U.S. patent application number 14/820761 was filed with the patent office on 2015-12-03 for pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same.
The applicant listed for this patent is Clarus Therapeutics, Inc.. Invention is credited to Panayiotis P. Constantinides, Robert E. Dudley.
Application Number | 20150343073 14/820761 |
Document ID | / |
Family ID | 37115755 |
Filed Date | 2015-12-03 |
United States Patent
Application |
20150343073 |
Kind Code |
A1 |
Dudley; Robert E. ; et
al. |
December 3, 2015 |
PHARMACEUTICAL DELIVERY SYSTEMS FOR HYDROPHOBIC DRUGS AND
COMPOSITIONS COMPRISING SAME
Abstract
A drug delivery system for oral administration of hydrophobic
drugs with enhanced and extended absorption and improved
pharmacokinetics is provided. In one embodiment, formulations
comprising testosterone and testosterone esters, e.g., testosterone
palmitate, are disclosed. Methods of treating a hormone deficiency
or effecting male contraception with the inventive formulations are
also provided.
Inventors: |
Dudley; Robert E.; (Rosemary
Beach, FL) ; Constantinides; Panayiotis P.; (Gurnee,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Clarus Therapeutics, Inc. |
Northbrook |
IL |
US |
|
|
Family ID: |
37115755 |
Appl. No.: |
14/820761 |
Filed: |
August 7, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13553586 |
Jul 19, 2012 |
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14820761 |
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11911446 |
Nov 12, 2007 |
8241664 |
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PCT/US2006/014207 |
Apr 14, 2006 |
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13553586 |
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60721971 |
Sep 30, 2005 |
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60671454 |
Apr 15, 2005 |
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Current U.S.
Class: |
514/178 |
Current CPC
Class: |
A61K 31/573 20130101;
A61K 47/26 20130101; A61K 9/0053 20130101; A61K 31/22 20130101;
A61K 31/568 20130101; A61P 5/24 20180101; A61K 9/4858 20130101;
A61P 43/00 20180101; A61K 31/573 20130101; A61K 47/14 20130101;
A61P 15/16 20180101; C07J 1/00 20130101; A61K 9/06 20130101; A61K
9/1075 20130101; A61K 47/10 20130101; A61P 5/26 20180101; A61K
31/22 20130101; A61P 15/00 20180101; A61K 47/12 20130101; A61K
47/44 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 47/44 20060101
A61K047/44; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14; A61K 31/568 20060101 A61K031/568 |
Claims
1.-223. (canceled)
224. A method of treating testosterone deficiency or its symptoms
comprising orally administering to a subject suffering from
testosterone deficiency or its symptoms an effective amount of a
pharmaceutical composition comprising (1) a testosterone ester
chosen from testosterone enanthate; testosterone undecanoate;
testosterone cypionate, and testosterone palmitate, (2) a
lipophilic surfactant chosen from mono- and/or di-glycerides of
fatty acids, (3) Cremophor RH40 (polyoxyl 40 hydrogenated castor
oil), and (4) a polyethylene glycol with an average molecular
weight of about 200 to about 10,000 g/mol, wherein said composition
is free of ethanol.
225. The method as recited in claim 224 wherein the testosterone
ester is testosterone undecanoate.
226. The method as recited in claim 224 wherein said mono and/or
di-glycerides of fatty acids is chosen from Precirol ATO 5
(glyceryl palmitostearate) and Maisine (glyceryl
mono-linoleate).
227. The method as recited in claim 224 wherein said composition
contains 10% to 20% w/w of testosterone ester.
228. The method as recited in claim 224 wherein said composition is
a semi-solid.
Description
CLAIM OF PRIORITY
[0001] This application claims priority to United States
provisional application nos. 60/671,454 filed Apr. 15, 2005 and
60/721,971 filed Sep. 30, 2005, both of which disclosures have been
incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to pharmaceutical
delivery systems of hydrophobic drugs and compositions comprising
same. More particularly, the present invention relates to
pharmaceutical compositions comprising testosterone and esters
thereof with enhanced and extended absorption and
pharmacokinetics.
BACKGROUND OF THE INVENTION
[0003] Many pharmaceutically active compounds intended for oral
administration are poorly soluble in water providing a challenge to
formulate these drugs in a drug delivery system that exhibits the
desirable pharmacokinetic profiles in vivo. Poor oral
bioavailability may lead to ineffective therapy, the need for
higher dosing and/or undesirable side effects. As well,
pharmaceutical preparations with relatively short half-lives
require frequent dosing at the expense of patient inconvenience and
higher therapy costs.
[0004] Sex hormones (e.g., testosterone and its esters) are
marginally water soluble, and attempts have been made to increase
their bioavailability, particularly when taken orally. However,
administration of testosterone, per se, presents additional
challenges. Indeed, while testosterone given by mouth is
essentially completely absorbed into the portal circulation,
because of extensive first-pass hepatic metabolism, the serum
concentration of testosterone following this route of
administration is low unless very large doses are administered. To
overcome this problem, attempts have been made to alkylate
testosterone at the C-17 position (e.g., with a methyl group to
form methyltestosterone) thereby reducing metabolism by the liver.
Unfortunately, however, mere alkylation of testosterone has not
yielded desirable bioavailability and has been associated with
potentially serious hepatotoxicity.
[0005] Other attempts have managed to increase the transient
bioavailability of testosterone and its derivatives with lipophilic
solvents and surfactants. Nonetheless, even in cases where
bioavailability was enhanced, the delivery systems failed to
maintain desirable serum concentrations over an extended period of
time.
[0006] Accordingly, there is a need for a drug delivery system that
can provide enhanced bioavailability of hydrophobic drugs in vivo.
In addition, with respect to testosterone therapy, there is a need
for an oral drug delivery system that may provide enhanced
bioavailability of testosterone and/or an ester thereof in vivo
over an extended period of time.
SUMMARY OF THE INVENTION
[0007] In one embodiment of the present invention, a pharmaceutical
composition is provided comprising testosterone palmitate (TP), or
a testosterone ester thereof, and two or more lipid components at
least the first of which comprises a hydrophilic surfactant and at
least the second of which comprises a lipophilic surfactant that
provides for the controlled release of TP, said lipid components
together providing for the solubilization of TP. The pharmaceutical
composition may further comprise at least three lipid components at
least the first of which comprises a hydrophilic surfactant, at
least the second of which comprises a lipophilic surfactant that
provides for the controlled release of TP and at least the third of
which comprises a lipophilic surfactant that further provides for
the solubilization of TP. As well, the pharmaceutical composition
may further comprise a second lipid-soluble therapeutic agent, such
as a synthetic progestin. Formulations comprising same may be
preferably in the form of an orally active male contraceptive.
[0008] The first lipid component may exhibit an HLB of 10 to 45,
preferably 10 to 30, and more preferably 10 to 20. The second lipid
component may exhibit an HLB of less than about 10, preferably less
than about 7, and more preferably less than about 5. Further, the
second lipid component may exhibit a melting point in the range of
about 25.degree. C. to about 80.degree. C., preferably about
35.degree. C. to about 65.degree. C., and more preferably about
40.degree. C. to about 60.degree. C. The second lipid component may
be chosen from the group consisting of stearic acid, palmitic acid,
glycerol and PEG esters thereof, Precirol ATO 5 and Gelucires.
[0009] In some embodiments, the lipophilic surfactant further
comprises a "sustained" or controlled-release" surfactant which may
be chosen from the group consisting of stearic acid, palmitic acid,
glycerol and PEG esters thereof, Precirol AT05, Imwitor 191,
Myverol 18-06, Imwitor 370, Imwitor 375, Caprol ET, Cithrol 2MS,
Marosol 183 and combinations thereof. The hydrophilic surfactant
may be a poloxyl derivative of castor oil. Commercially available
products of this class are supplied under the tradenames, Cremophor
or Etocas and include, Cremophor EL and RH 40 and Etocas 35 and 40.
Chemophor, RH40 or Etocas 40 are preferred.
[0010] Compositions of the present invention may comprise, based on
weight, 10-70% a lipophilic surfactant; 1-40% a controlled release
surfactant; and 5-60% a hydrophilic surfactant; and preferably
30-50% a lipophilic surfactant; 5-25% a controlled release
surfactant; and 30-40% a hydrophilic surfactant. The compositions
further comprise about 5 to about 50 percent, by weight,
testosterone palmitate, preferably, about 20 to about 40 percent,
by weight, testosterone palmitate. The inventive pharmaceutical
compositions may also comprise one or more cosolvents and/or filled
into a hard or soft gelatin capsule.
[0011] In another aspect of the present invention, a method of
preventing or alleviating the symptoms of testosterone deficiency
in a mammalian subject is provided comprising administering to the
mammalian subject an effective amount of testosterone palmitate
(TP) solubilized in two or more lipid components, such that the
administration of said solubilized TP raises the mammalian
subject's steady state serum level of testosterone to within those
levels found in mammalian subjects having no testosterone
deficiency and providing at least some relief from such symptoms.
