Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/4858—Organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
  • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/26—Androgens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/30—Oestrogens
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

• the invention relates to pharmaceutical compositions adapted for oral delivery and optionally delivery in accordance with a circadian rhythm; and including methods for the treatment of hormone related conditions that use the compositions.
• Steroid hormones represent a large generic group of compounds that include adrenal steroids (aldosterone, Cortisol, DHE ⁇ A, DHE ⁇ AS), thyroid hormone and retinoic acid, vitamin D and gonadal steroids (androstenedione, dihydrotestosterone, estradiol, progesterone and testosterone) that regulate male and female homeostasis and development.
• adrenal steroids aldosterone, Cortisol, DHE ⁇ A, DHE ⁇ AS
• thyroid hormone and retinoic acid vitamin D and gonadal steroids (androstenedione, dihydrotestosterone, estradiol, progesterone and testosterone) that regulate male and female homeostasis and development.
• oestrogens and androgens Two important groups of steroid hormone are the oestrogens and androgens.
• Oestrogens are female steroids that regulate the female oestrous cycle and are crucial in female reproduction and in the development of female secondary sexual characteristics. There are three types of o
• the oestrogens are produced primarily by the ovaries in response to follicle stimulating hormone and luteinizing hormone. Oestrogens exert their effects via oestrogen receptors which initiate signal transduction cascades to regulate gene expression.
• An example of an androgen is testosterone. Testosterone is produced in the testes of males and the ovaries of females with small amounts secreted by the adrenal glands. In both males and females testosterone is a key steroid involved in regulating fertility, development, libido, body composition and energy metabolism. The androgens exert their effects through interaction with androgen receptors to regulate gene expression in target tissues. Testosterone can be produce in its natural form or as synthetic analogues that have better bioavailability when administered [e.g. either by alkylation or esterification of testosterone].
• Hormone therapy includes the administration of hormone agonists or antagonists in the treatment of diseases.
• hormone therapy is used in the treatment of cancer typically by the administration of steroid hormones.
• Hormone replacement therapy is used to replace oestrogen and testosterone in premenopausal and post-menopausal women and also to replace hormones lost as a consequence of surgically induce menopause [e.g. hysterectomy or orchidectomy].
• Oestrogen therapy is used in post menopausal women to treat or prevent osteoporosis and other symptoms of menopause.
• Oestrogens are also used in the treatment vaginal atrophy, amenorrhea and dysmenorrhea.
• Testosterone and testosterone analogues are used in the treatment of hypogonadism in males which results from little or no testosterone production by the testes.
• Other indications that use testosterone or analogues of testosterone include the treatment of fertility, lack of libido, osteoporosis, increase muscle growth, anaemia and depression.
• Steroid hormone replacement therapy in particular testosterone replacement therapy
• testosterone replacement therapy is facilitated by a number formulations and routes of delivery.
• most testosterone regimes involve the use of parenteral injections, skin patches, gels or buccal tablets because currently available oral forms of testosterone (either alkylated or esterified), present significant pharmacokinetic variability and long-term safety issues.
• Injections administered via intramuscular route every 1-3 weeks offer a solution to the pharmacokinetic variability issue however they are known to be painful and highly inconvenient to use.
• Testosterone undecanoate injections maybe given once every 10 to 12 weeks but do not provide any circadian variation and are painful.
• Testosterone patches are generally preferred by patients but can cause moderate to severe skin reactions due to the vehicle that facilitates enhancement in the dermal absorption of testosterone.
• Testosterone gels are by far the most effective and widely used products. They are however, expensive and care must be taken to avoid inadvertent exposure to women and children. In addition many patients do not like applying the gel because of the quantity and inconvenience.
• a preferred route of delivery is oral.
• WO2005/076899 discloses oral administration of testosterone in an oil vehicle in combination with finasteride or dutasteride to increase bioavailability.
• Finasteride and dutasteride are 5 alpha reductase inhibitors which inhibit the conversion of testosterone to a more active form dihydrotestosterone.
• EPO 001 851 discloses oral formulations of steroids in combination with tocol [a condensate of hydroquinone and phytol].
• US2007/0026066 describes a complex delivery vehicle that provides for the sustained release of drugs, for example testosterone by combining the active agent in a lipid vehicle which is microencapsulated.
• lipid based delivery vehicle that includes multiple lipid entities comprising hydrophilic and lipophilic functions that is adapted for the oral delivery of hydrophobic drugs such as testosterone and testosterone esters.
