In some embodiments, oral transmucosal compositions allow
the delivery of AIs directly into the patient's bloodstream
bypassing the gastrointestinal tract and the hepatic metabolism. In
these embodiments, bypassing the gastrointestinal tract and the
hepatic metabolism results in a higher percentage of
bioavailability of AIs to the patient. Further to these
embodiments, adjustments of AIs dosages may be achieved when using
the disclosed oral transmucosal compositions.
[0067] In some embodiments, oral transmucosal compositions may be
administered in the oral cavity at the sublingual, palatal, buccal,
gingival, or the like. Oral transmucosal compositions may be
self-administered by the patient or administered by a medical
practitioner, such as a physician or nurse.
[0068] In some embodiments, oral transmucosal compositions may
include liquid dosage forms such as sublingual solutions,
emulsions, suspensions, and liquid sprays, among others. In other
embodiments, oral transmucosal compositions may include solid
dosage forms such as sublingual tablets, and buccal troches, among
others. In yet other embodiments, oral transmucosal dosage forms
may include chewing gums.
[0069] In some embodiments, oral transmucosal dosage forms include
mucoadhesive polymers as part of the compositions. Examples of
dosage forms include mucoadhesive thin strips, thin films, tablets,
patches, and tapes, among others. In other embodiments, dosage
forms include: mucoadhesive liquids such as gel-forming liquid;
semisolids such as gels, gel-forming ointments, and gel-forming
pastes; gel-forming powders, or any other dosage forms that exhibit
mucoadhesive properties and provide oral transmucosal delivery of
AIs.
[0070] Absorption sites, within the oral cavity, for oral
transmucosal dosage forms may be sublingual, buccal, gingival,
palatal, or the like.
[0071] In some embodiments, dosage forms are designed for immediate
release and transmucosal absorption of AIs. In other embodiments,
AIs may be released and absorbed over a prolonged period of time
for systemic effects.
[0072] In some embodiments, oral transmucosal compositions may be
administered in a single administration whereby a certain amount of
Al may be administered at once. In an example, one puff of a spray
solution may be administered representing the full desired dose. In
other embodiments, oral transmucosal compositions may be
administered by multiple administrations in one or more sub-doses
over a specified period of time. In an example, one, two or more
puffs of a smaller dose may be administered preferably shortly
after one another.
[0073] In some embodiments, oral transmucosal compositions may
provide dosage regimens of AIs that are tailored for individual
patients. In an example, depending on the baseline serum
concentrations of testosterone and estradiol in a patient, a
medical doctor may prescribe an oral transmucosal composition with
a dosage regimen to more closely mimic the circadian rhythm and
physiological pulsatile secretion of testosterone thereby keeping
the testosterone and estradiol levels within suitable ranges.
[0074] In some embodiments, providing low dose formulations in any
of the above identified methodologies will result in acceptable
testosterone levels in the patient. This contrasts with current
popular topical treatment options, which use very high dosages of
testosterone to get a few milligrams of testosterone absorbed into
the bloodstream.
[0075] In various embodiments, the dosages (e.g., daily) required
depend on the type of Al included in the disclosed oral
transmucosal compositions. In other words, some AIs are more potent
than others, and hence, the dosing can vary among the various AIs
used.
[0076] Examples of oral transmucosal compositions that may be
administered include dosage ranges of: about 0.05 mg/day to about
1.0 mg/day of Anastrozole, preferably about 0.1 mg/day to about 0.5
mg/day; about 10 mg/day to about 50 mg/day of Exemestane,
preferably about 25 mg/day to about 50 mg/day; or about 0.025
mg/day to about 5.0 mg/day of Letrozole, preferably about 0.25
mg/day to about 2.5 mg/day.
[0077] In some embodiments, providing low dose oral transmucosal
compositions allows controlling the increase of testosterone levels
in relation to the administered dosages of AIs.
[0078] The following examples are intended to illustrate the scope
of the disclosure and are not intended to be limiting. It is to be
understood that other procedures known to those skilled in the art
may alternatively be used.
EXAMPLES
[0079] The following are exemplary of dosage forms of the oral
transmucosal compositions.
[0080] Example #1 illustrates formula for one Anastrozole
sublingual tablet:
TABLE-US-00001 Ingredient Composition Anastrozole 0.1-0.5 mg
Penetration enhancer(s) Appropriate concentration Lactose/sucrose
(80:20) q.s. 100%
[0081] Example #2 illustrates formula for one dose of Anastrozole
sublingual drops:
TABLE-US-00002 Ingredient Composition Anastrozole 0.1-0.5 mg
Co-solvent(s) 10-50% Penetration enhancer(s) Appropriate
concentration Flavors As needed Sweeteners As needed Base Solvent
(Glycerin) q.s. 100%
[0082] Example #3 illustrates formula for one dose of Letrozole
oral adhesive paste:
TABLE-US-00003 Ingredient Composition Letrozole 0.25-2.5 mg Gelatin
1-5% Pectin 1-5% Sodium Carboxymethylcellulose 1-10% Xanthan gum
0.1-5% PEG-90M 1-10% Penetration enhancer(s) Appropriate
concentration PCCA Plasticized Base q.s. 100%
[0083] While various aspects and embodiments have been disclosed,
other aspects and embodiments are contemplated. The various aspects
and embodiments disclosed are for purposes of illustration and are
not intended to be limiting, with the true scope and spirit being
indicated by the following claims.
* * * * *