In human males, the administering is preferably once or twice daily
and the mammal's steady state serum level of testosterone is raised
to fall within a range of about 300 ng/dl to about 1100 ng/dl. With
human females, a similar dosing schedule (with a lower daily TP
dose) is preferred to achieve serum testosterone levels of
approximately 10 to 100 ng/dl. In some embodiments, the method may
raise the mammal's steady state serum level of testosterone by
150%, 200%, 300% or 400%. The method may further comprise
administering an amount of a synthetic progestin sufficient to
inhibit gonadotropin release in said mammalian subject and produce
severe oligospermia or azospermia.
[0012] In yet another aspect of the present invention, a method of
delivering steady-state serum levels of testosterone effective to
provide at least some relief from symptoms of testosterone
deficiency is provided comprising solubilizing testosterone
palmitate (TP) in two or more lipid components at least the first
of which comprises a hydrophilic surfactant and at least the second
of which comprises a lipophilic surfactant that provides for the
controlled release of TP and administering an effective amount of
the solubilized TP to a subject suffering from the symptoms of
testosterone deficiency. The method can further comprise
solubilizing TP in at least three lipid components at least the
first of which comprises a hydrophilic surfactant, at least the
second of which comprises a lipophilic surfactant that provides for
the controlled release of TP and at least the third of which
comprises a lipophilic surfactant that further provides for the
solubilization of TP.
[0013] In further yet another aspect of the present invention, a
method of providing extended release of testosterone in vivo is
provided, the method comprising solubilizing testosterone palmitate
(TP) in a lipid mixture comprising two or more lipid components at
least the first of which comprises a hydrophilic surfactant and at
least the second of which comprises a lipophilic surfactant having
a melting point of greater than about 35.degree. C.
[0014] In still further yet another embodiment of the present
invention, a pharmaceutical composition is provided comprising
testosterone palmitate (TP) and two or more lipid components at
least the first of which comprises a hydrophilic surfactant and at
least the second of which comprises a lipophilic surfactant, in
which the at least first hydrophilic component or the at least
second lipophilic component provides for the controlled release of
TP, and said lipid components together provide for the
solubilization of TP. In one embodiment, the at least first
hydrophilic component provides for the controlled release of
TP.
[0015] In this respect, before explaining at least one embodiment
of the invention in detail, it is to be understood that the
invention is not limited in its application to the details of
construction and to the arrangements of the components set forth in
the following description or illustrated in the drawings. The
invention is capable of embodiments in addition to those described
and of being practiced and carried out in various ways. Also, it is
to be understood that the phraseology and terminology employed
herein, as well as the abstract, are for the purpose of description
and should not be regarded as limiting.
[0016] As such, those skilled in the art will appreciate that the
conception upon which this disclosure is based may readily be
utilized as a basis for the designing of other structures, methods
and systems for carrying out the several purposes of the present
invention. For example, some embodiments of the invention may
combine TP with other active drugs, including hormonals, in an oral
delivery system that, in part, prevents or alleviates symptoms
associated with testosterone deficiency. It is important,
therefore, that the claims be regarded as including such equivalent
constructions insofar as they do not depart from the spirit and
scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which maximizes diurnal variation while producing an early
Tmax, preferably compatible with early morning, once-daily
dosing.
[0018] FIG. 2 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP which maximizes diurnal variation while producing a late
Tmax, preferably compatible with night-time, once-daily dosing.
[0019] FIG. 3 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP which provides physiological diurnal variation and an early
Tmax, preferably compatible with early morning, once-daily
dosing.
[0020] FIG. 4 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which provides physiological diurnal variation and a delayed
Tmax, preferably compatible with early morning, once-daily
dosing.
[0021] FIG. 5 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which provides a short elimination half-life and an early
Tmax, preferably compatible with maximal patient activity soon
after waking and twice-daily dosing.
[0022] FIG. 6 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which provides a relatively short elimination half-life and
a delayed Tmax with maximal activity about waking time. One of the
twice-daily doses is preferably scheduled before bedtime.
[0023] FIG. 7 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which provides and intermediate elimination half-life and a
Tmax preferably compatible with maximal activity soon after walking
while reducing the extent of fluctuation to the physiological level
with twice-daily dosing.
[0024] FIG. 8 depicts a steady-state pharmacokinetic profile of the
serum concentration of testosterone upon ingestion of a formulation
of TP, which provides a longer elimination half-life and a delayed
Tmax, preferably compatible with maximal activity about awakening
time following bedtime administration. This formulation reduces the
extent of fluctuation to the physiological levels of testosterone
with twice-daily dosing.
[0025] FIG. 9 shows dissolution curves of TP from three
formulations (9, 23 and 24 the compositions of which are listed in
Table 2) in a phosphate buffered dissolution medium incorporating
TritonX-100 as a surfactant in accordance with the present
invention.
[0026] FIG. 10 shows dissolution curves of TP from three
formulations (47, 50, 51 and 54 the compositions of which are
listed in Table 3) in a phosphate buffered dissolution medium
incorporating TritonX-100 as a surfactant in accordance with the
present invention.
[0027] FIG. 11 provides the mean steady-state profile of treatment
with three regimens for seven days.
[0028] FIG. 12 shows the mean steady-state serum T and DHT Levels
after seven days of BID administration of formulation 54.
[0029] FIG. 13 provides a simulated mean steady-state profile of
formulation 50 with respect to the observed profile for formulation
54 (both administered BID for seven days).
[0030] FIG. 14 shows representative in vitro dissolution profiles
for various TP formulations in phosphate buffer (PBS)
[0031] FIG. 15 shows representative in vitro dissolution profiles
for various TP formulations in fed-state simulated intestinal fluid
(FeSSIF).
DETAILED DESCRIPTION OF THE INVENTION
[0032] The present invention provides pharmaceutical delivery
systems, preferably oral, for hydrophobic drugs. Accordingly, while
the instant invention will be described, to some extent, with
reference to oral delivery systems, the present invention may be
suitable for topical and intramuscular injection. Further,
hydrophobic drugs defined herein encompass both those drugs that
are inherently hydrophobic (i.e., having a log P of at least 2) as
well as otherwise hydrophilic medicaments that have been rendered
hydrophobic with suitable modification (e.g., conjugation to fatty
acids and/or lipids). (Log P is the log of the octanol-water or
buffer partition coefficient and can be determined by a variety of
methods for those skilled in the art. The higher the value of log
P, the greater the lipophilicity and thus lipid solubility of the
chemical entity in question.)
[0033] In one embodiment of the present invention, testosterone
and/or esters at the C-17 position of the testosterone molecule,
alone or in combination with other active ingredients, may be
orally delivered using the inventive delivery system. While many of
the embodiments of the present invention will be described and
exemplified with the palmitic acid ester of testosterone (also
referred to as "testosterone palmitate" or "TP"), the scope of the
present invention should not be construed nor limited solely to the
delivery of TP or testosterone per se. In fact, it should be
readily apparent to one of ordinary skill in the art from the
teachings herein that the inventive drug delivery systems and
compositions therefrom may be suitable for oral delivery of other
testosterone esters, such as short-chain (C.sub.2-C.sub.6),
medium-chain (C.sub.7-C.sub.13) and long-chain (C.sub.14-C.sub.24)
fatty acid esters, preferably long-chain fatty acid esters of
testosterones and numerous hydrophobic medicaments. Such suitable
medicaments, which may be formulated in accordance with the present
invention include, but should not be limited to, the following:
[0034] Analgesics and anti-inflammatory agents: aloxiprin,
auranofin, azapropazone, benorylate, diflunisal, etodolac,
fenbufen, fenoprofen calcim, flurbiprofen, ibuprofen, indomethacin,
ketoprofen, meclofenamic acid, mefenamic acid, nabumetone,
naproxen, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.
[0035] Anthelmintics: albendazole, bephenium hydroxynaphthoate,
cambendazole, dichlorophen, ivermectin, mebendazole, nitazoxamide,
oxamniquine, oxfendazole, oxantel embonate, praziquantel, pyrantel
embonate, thiabendazole.
[0036] Anti-arrhythmic agents: amiodarone HCl, disopyramide,
flecainide acetate, quinidine sulphate.
[0037] Anti-bacterial agents: benethamine penicillin, cinoxacin,
ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin,
demeclocycline, doxycycline, erythromycin, ethionamide, imipenem,
nalidixic acid, nitrofurantoin, rifampicin, spiramycin,
sulphabenzamide, sulphadoxine, sulphamerazine, sulphacetamide,
sulphadiazine, sulphafurazole, sulphamethoxazole, sulphapyridine,
tetracycline, trimethoprim.
[0038] Anti-coagulants: dicoumarol, dipyridamole, nicoumalone,
phenindione.
[0039] Anti-depressants: amoxapine, maprotiline HCl, mianserin HCl,
nortriptyline HCl, trazodone HCl, trimipramine maleate.
[0040] Anti-diabetics: acetohexamide, chlorpropamide,
glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.
[0041] Anti-epileptics: beclamide, carbamazepine, clonazepam,
ethotoin, methoin, methsuximide, methylphenobarbitone,
oxcarbazepine, paramethadione, phenacemide, phenobarbitone,
phenytoin, phensuximide, primidone, sulthiame, valproic acid.
[0042] Anti-fungal agents: amphotericin, butoconazole nitrate,
clotrimazole, econazole nitrate, fluconazole, flucytosine,
griseofulvin, itraconazole, ketoconazole, miconazole, natamycin,
nystatin, sulconazole nitrate, terbinafine HCl, terconazole,
tioconazole, undecenoic acid.
[0043] Anti-gout agents: allopurinol, probenecid,
sulphin-pyrazone.
[0044] Anti-hypertensive agents: amlodipine, benidipine,
darodipine, dilitazem HCl, diazoxide, felodipine, guanabenz
acetate, isradipine, minoxidil, nicardipine HCl, nifedipine,
nimodipine, phenoxybenzamine HCl, prazosin HCl, reserpine,
terazosin HCl.
[0045] Anti-malarials: amodiaquine, chloroquine, chlorproguanil
HCl, halofantrine HCl, mefloquine HCl, proguanil HCl,
pyrimethamine, quinine sulphate.
[0046] Anti-migraine agents: dihydroergotamine mesylate, ergotamine
tartrate, methysergide maleate, pizotifen maleate, sumatriptan
succinate.
[0047] Anti-muscarinic agents: atropine, benzhexol HCl, biperiden,
ethopropazine HCl, hyoscyamine, mepenzolate bromide,
oxyphencylcimine HCl, tropicamide.
[0048] Anti-neoplastic agents and Immunosuppressants:
aminoglutethimide, amsacrine, azathioprine, busulphan,
chlorambucil, cyclosporin, dacarbazine, estramustine, etoposide,
lomustine, melphalan, mercaptopurine, methotrexate, mitomycin,
mitotane, mitozantrone, procarbazine HCl, tamoxifen citrate,
testolactone.
[0049] Anti-protazoal agents: benznidazole, clioquinol,
decoquinate, diiodohydroxyquinoline, diloxanide furoate,
dinitolmide, furzolidone, metronidazole, nimorazole, nitrofurazone,
ornidazole, tinidazole.
[0050] Anti-thyroid agents: carbimazole, propylthiouracil.
[0051] Anxiolytic, sedatives, hypnotics and neuroleptics:
alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam,
bromperidol, brotizolam, butobarbitone, carbromal,
chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam,
clotiazepam, clozapine, diazepam, droperidol, ethinamate,
flunanisone, flunitrazepam, fluopromazine, flupenthixol decanoate,
fluphenazine decanoate, flurazepam, haloperidol, lorazepam,
lormetazepam, medazepam, meprobamate, methaqualone, midazolam,
nitrazepam, oxazepam, pentobarbitone, perphenazine pimozide,
prochlorperazine, sulpiride, temazepam, thioridazine, triazolam,
zopiclone.
[0052] Beta-blockers: acebutolol, alprenolol, atenolol, labetalol,
metoprolol, nadolol, oxprenolol, pindolol, propranolol.
[0053] Cardiac Inotropic agents: amrinone, digitoxin, digoxin,
enoximone, lanatoside C, medigoxin.
[0054] Corticosteroids: beclomethasone, betamethasone, budesonide,
cortisone acetate, desoxymethasone, dexamethasone, fludrocortisone
acetate, flunisolide, flucortolone, fluticasone propionate,
hydrocortisone, methylprednisolone, prednisolone, prednisone,
triamcinolone.
[0055] Diuretics: acetazolamide, amiloride, bendrofluazide,
bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid,
frusemide, metolazone, spironolactone, triamterene.
[0056] Anti-parkinsonian agents: bromocriptine mesylate, lysuride
maleate.
[0057] Gastro-intestinal agents: bisacodyl, cimetidine, cisapride,
diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine,
nizatidine, omeprazole, ondansetron HCl, ranitidine HCl,
sulphasalazine.
[0058] Histamine H,-Receptor Antagonists: acrivastine, astemizole,
cinnarizine, cyclizine, cyproheptadine HCl, dimenhydrinate,
flunarizine HCl, loratadine, meclozine HCl, oxatomide,
terrenadine.
[0059] Lipid regulating agents: bezafibrate, clofibrate,
fenofibrate, gemfibrozil, probucol.
[0060] Nitrates and other anti-anginal agents: amyl nitrate,
glyceryl trinitrate, isosorbide dinitrate, isosorbide mononitrate,
pentaerythritol tetranitrate.
[0061] Nutritional agents: betacarotene, vitamin A, vitamin
B.sub.2, vitamin D, vitamin E, vitamin K.
[0062] Opioid analgesics: codeine, dextropropyoxyphene,
diamorphine, dihydrocodeine, meptazinol, methadone, morphine,
nalbuphine, pentazocine.
[0063] Sex hormones: clomiphene citrate, danazol,
ethinyloestradiol, medroxyprogesterone acetate, mestranol,
methyltestosterone, norethisterone, norgestrel, oestradiol,
conjugated oestrogens, progesterone, synthetic progestins (also
referred to as progestogens), stanozolol, stiboestrol, tibolone,
testosterone, esters of testosterone, including esters of oleic
acid, linoleic acid, linolenic acid, stearic acid, myristic acid,
lauric acid, palmitic acid, capric or decanoic acid octanoic or
caprylic acid, pelargonic acid, undecanoic acid, tridecanoic acid,
pentadecanoic acid, and the branched chain, cyclic analogues of
these acids, testosterone analogues such as methyl-nortestosterone,
and combinations thereof. Synthetic progestins include, for
example, levonorgestrel, levonorgestrel butanoate, drospirenone,
norethisterone, desogestrel, etonorgestrel and
medroxyprogesterone.
[0064] Gonadotropin releasing hormone (GnRH) antagonists that are
orally active.
[0065] Stimulants: amphetamine, dexamphetamine, dexfenfluramine,
fenfluramine, mazindol.
[0066] Mixtures of hydrophobic drugs may, of course, be used where
therapeutically effective. For example, the combination of
testosterone palmitate with an orally active inhibitor or Type I or
Type II 5.alpha.-reductase or the combination of testosterone
palmitate with a synthetic progestin may be preferable in some
embodiments.
[0067] Drug delivery systems of the present invention and
compositions comprising same, comprise a hydrophobic drug or drugs
dissolved in a lipophilic surfactant and a hydrophilic surfactant.
A lipophilic surfactant as defined herein has a
hydrophilic-lipophilic balance (HLB) less than 10, and preferably
less than 5. A hydrophilic surfactant as defined herein has an HLB
of greater than 10. (HLB is an empirical expression for the
relationship of the hydrophilic and hydrophobic groups of a surface
active amphiphilic molecule, such as a surfactant. It is used to
index surfactants and its value varies from about 1 to about 45.
The higher the HLB, the more water soluble the surfactant.)
[0068] According to one aspect of the present invention, each of
the components of the delivery system (i.e., the lipophilic and
hydrophilic surfactants) individually have solvent characteristics
and contribute, in part, to solubilizing the active ingredient.
Those lipophilic surfactants that contribute substantially to
dissolving the drug are defined herein as a "primary" solvent.
Primary solvents can also provide "sustained-release" or
"controlled-release" characteristics to the drug delivery system.
"Secondary" solvents are hydrophilic surfactants that also
solubilize the drug, albeit to a lesser extent than a primary
solvent. In addition to dissolving the drug, secondary solvents
facilitate the dispersion of the delivery system in aqueous media
or intestinal fluids and subsequent release of the drug. In cases
where the secondary solvent is a high melting point hydrophilic
surfactant, it can also provide for a sustained drug release,
acting synergistically with the lipophilic surfactant.
[0069] A hydrophilic surfactant component may be necessary to
achieve desirable emission of the drug from within the formulation.
That is, a hydrophilic surfactant may be required to free the drug
from within the lipid carrier matrix, or primary solvent. In this
respect, a high HLB surfactant, such as Cremophor RH40, can
generally suffice. In some formulations incorporating high levels
of solubilized TP, the inventors have observed that in the absence
of a high HLB surfactant, there can be substantially no release of
the drug from blends solely comprising lipophilic surfactants. The
levels of the high HLB surfactant can be adjusted to provide
optimum drug release without compromising the solubilization of the
active ingredient.
[0070] The lipophilic surfactant component, in some embodiments,
may further comprise a "controlled-release" surfactant. In other
words, in addition to being a solvent for the drug, the lipophilic
surfactant may also provide a semi-solid and sustained release (SR)
matrix. Many semi-solid/SR excipients are available to one of
ordinary skill in the art, but those that additionally are good
solvents for the drug are desirable in the instant invention. Thus,
preference should be given to semi-solid lipid excipients having
high solubilization potential for the drug. In one aspect,
"controlled-release" lipophilic surfactants exhibit a melting point
of about 25.degree. C. to about 80.degree. C., preferably about
35.degree. C. to about 65.degree. C., and more preferably
40.degree. C. to about 60.degree. C.
[0071] To be sure, however, "controlled-release" surfactants need
not be limited to lipophilic surfactants alone. Indeed, some
hydrophilic surfactants in compositions of the instant invention
may also provide controlled-release characteristics in conjunction
with a lipophilic surfactant.
[0072] Lipophilic surfactants suitable in drug delivery systems of
the present invention include:
[0073] Fatty acids (C.sub.6-C.sub.24, preferably C.sub.10-C.sub.24,
more preferably C.sub.14-C.sub.24), for example, octanoic acid,
decanoic acid, undecanoic acid, lauric acid, myristic acid,
palmitic acid, stearic acid, oleic acid, linoleic acid, and
linolenic acid. Stearic acid and palmitic acid are preferred.
[0074] Mono- and/or di-glycerides of fatty acids, such as Imwitor
988 (glyceryl mono-/di-caprylate), Imwitor 742 (glyceryl
mono-di-caprylate/caprate), Imwitor 308 (glyceryl mono-caprylate),
Imwitor 191 (glyceryl mono-stearate), Softigen 701 (glyceryl
mono-/di-ricinoleate), Capmul MCM (glyceryl caprylate/caprate),
Capmul MCM(L) (liquid form of Capmul MCM), Capmul GMO (glyceryl
mono-oleate), Capmul GDL (glyceryl dilaurate), Maisine (glyceryl
mono-linoleate), Peceol (glyceryl mono-oleate), Myverol 18-92
(distilled monoglycerides from sunflower oil) and Myverol 18-06
(distilled monoglycerides from hydrogenated soyabean oil), Precirol
ATO 5 (glyceryl palmitostearate) and Gelucire 39/01 (semi-synthetic
glycerides, i.e., C.sub.12-18 mono-, di- and tri-glycerides). The
preferred members of this class of lipophilic surfactants are the
partial glycerides of oleic, palmitic and stearic acids and blends
thereof.
[0075] Acetic, succinic, lactic, citric and/or tartaric esters of
mono- and/or di-glycerides of fatty acids, for example, Myvacet
9-45 (distilled acetylated monoglycerides), Miglyol 829
(caprylic/capric diglyceryl succinate), Myverol SMG
(mono/di-succinylated monoglycerides), Imwitor 370 (glyceryl
stearate citrate), Imwitor 375 (glyceryl
monostearate/citrate/lactate) and Crodatem T22 (diacetyl tartaric
esters of monoglycerides).
[0076] Propylene glycol mono- and/or di-esters of fatty acids, for
example, Lauroglycol (propylene glycol monolaurate), Mirpyl
(propylene glycol monomyristate), Captex 200 (propylene glycol
dicaprylate/dicaprate), Miglyol 840 (propylene glycol
dicaprylate/dicaprate) and Neobee M-20 (propylene glycol
dicaprylate/dicaprate).
[0077] Polyglycerol esters of fatty acids such as Plurol oleique
(polyglyceryl oleate), Caprol ET (polyglyceryl mixed fatty acids)
and Drewpol 10.10.10 (polyglyceryl oleate).
[0078] Castor oil ethoxylates of low ethoxylate content (HLB<10)
such as Etocas 5 (5 moles of ethylene oxide reacted with 1 mole of
castor oil) and Sandoxylate 5 (5 moles of ethylene oxide reacted
with 1 mole of castor oil.
[0079] Acid and ester ethoxylates formed by reacting ethylene oxide
with fatty acids or glycerol esters of fatty acids (HLB<10) such
as Crodet 04 (polyoxyethylene (4) lauric acid), Cithrol 2MS
(polyoxyethylene (2) stearic acid), Marlosol 183 (polyoxyethylene
(3) stearic acid) and Marlowet G12DO (glyceryl 12 EO dioleate).
Sorbitan esters of fatty acids, for example, Span 20 (sorbitan
monolaurate), Crill 1 (sorbitan monolaurate) and Crill 4 (sorbitan
mono-oleate).
[0080] Transesterification products of natural or hydrogenated
vegetable oil triglyceride and a polyalkylene polyol (HLB<10),
e.g. Labrafil M1944CS (polyoxyethylated apricot kernel oil),
Labrafil M2125CS (polyoxyethylated corn oil) and Gelucire 37/06
(polyoxyethylated hydrogenated coconut). Labrafil M1944CS is
preferred.
[0081] Alcohol ethyoxylates (HLB<10), e.g. Volpo N3
(polyoxyethylated (3) oleyl ether), Brij 93 (polyoxyethylated (2)
oleyl ether), Marlowet LA4 (polyoxyethylated (4) lauryl ether)
and
[0082] Pluronics, for example, Polyoxyethylene-polyoxypropylene
co-polymers and block co-polymers (HLB<10) e.g. Synperonic PE
L42 (HLB=8) and Synperonic PE L61 (HLB=3)
[0083] Mixtures of suitable lipophilic surfactants, such as those
listed above, may be used if desired, and in some instances are
found to be advantageous. For instance, glycerol palmitate and
glycerol stearate esters alone and in blends are preferred
lipophilic surfactants and controlled-release matrices.
[0084] Of the lipophilic surfactants listed above, those suitable
as a "controlled-release" component include, but are not limited
to, stearic acid, palmitic acid, and their glycerol and PEG esters,
Precirol AT05, Imwitor 191, Myverol 18-06, Imwitor 370, Imwitor
375, Caprol ET, Cithrol 2MS, Marosol 183, Gelucire 39/01 and
combinations thereof.
[0085] Any pharmaceutically acceptable hydrophilic surfactant
(i.e., having an HLB value greater than 10) may be used in the
present invention. Some non-limiting examples include:
[0086] Polyoxyethylene sorbitan fatty acid derivates e.g. Tween 20
(polyoxyethylene (20) monolaureate), Tween 80 (polyoxyethylene (20)
monooleate), Crillet 4 (polyoxyethylene (20) monooleate) and
Montanox 40 (polyoxyethylene (20) monopalmitate). Tween 80
(Polysorbate 80) is preferred.
[0087] Castor oil or hydrogenated caster oil ethoxylates
(HLB>10), e.g. Cremophor EL (polyoxyethylene (35) castor oil),
Cremophor RH40 (polyoxyethylene (40) hydrogenated castor oil),
Etocas 40 (polyoxyethylene (40) castor oil), Nildcol HCO-60
(polyoxyethylene (60) hydrogenated castor oil), Solutol HS-15
(polyethylene glycol 660 hydroxystearate), Labrasol (caprylocaproyl
macrogol-8 glycerides), .alpha.-tocopherol-polyethylene
glycol-1000-succinate (TPGS) and ascorbyl-6 palmitate. Cremophor
RH40 is preferred.
[0088] Gelucires, preferably Gelucire 50/13 (PEG mono- and diesters
of palmitic and stearic acids. (In reference to Gelucires, the
first number (i.e., 50) corresponds to the melting point of the
material and the second (i.e., 13) to the HLB number.)
[0089] Fatty acid ethoxylates (HLB>10), e.g. Myrj 45
(polyoxyethylene (8) stearate), Tagat L (polyoxyethylene (30)
monolaurate), Marlosol 1820 (polyoxyethylene (20) stearate) and
Marlosol OL15 (polyoxyethylene (15) oleate). Myrj 45 is
preferred.
[0090] Alcohol ethoxylates (HLB>10), e.g. Brij 96
(polyoxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15)
oleyl ether), Marlowet OA30 (polyoxyethylene (30) oleyl ether) and
Marlowet LMA20 (polyoxyethylene (20) C.sub.12-C.sub.14 fatty
ether).
[0091] Polyoxyethylene-polyoxypropylene co-polymers and block
co-polymers (HLB>10), that are commercially available under the
trade name Pluronics or Poloxamers, such as Poloxamers 188 and 407
also known as Syperonic PE L44 (HLB=16) and Syperonic F127
(HLB=22), respectively.
[0092] Anionic surfactants e.g. sodium lauryl sulphate, sodium
oleate and sodium dioctylsulphosuccinate.
[0093] Alkylphenol surfactants (HLB>10) e.g. Triton N-101
(polyoxyethylene (9-10) nonylphenol) and Synperonic NP9
(polyoxyethylene (9) nonylphenol).
[0094] Of the hydrophilic surfactants listed above, those suitable
as a "controlled-release" surfactant include, but are not limited
to Gelucires of high HLB value, such as Gelucire 50/13.
[0095] As mentioned, in one aspect of the present invention, each
of the components of the delivery system (i.e., the lipophilic and
hydrophilic surfactants) individually has solvent characteristics
and contributes, in part, to solubilizing the active ingredient. In
this way, without being bound by or limited to theory, the present
invention does not require additional solvents, such as additional
digestible oils and/or cosolvents, but these may be optionally
included in the inventive systems and formulations.
[0096] A digestible oil is defined herein as an oil that is capable
of undergoing de-esterification or hydrolysis in the presence of
pancreatic lipase in vivo under normal physiological conditions.
Specifically, digestible oils may be complete glycerol triesters of
medium chain (C.sub.7-C.sub.13) or long chain (C.sub.14-C.sub.22)
fatty acids with low molecular weight (up to C.sub.6) mono-, di- or
polyhydric alcohols. Some examples of digestible oils for use in
this invention thus include: vegetable oils (e.g., soybean oil,
safflower seed oil, corn oil, olive oil, castor oil, cottonseed
oil, arachis oil, sunflower seed oil, coconut oil, palm oil,
rapeseed oil, evening primrose oil, grape seed oil, wheat germ oil,
sesame oil, avocado oil, almond, borage, peppermint and apricot
kernel oils) and animal oils (e.g., fish liver oil, shark oil and
mink oil).
[0097] As well, optional cosolvents suitable with the instant
invention are, for example, water, short chain mono-, di-, and
polyhydric alcohols, such as ethanol, benzyl alcohol, glycerol,
propylene glycol, propylene carbonate, polyethylene glycol with an
average molecular weight of about 200 to about 10,000, diethylene
glycol monoethyl ether (e.g., Transcutol HP), and combinations
thereof.
[0098] Other optional ingredients which may be included in the
compositions of the present invention are those which are
conventionally used in the oil-based drug delivery systems, e.g.
antioxidants such as tocopherol, tocopherol acetate, ascorbic acid,
butylhydroxytoluene, butylhydroxyanisole and propyl gallate; pH
stabilizers such as citric acid, tartaric acid, fumaric acid,
acetic acid, glycine, arginine, lysine and potassium hydrogen
phosphate; thickeners/suspending agents such as hydrogenated
vegetable oils, beeswax, colloidal silicon dioxide, mannitol, gums,
celluloses, silicates, bentonite; flavoring agents such as cherry,
lemon and aniseed flavors; sweeteners such as aspartame, acesulfane
K, sucralose, saccharin and cyclamates; etc.
[0099] The relative proportions of the lipophilic surfactant and
hydrophilic surfactant in the preferred hydrophobic drug carrier
system of this invention are, in general, not especially critical,
save that the concentration of lipophilic and hydrophilic
surfactants must be sufficient to solubilize the hydrophobic drug,
yet release same both in vitro and in vivo. It should be noted that
in some embodiments of the invention, one hydrophobic drug may
serve as a lipid vehicle for another. More specifically, for
example, a testosterone ester may serve as a carrier for
testosterone. Even more specifically, TP may serve as a lipid
vehicle for testosterone. As well, TP may serve, in some
embodiments, as its own "controlled-release" vehicle, which may
obviate the need for additional "controlled-release" lipids
mentioned above.
[0100] Generally, the following relative concentrations, by weight,
are preferred (the percentages are based on the total content of
hydrophilic surfactant and lipophilic surfactant(s)):
Hydrophilic surfactant: 5-60%, more preferably 15-45%, and most
preferably 30-40% Lipophilic surfactant: 10-90%, more preferably
20-80%, and most preferably 30-60% Lipophilic "controlled-release"
surfactant: 1-40%, more preferably 2.5-30%, and most preferably
5-25%.
[0101] The concentration of drug in the final pharmaceutical
formulation will be that which is required to provide the desired
therapeutic effect from the drug concerned, but generally will lie
in the range 0.1% to 50% by weight, preferably between about 10% to
30% by weight, and most preferably about 10% and 20% by weight,
based on the weight of the final composition. However, in many
instances, because the present compositions may have better
bioavailability than known compositions of the drug concerned, the
drug concentration may be reduced as compared with the conventional
preparations without loss of therapeutic effect. With specific
reference to testosterone therapy, the present inventors have
learned that the use of the palmitate ester of T, in particular, is
desirable. Indeed, once absorbed, the long and fully saturated
chain of the fatty acid on T slows the rate of hydrolysis of the
ester bond thus prolonging the circulation of the TP and
consequently T. For example, formulations of the present invention
(e.g., formulation nos. 50 and 54 (below)) comprising TP have a T
half-life of about 8-9 hours. By comparison, the half-life for T is
about 30 minutes and that of T-undecanoate is about 1.5 hours.
[0102] In other embodiments, formulations of the present invention
may have self-emulsifying properties, forming a fine emulsion upon
dilution with aqueous media or intestinal fluids in vivo. In other
words, the formulations may have high surfactant and lipid content
designed for adequate dispersion upon mixing with an aqueous
medium. Qualitative description of the self-emulsification property
of the inventive formulations can be visually observed during the
dissolution of same in vitro. On the other hand, quantitative
measurements may be taken of the particle size of the emulsified
droplets using laser light scattering and/or turbidity measurements
in the dissolution medium by UV/VIS spectrophotometer. Any of these
methodologies are available and known to one of ordinary skill in
the art.
[0103] The pharmaceutical compositions according to the present
invention may be liquid, semi-solid, or solid at ambient
temperatures, but preferably are presented as liquids or
semi-solids. Solid preparations are defined as solid, powdered
medicaments blended with powdered excipients and directly filled
into hard gelatin or cellulose capsule or compressed into a tablet.
The instant invention, however, preferably comprises a solid,
powdered medicament (e.g., TP) that is solubilized in the presence
of the lipid surfactant excipients (e.g., any combination of the
lipophilic and hydrophilic surfactants noted above). Accordingly,
the melting point of the surfactants used is one factor that can
determine whether the resulting composition will be liquid or
semi-solid at ambient temperature. Particularly preferred
compositions of the present invention are liquid or semi-solid oral
unit dosage forms, more preferably filled into hard or soft
capsules, e.g. gelatin or cellulose capsules. The technology for
encapsulating lipid-based pharmaceutical preparations is well known
to one of ordinary skill in the art. As the inventive delivery
systems and formulations described herein are not limited to any
one encapsulation method, specific encapsulation techniques will
not be further discussed.
[0104] The drug carrier systems and pharmaceutical preparations
according to the present invention may be prepared by conventional
techniques for lipid-based drug carrier systems. In a typical
procedure for the preparation of the preferred carrier systems of
this invention, the lipophilic surfactant is weighed out into a
suitable stainless steel vessel and the hydrophilic surfactant is
then weighed and added to the container. Mixing of the two
components may be effected by use of a homogenizing mixer or other
high shear device. If the material is solid at room temperature,
sufficient heat is applied to ensure metling and fluidity without
chemical decomposition.
[0105] The lipophilic "controlled-release" surfactant is then
added, if desired, to the two other components in the stainless
steel vessel and mixed using the appropriate equipment. The
hydrophobic drug is then weighed and added to the combined lipid
mixture and mixing continued until either a homogenous solution is
prepared. The formulation may be de-aerated before encapsulation in
either soft or hard capsules. In some instances the fill
formulation may be held at elevated temperature using a suitable
jacketed vessel to aid processing.
[0106] Returning now to the delivery of testosterone, in one
embodiment of the present invention, drug delivery systems of the
present invention may be suitable for testosterone therapy.
Testosterone is the main endogenous androgen in men. Leydig cells
in the testes produce approximately 7 mg of testosterone each day
resulting in serum concentrations ranging from about 300 to about
1100 ng/dL. Women also synthesize testosterone in both the ovary
and adrenal gland, but the amount is about one-tenth that observed
in eugonadal men. The majority (about 98%) of circulating
testosterone is bound to sex hormone binding globulin and is
biologically active only when released to the free form. The term
"free" is thus defined as not being bound to or confined within,
for example, biomolecules, cells and/or lipid matrices of the
inventive formulations described herein. Generally, "free"
medicaments described herein refer to medicament that is accessible
to metabolic enzymes circulating in serum.
[0107] While the present invention should not be limited to the
delivery of testosterone or any particular ester thereof, TP has
been found to offer unique chemical and physical characteristics
that make its use preferable in some embodiments. The present
inventors have learned that the palmitic acid ester of
testosterone, in particular, can yield superior bioavailability to
that found with other equivalent esters (e.g., testosterone
undecanoate (TU)). Without being held to or bound by theory, it is
believed that TP is superior, in part, to other testosterone
esters, because it has a particularly high log P compared to
similar analogs. (The log P for TP is greater than 9 compared to a
log P for TU of about 6.5)
[0108] Consequently, TP absorbed into the bloodstream may passively
diffuse into red blood cells (RBCs) circulating in the blood.
Specifically, because palmitic acid is both a significant component
of the RBC membrane and has been shown to be transported across
this membrane, TP is better suited to be in an equilibrium with and
pass said membrane. In this manner, some portion of the total
concentration of free TP at any given time may be found within
RBCs. Further, when confined to a RBC, any TP therein is shielded
from the esterases found in the serum. As the conversion of TP to
testosterone is a direct consequence of esterase activity, greater
inaccessibility to the esterases is expected to prolong the
half-life of TP. For this reason, it is believed that the residence
time of TP in the blood is greater than that would be expected from
other saturated esters of shorter hydrocarbon chain-length.
[0109] What is more, the use of TP, in contrast to that for other
orally administered testosterone esters, does not appear to
dramatically elevate serum dihydrotestosterone ("DHT") above
physiological levels, which are typically about 1/10th that of
testosterone (i.e., about 30 to 100 ng/dL) in eugonadal men.
Testosterone interacts with respective androgen receptors either
directly or following its conversion to DHT via the action of
5.alpha.-reductase. DHT is a more potent androgen than testosterone
and its elevated levels are thought by some scientists to increase
the risk of prostate cancer. Elevated levels of DHT are a noted
problem with the administration of, for example, TU. In this way,
TP provides yet another unexpected advantage over other
testosterone esters.
[0110] Specific embodiments of the instant invention will now be
described in non-limiting examples. Table 1 provides composition
details of various formulations of testosterone (T) or
testosterone-esters (T-esters), in accordance with the teachings of
the instant invention. For calculation purposes, 1 mg of T is
equivalent to: 1.39 mg T-enanthate; 1.58 mg T-undecanoate; 1.43 mg
T-cypionate, and 1.83 mg T-palmitate. TP is a preferred T-ester in
some of the formulations listed below. The compositions details of
Table 1 (mg/capsule and wt. percentage) are based on 800 mg fill
weight per `00` hard gelatin capsule. However, at
testosterone-ester amounts less than about 100 mg/capsule, the
formulations may be proportionally adjusted for smaller total fill
weights that would permit use of smaller hard gelatin capsules
(e.g., `0` size).
[0111] As well, it should be apparent to one of ordinary skill in
the art that many, if not all, of the surfactants within a category
(e.g., lipophilic, hydrophilic, etc.) may be exchanged with another
surfactant from the same category. Thus, while Table 1 lists
formulations comprising Labrafil M1944CS (HLB=3) and Precirol ATO5
(HLB=2), one of ordinary skill in the art should recognize other
lipophilic surfactants (e.g., those listed above) may be suitable
as well. Similarly, while Table 1 lists formulations comprising
Cremophor RH40 (HLB=13) and Labrasol (HLB=14), one of ordinary
skill in the art should recognize other hydrophilic surfactants
(e.g., those listed above) may be suitable.
TABLE-US-00001 TABLE 1 Labrafil Precirol Cremophor ID T or T-ester
M1944CS AT05 RH40 Labrasol A 400 109.68 66.49 223.83 -- 50.00%
13.71% 8.31% 27.98% -- B 360 120.64 73.14 246.21 -- 45.00% 15.08%
9.14% 30.78% -- C 320 131.61 79.79 268.60 -- 40.00% 16.45% 9.97%
33.57% -- D 280 142.58 86.44 290.98 -- 35.00% 17.82% 10.80% 36.37%
-- E 240 153.55 93.09 313.36 -- 30.00% 19.19% 11.64% 39.17% -- F
228.32 156.75 95.03 319.9 -- 28.54% 19.59% 11.88% 39.99% -- G 200
164.52 99.74 335.75 -- 25.00% 20.56% 12.47% 41.97% -- H 160 175.48
106.39 358.13 -- 20.00% 21.94% 13.30% 44.77% -- I 120 186.45 113.04
380.51 -- 15.00% 23.31% 14.13% 47.56% -- J 80 197.42 119.69 402.90
-- 10.00% 24.68% 14.96% 50.36% -- K 40 208.39 126.33 425.28 --
5.00% 26.05% 15.79% 53.16% -- L 20 213.87 129.66 436.47 -- 2.50%
26.73% 16.21% 54.56% -- M 400 199.97 66.62 133.40 -- 50.00% 25.00%
8.33% 16.68% -- N 360 219.97 73.29 146.74 -- 45.00% 27.50% 9.16%
18.34% -- O 320 239.97 79.95 160.08 -- 40.00% 30.00% 9.99% 20.01%
-- P 280 259.96 86.61 173.42 -- 35.00% 32.50% 10.83% 21.68% -- Q
240 279.96 93.27 186.76 -- 30.00% 35.00% 11.66% 23.35% -- R 228.32
285.8 95.22 190.66 -- 28.54% 35.73% 11.90% 23.83% -- S 200 299.96
99.94 200.10 -- 25.00% 37.49% 12.49% 25.01% -- T 160 319.96 106.60
213.45 -- 20.00% 39.99% 13.32% 26.68% -- U 120 339.95 113.26 226.79
-- 15.00% 42.49% 14.16% 28.35% -- V 80 359.95 119.92 240.13 --
10.00% 44.99% 14.99% 30.02% -- W 40 379.95 126.59 253.47 -- 5.00%
47.49% 15.82% 31.68% -- X 20 389.95 129.92 260.14 -- 2.50% 48.74%
16.24% 32.52% -- AA 400 109.79 66.55 149.72 73.94 50.00% 13.72%
8.32% 18.72% 9.24% BB 360 120.77 73.21 164.69 81.33 45.00% 15.10%
9.15% 20.59% 10.17% CC 320 131.75 79.87 179.66 88.72 40.00% 16.47%
9.98% 22.46% 11.09% DD 280 142.73 86.52 194.64 96.12 35.00% 17.84%
10.82% 24.33% 12.01% EE 240 153.70 93.18 209.61 103.51 30.00%
19.21% 11.65% 26.20% 12.94% FF 228.32 156.91 95.12 213.98 105.67
28.54% 19.61% 11.89% 26.75% 13.21% GG 200 164.68 99.83 224.58
110.90 25.00% 20.59% 12.48% 28.07% 13.86% HH 160 175.66 106.49
239.55 118.30 20.00% 21.96% 13.31% 29.94% 14.79% II 120 186.64
113.14 254.52 125.69 15.00% 23.33% 14.14% 31.82% 15.71% JJ 80
197.62 119.80 269.50 133.09 10.00% 24.70% 14.97% 33.69% 16.64% KK
40 208.60 126.45 284.47 140.48 5.00% 26.07% 15.81% 35.56% 17.56% LL
20 214.09 129.78 291.95 144.18 2.50% 26.76% 16.22% 36.49% 18.02% MM
400 81.62 94.47 223.91 -- 50.00% 10.20% 11.81% 27.99% -- NN 360
89.78 103.92 246.30 -- 45.00% 11.22% 12.99% 30.79% -- OO 320 97.94
113.37 268.69 -- 40.00% 12.24% 14.17% 33.59% -- PP 280 106.10
122.81 291.08 -- 35.00% 13.26% 15.35% 36.39% -- QQ 240 114.27
132.26 313.47 -- 30.00% 14.28% 16.53% 39.18% -- RR 228.32 116.65
135.02 320.01 -- 28.54% 14.58% 16.88% 40.00% -- SS 200 122.43
141.71 335.86 -- 25.00% 15.30% 17.71% 41.98% -- TT 160 130.59
151.16 358.25 -- 20.00% 16.32% 18.89% 44.78% -- UU 120 138.75
160.60 380.64 -- 15.00% 17.34% 20.08% 47.58% -- VV 80 146.91 170.05
403.04 -- 10.00% 18.36% 21.26% 50.38% -- WW 40 155.08 179.50 425.43
-- 5.00% 19.38% 22.44% 53.18% -- XX 20 159.16 184.22 436.62 --
2.50% 19.89% 23.03% 54.58% --
[0112] Table 2 provides composition details of various TP
formulations in accordance with the teachings of the instant
invention and FIG. 9 provides in vitro dissolution of select
formulations therein. TP may be synthesized through esterification
of testosterone with palmitoyl chloride in an acetone/pyridine
mixture. Testosterone palmitate crude is purified by filtration,
crystallized from a methanol/methylene chloride mixture and washed
with methanol. When necessary, recrystallization can be done from
heptane, followed by washing with methanol.
TABLE-US-00002 TABLE 2 F. Composition details (mg/capsule and wt.
percentage)* Fill wt No. TP LBR PRC5 OA Peceol TPGS SO CRH40 L'sol
M'tol (mg)** 1 228.32 285.84 57 570 (40.0) (50.0) (10.0) 2 228.32
57 228 57 570 (40.0) (10.0) (40.0) (10.0) 3 228.32 171 114 57 570
(40.0) (30.0) (20.0) (10.0) 4 228.32 171 114 57 570 (40.0) (30.0)
(20.0) (10.0) 5 228.32 114 57 171 570 (40.0) (20.0) (10.0) (30.0) 6
228.32 476 95.2 800 (28.5) (59.5) (11.9) 7 228.32 95.2 380.8 95.2
800 (28.5) (11.9) (47.6) (11.9) 8 228.32 190.4 95.2 285.6 800
(28.5) (23.8) (11.9) (35.7) 9 228.32 285.84 95.2 190.56 800 (28.5)
(35.7) (11.9) (23.8) 10 228.32 190.56 190.56 190.56 800 (28.5)
(23.8) (23.8) (23.8) 11 228.32 190.56 95.2 190.56 95.2 800 (28.5)
(23.8) (11.9) (23.8) (11.9) 12 228.32 190.56 190.56 95.2 95.2 800
(28.5) (23.8) (23.8) (11.9) (11.9) 13 228.32 190.56 190.56 95.2
95.2 800 (28.5) (23.8) (23.8) (11.9) (11.9) 14 228.32 285 95.2 95.2
95.2 800 (28.5) (35.7) (11.9) (11.9) (11.9) 15 228.32 285.84 20.0
265.6 800 (28.5) (35.7) (2.50) (33.2) 16 228.32 285.84 20.0 40.0
225.6 800 (28.5) (35.7) (2.50) (5.00) (28.2) 17 228.32 285.84 80.0
205.6 800 (28.5) (35.7) (10.0) (25.7) 18 228.32 95.20 190.56 285.6
800 (28.5) (11.9) (23.8) (35.7) 19 228.32 133.08 88.672 450 (50.73)
(29.57) (19.7) 20 228.32 285.84 200.28 85.72 800 (28.5) (35.7)
(25.0) (10.7) 21 228.32 285.84 95.2 190.67 800 (28.5) (35.7) (11.9)
(23.8) 22 228.32 240.33 65.7 160.22 105.74 800 (28.5) (30.0) (8.2)
(20.0) (13.2) 23 228.32 157.02 95.2 320.45 800 (28.5) (19.6) (11.9)
(40.0) 24 228.32 157.02 95.2 214.4 105.74 800 (28.5) (19.6) (11.9)
(26.8) (13.2) 25 228.32 157.02 65.6 349.6 800 (28.5) (19.6) (8.2)
(43.7) 26 228.32 157.02 40.0 375.2 800 (28.5) (19.6) (5.0) (46.9)
57 182.65 229.35 20.0 368.0 800 (22.83) (28.7) (2.5) (46.0) 58
120.0 520.0 20.0 140.0 800 (15.0) (65.0) (2.5) (17.5) *TP:
Testosterone palmitate; LBR: Labrafil M1944CS; PRC5: PrecirolATO5;
OA: Refined Oleic acid; SO: Refined Soybean oil; TPGS:
D-.alpha.-tocopheryl PEG1000 succinate; CRH 40: Cremophor RH40;
L'sol: Labrasol; M'tol: Mannitol **Filled into size"0" capsule (570
mg) or "00"capsule (800 mg)
[0113] A preferred formulation of TP in accordance with the present
invention is:
TABLE-US-00003 Component mg/capsule %, w/w Testosterone palmitate
228.32 28.5 Cremophor .RTM. RH40 320.45 40.0 Labrafil .RTM. M 1944
CS 157.02 19.6 Precirol .RTM. ATO 5 95.20 11.9 Total: 800 100.0
[0114] In some embodiments, it may be desirable to reduce the
absolute concentration of testosterone and/or an ester thereof in
order to promote a relatively faster release of the testosterone
and/or ester from within the lipid vehicle. That is, it has been
found, surprisingly, that reducing the concentration of TP, may in
some cases, confer quicker release kinetics. For example, for
significant release of TP within about a two hour period, a
concentration of TP of less than about 23 percent by weight. In
some embodiment, a weight percentage of less than about 20 is
preferred, more preferably a weight percentage of less than about
18, and most preferably a weight percentage of less than about 15.
Without being bound by or limited to theory, it is believed that TP
at levels greater than about 23 weight percent may, in fact, retard
its own release. For example, formulations according to the instant
invention comprising less than about 23 weight percent TP can
release 50-70% of the drug at 1 hour and 80 to near 100% at 2
hours. On the other hand, formulations according to the instant
invention comprising greater than about 23 weight percent TP
release less than 5% of the drug at 1 hr and less than 70% at 6
hours.
[0115] Table 3 provides composition details of various TP
formulations, that in some cases, are at TP concentrations lower
than those in Table 2 and in accordance with the teachings of the
instant invention. FIG. 10 provides in vitro dissolution of select
Table 3 formulations.
TABLE-US-00004 TABLE 3 Composition (mg/capsule and weight %) Fill
F. Cremophor Oleic Capmul Tween Precirol Gelucire Wt. No. TP
Labrasol RH40 Acid MCM (L) 80 ATO 5 39/01 (mg) 27 320.0 (40.0%) --
240.0 (30.0%) 220.0 (27.5%) -- -- 20.0 (2.5%) -- 800 28 364.0
(45.5%) -- 160.0 (20.0%) 80 (10.0%) 176.0 (22.0%) -- 20.0 (2.5%)
800 29 320.0 (40%) 160.0 (20%) -- -- 300.0 (37.5%) -- -- 20.0
(2.5%) 800 30, 120.0 (15.0%) -- -- -- 680.0 (85.0%) -- -- -- 800 34
31, 120.0 (15.0%) -- -- -- 560.0 (70.0%) 120.0 (15.0%) -- -- 800 35
32 228.0 (28.5%) -- 296.0 (37.0%) 80.0 (10.0%) 176.0 (22.0%) --
20.0 (2.5%) -- 800 33 228.0 (28.5%) 240.0 (30.0%) -- -- 312.0
(39.0%) -- -- 20.0 (2.5%) 800 36 120.0 (15%) -- 300.0 (37.5%) 120.0
(15.0%) 240.0 (30.0%) -- 20.0 (2.5%) -- 800 37 120.0 (15%) 300.0
(37.5%) -- -- 360.0 (45.0%) -- -- 20.0 (2.5%) 800 38 176.0 (22.0%)
-- -- -- 624.0 (78.0%) -- -- 800 39 228.0 (28.5%) -- -- -- 572.0
(71.5%) -- -- -- 800 40 176.0 (22.0%) -- -- -- 504.0 (63.0%) 120.0
(15.0%) -- -- 800 41 176.0 (22.0%) -- 120.0 (15.0%) -- 504.0
(63.0%) -- -- -- 800 42 176.0 (22.0%) 120.0 (15.0%) -- -- 504.0
(63.0%) -- -- 800 43 120.0 (15%) 680.0 (85%) -- -- -- -- -- 800 44
120.0 (15%) 340.0 (42.5%) -- -- 320.0 (40.0) -- -- 20.0 (2.5%) 800
45 120.0 (15%) -- -- 680.0 (85%) -- -- -- -- 800 46 120.0 (15%) --
680.0 (85%) -- -- -- -- -- 800 47 120.0 (15%) -- 660.0 (82.5%) --
-- -- -- 20.0 (2.5%) 800 48 176.0 (22.0%) 120.0 (15.0%) -- -- 504.0
(63.0%) -- -- -- 800 49 120.0 (15%) -- 408.0 (51%) 272.0 (34%) --
-- 800 50 120.0 (15%) -- -- 370.48 (46.31) 246.88 (30.86%) -- -- --
800 51 120.0 (15%) 140.0 (17.5%) -- -- 520.0 (65.0%) -- -- 20.0
(2.5%) 800 52 182.65 (22.83%) 97.36 (12.17%) 520.0 (65.0%) 800 53
182.65 (22.83%) 97.36 (12.17%) 208.0 (26%) 312.0 (39%) 800 54 120.0
(15%) -- -- 204.0 (25.5%) 476.0 (59.5%) -- -- -- 800 55 182.65
(22.83%) -- -- 185.21 (23.15%) 432.15 (54.02%) -- -- -- 800 56
182.65 (22.83%) -- -- 185.21 (67.01%) 81.28 (10.16%) -- -- -- 800
59 120.0 (15%) -- 320.0 (40%) -- 340.0 (42.5%) -- -- 20.0 (2.5%)
800
[0116] Formulation numbers 50, 51 and 54 are preferred embodiments.
As well, while a variety of solvents may be useful in the
formulations presented in Table 3, preferred solvents may have the
following characteristics: C.sub.4-C.sub.24 fatty acids and/or
their glycerol-, propylene glycol-, polyethylene glycol,
sorbitan-mono-/diesters alone and in mixtures. Preferred fatty
acids and esters are C.sub.8-C.sub.18, saturated and unsaturated.
In addition, the solvents include, fatty acid esters with lower
alcohols, such as ethyl oleate, ethyl linoleate, isopropyl
myristate, isopropylpalmitate, isopropyloleate and
isopropyllinoleate.
Example
[0117] Formulations 50 and 54 were administered to 6 patients;
number 50 was administered once-daily ("QD") in the form of two
capsules per dose (100 mg T equivalents/capsule) and number 54 was
administered once- and twice-daily ("BID") in the form of three
capsules per dose (66 mg T equivalents/capsule). The mean
steady-state profiles after 7 days of treatment with one of the
three, respective, regimens are shown in FIG. 11. The
pharmacokinetic profile for formulation 54 BID was relatively
uniform over the entire 24 hr period and had a trough of the mean
profile about 70% of the peak of the mean profile. Additional data
from formulation 54 include: [0118] Average serum T increase from
baseline of 275 ng/dL [0119] Mean serum T levels at lower end of
normal range, i.e., about 325 ng/dL. [0120] Relatively fast release
(T.sub.max of about 1 hour) [0121] Estimated terminal half-life of
T at steady-state of approximately 8-9 hours [0122] Consistent
dose-related elevation in serum T baseline levels over the 7-day
treatment period [0123] Average steady-state serum DHT level of 114
ng/dL (FIG. 12)
[0124] A simulation of the pharmacokinetic profile of formulation
50 administered BID was performed and compared to the observed
profile for formulation 54 administered BID. The simulation
predicts about a 384 ng/dL increase in C.sub.an over the 24-hour
period for formulation 50 over formulation 54 (FIG. 13).
[0125] In other embodiments of the present invention, methods and
compositions for modulating (i.e., sustaining) the rate of
available serum testosterone by incorporating component(s) that may
biochemically modulate (1) TP absorption, (2) TP metabolism to T,
and/or (3) metabolism of T to DHT. For example, the inclusion of
medium to long chain fatty acid esters can enhance TP absorption.
Without being held to or bound by theory, the present inventors
believe that the use of effective amounts fatty acid esters,
particularly palmitate esters such as ascorbyl-palmitate,
retinyl-palmitate, sorbitan-palmitate and blends thereof may
establish competition between said ester and TP for endogenous
esterase activity. Indeed, it is believed that testosterone ester
metabolism, generally, may be retarded with the administration of
an effective amount of an ester of a medium or long chain fatty
acid (e.g., esters of oleic acid, linoleic acid, linolenic acid,
stearic acid, myristic acid, lauric acid, palmitic acid, capric or
decanoic acid octanoic or caprylic acid, pelargonic acid,
undecanoic acid, tridecanoic acid, pentadecanoic acid, and the
branched chain, cyclic analogues of these acids). In this way, more
TP may stave off hydrolysis in the gut and enter the blood stream.
In other words, the fatty acid ester may competitively inhibit
esterases that would otherwise metabolize TP. Table 4 provides
effective amounts of inhibitors of testosterone ester metabolism.
Examples of other esters or combinations thereof include botanical
extracts or benign esters used as food additives (e.g.,
propylparben, octylacetate, and ethylacetate).
[0126] Other components that can modulate TP absorption include
"natural" and synthetic inhibitors of 5.alpha.-reductase, which is
present in enterocytes and catalyze the conversion of T to DHT.
Complete or partial inhibition of this conversion may both increase
and sustain increases serum levels of T after oral dosing with TP
while concomitantly reducing serum DHT levels. Borage oil, which
contains a significant amount of the 5.alpha.-reductase inhibitor
gamma-linoleic acid (GLA), is an example of a "natural" modulator
of TP metabolism. Other than within borage oil, of course, GLA
could be directly added as a separate component of TP formulations
described herein. Many natural inhibitors of 5.alpha.-reductase are
known in the art (e.g., epigallocatechin gallate, a catechin
derived primarily from green tea and saw palmetto extract from
berries of the Serenoa repens species), all of which may be
suitable in the present invention. Non-limiting examples of
synthetic 5.alpha.-reductase inhibitors suitable in the present
invention include finasteride and dutasteride.
[0127] In addition to 5.alpha.-reductase inhibitors, the present
invention contemplates the use of inhibitors of T metabolism via
other mechanisms. One such point of inhibition may be the
cytochrome P450 isozyme CYP3A4 that is present in enterocytes and
in liver cells and thus capable of metabolizing testosterone.
Accordingly, formulations of the present invention, in some
embodiments, include peppermint oil, which is known to contain
factors capable of inhibiting CYP3A4.
[0128] Table 4 provides composition details of various TP
formulations comprising ingredients to modulate TP absorption
(i.e., ascorbyl-palmitate, borage oil and peppermint oil). FIGS. 14
and 15 show representative in vitro dissolution profiles for select
TP formulations therein in either phosphate buffer (PBS) or
fed-state simulated intestinal fluid (FeSSIF), respectively.
TABLE-US-00005 TABLE 4 Composition % w/w (mg/"00" capsule).sup.1
Fill F. Ascorbyl- Cremophor Cremophor Oleic Borage Peppermint Wt.
No. TP Palmitate RH40 EL Acid Peceol Oil Oil (mg).sup.2 62 30.0
(240) 2.5 (20) -- -- 67.5 (540) -- -- -- 800 62A 15.0 (120) 2.5
(20) -- -- 82.5 (660) -- -- -- 800 63 30.0 (240) 5.0 (40) -- --
65.0 (520) -- -- -- 800 63A 22.9 (183) 5.0 (40) 12.2 (97) -- 60.0
(480) -- -- -- 800 64 15.0 (120) 15.0 (120) -- -- 70.0 (560) -- --
-- 800 64A 15.0 (120) 10.0 (80) 25.0 (200) -- 50.0 (400) -- -- --
800 65 22.9 (183) -- 25.0 (200) -- 52.0 (417) -- -- -- 800 66 15.0
(120) -- 42.5 (340) -- -- 42.5 (340) -- -- 800 67 15.0 (120) --
30.0 (240) -- -- 55.0 (440) -- -- 800 68 22.9 (183) -- 20.0 (160)
-- 45.0 (360) 12.0 (96) -- -- 800 69 22.9 (183) -- -- -- 53.0 (424)
19.0 (152) -- -- 800 70 22.9 (183) 10.0 (80) 25.0 (200) -- 22.1
(177) -- 10.0 (80) 10.0 (80) 800 70B 22.9 (183) 2.5 (20) 20.0 (160)
-- 39.7 (318) -- 10.0 (80) 5.0 (40) 800 71 15.0 (120) 10.0 (80)
25.0 (200) -- 30.0 (240) -- 10.0 (80) 10.0 (80) 800 71A 10.0 (80)
2.5 (20) 20.0 (160) -- 52.5 (420) -- 10.0 (80) 5.0 (40) 800 71B
15.0 (120) 2.5 (20) 20.0 (160) -- 47.5 (380) -- 10.0 (80) 5.0 (40)
800 72 15.0 (120) -- 60.0 (480) -- 25.0 (200) -- -- -- 800 73 15.0
(120) -- -- 60.0 (480) 25.0 (200) -- -- -- 800 .sup.1Milligram
weights rounded to nearest whole number .sup.2.+-.1 mg
[0129] In yet another embodiment of the present invention, drug
delivery systems disclosed herein may also be suitable for
ameliorating some of the side-effects of certain strategies for
male contraception. For example, progestin-based male contraception
substantially suppresses luteinizing hormone (LH) and
follicle-stimulating hormone (FSH), and thereby suppresses
spermatogenesis, resulting in clinical azoospermia (defined as less
than about 1 million sperm/ml semen for 2 consecutive months).
However, administration of progestins also has the undesirable
side-effect of significantly reducing steady-state serum
testosterone levels.
[0130] In such situations, for example, it may be preferable to
provide preparations of progestin concomitantly with testosterone
or a testosterone derivative (e.g., TP). More preferably, a
pharmaceutical preparation according to the invention is provided,
comprising progestin--in an amount sufficient to substantially
suppress LH and FSH production--in combination with testosterone.
In some embodiments, the pharmaceutical preparation is for
once-daily, oral delivery.
[0131] Drug delivery systems, in one aspect of the present
invention, afford the flexibility to achieve desirable
pharmacokinetic profiles. Specifically, the formulations can be
tailored to deliver medicament in a relatively early peak serum
concentration (T.sub.max) or one that appears later. See FIGS. 1,
3, 5 and 7 versus FIGS. 2, 4, 6 and 8, respectively. Similarly, the
formulations may be tailored to have a relative steep or wide drop
in drug serum concentration upon obtaining T.sub.max. See FIGS. 1,
3, 5 and 7 versus FIGS. 2, 4, 6 and 8, respectively. Accordingly,
pharmaceutical preparations of the instant invention may be
administered once-daily, twice-daily, or in multiple doses per day,
depending on, for example, patient preference and convenience.
[0132] One way in which the formulations may be modified to affect
these changes is to calibrate the ratio of lipophilic surfactants.
The magnitude and timing of the T.sub.max, for example, can be
affected by not only the type of lipids used, but also the ratios
thereof. For example, to obtain a relatively early T.sub.max, or
fast release of the medicament from the delivery system, the
concentration of the "controlled-release" lipophilic surfactant
(e.g., Precirol) may be reduced relative to the concentration of
the other lipophilic solvents (e.g., Labrafil M1944CS). On the
other had, to achieve a delayed T.sub.max, the percentage of
"controlled-release" lipophilic surfactant in composition can be
increased. FIGS. 9 and 10 show in vitro dissolution curves of TP
from three formulations, respectively, in a phosphate buffered
dissolution medium incorporating TritonX-100 as a surfactant in
accordance with the present invention.
[0133] Without being bound by or limited to theory, it is believed
that the inventive formulations described herein, in one aspect,
enhance absorption of a medicament therein by the intestinal
lymphatic system. In this way, drug delivery systems of the present
invention can provide extended release formulations that can
deliver testosterone into the serum over several hours. The serum
half-life of testosterone in men is considered to be in the range
of 10 to 100 minutes, with the upper range for testosterone
administered in a form (i.e., TU) that favors lymphatic absorption.
However, oral dosages of the present invention can be taken by a
patient in need of testosterone therapy once every about twelve
hours to maintain desirable levels of serum testosterone. In a more
preferred embodiment, oral dosages are taken by a patient in need
of testosterone therapy once every about twenty four hours. In
general, "desirable" testosterone levels are those levels found in
a human subject characterized as not having testosterone
deficiency.
[0134] While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is
capable of further modifications and this application is intended
to cover any variations, uses, or alterations of the invention
following. In general, the principles of the invention and
including such departures from the present disclosure as come
within known or customary practice within the art to which the
invention pertains and as may be applied to the essential features
hereinbefore set forth and as follows in the scope of the appended
claims.
* * * * *