• Lipid based formulations for oral drug delivery comprise either "simple" mono or binary oil mixtures, or more "elaborate” multi-component systems such as micelles, micro- emulsions, self-emulsifying systems, liposomes or macro-emulsions.
• the utility of multiple component lipid based formulations are thought to improve drug solubilisation and increase the propensity for the formulation to undergo emulsification in vivo thus enabling rapid uptake into the lymphatic system.
• these assertions may not be correct as sufficient emulsification occurs in vivo without the need for additional exogenous emulsifying agents.
• the colloidal particle size ranges (which have been engineered to match those required for lymphatic uptake) are not generally replicated in vivo due to the differing environmental conditions and high variability in gastro-intestinal secretions.
• the nocturnal testosterone rhythm is related to deep sleep and to rapid eye movement (REM)/non-REM sleep cycles. Peaks in testosterone coincide with the onset of REM sleep. In young men the sleep-related testosterone rise is linked with the appearance of the first REM sleep episode. Increased understanding of the pattern of testosterone production may be of clinical relevance in selecting the appropriate therapeutic regimen and the correct dose required for physiological replacement over the 24-h period for men on long-term testosterone replacement and may aid in the development of male hormonal contraception. Both supraphysiological and subphysiological doses at different time points may have adverse effects reflecting the very widespread distribution of androgen receptors.
• testosterone levels have been related to cognitive function specifically spatial awareness and the correct physiological rhythm of testosterone maybe important for optimal cognition.
• This disclosure relates to an alternative lipid based formulation for the delivery of steroid hormones, for example testosterone, via the oral lymphatic system and its use in circadian delivery of hormone therapy.
• steroid hormones for example testosterone
• a pharmaceutical composition adapted for oral delivery of a steroid comprising: a steroid hormone a lipid based carrier wherein said carrier includes at least one triglyceride fatty acid wherein the fatty acid is at least 10 carbon atoms in length.
• a pharmaceutical composition adapted for oral delivery of testosterone or a functional variant of testosterone comprising: testosterone, or a functional variant of testosterone, a lipid based carrier wherein said carrier includes at least one triglyceride fatty acid wherein the fatty acid is at least 10 carbon atoms in length and at least one agent that enhances the solubility of testosterone or said functional variant in the composition
• said steroid hormone is an androgen.
• said androgen is testosterone or dihydrotestosterone.
• said androgen is a functional variant of testosterone.
• said functional variant is selected from the group consisting of: testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone buciciate, methyltestosterone, fluoxymesterone or mesterolone.
• said steroid hormone is an oestrogen.
• said oestrogen is selected from the group consisting of: oestradiol, estriol and estrone.
• said fatty acid chain length is 10-22 carbon atoms; preferably 14-18 carbon atoms in length.
• the ratio of unsaturated fatty acid to saturated fatty acid is at least or greater than 3.
• said fatty acid is monosaturated.
• said monosaturated fatty acid is at least 30% of the lipid content of the composition.
• said fatty acid is polysaturated.
• said polysaturated fatty acid is at least 30% of the lipid content of the composition.
• said fatty acid is an essential fatty acid.
• Essential fatty acid means a fatty acid that cannot be naturally synthesized by a human or animal and therefore has to be obtained from the diet.
• essential fatty acids found in plants [e.g. linoleic acid, linolenic acid, oleic acid] and obtained from fish [e.g. docosahexaenoic acid, eicosapentaenoic acid].
• said essential fatty acid is selected from the group consisting of: linoleic acid, linolenic acid, oleic acid, myristoleic acid, palmitoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid or docohexaenoic acid.
• said essential fatty acid is linoleic acid.
• said essential fatty acid is linolenic acid.
• said essential fatty acid is oleic acid.
• said lipid based carrier is oil.
• said oil is a vegetable oil.
• said vegetable oil is selected from the group consisting of: almond oil, arachis oil, canola oil, cod liver oil, corn oil, cotton seed oil, flaxseed oil, grape seed oil, peanut oil, safflower oil, sesame oil, soybean oil, sunflower oil or walnut oil.
• said oil is sesame oil.
• said composition comprises at least 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40% w/w sesame oil.
• said vegetable oil includes at least one polyalkylene polyol; preferably polyoxyethylated apricot kernel oil polyoxyethylated corn oil or polyethylated hydrogenated coconut.
• said lipid based carrier includes at least one or a combination of fatty acids selected from the group consisting of: caprylic/capric triglycerides (Migyol 810 and 812), caprylic/capric/linoleic triglycerides (Miglyol 818), caprylic/capric/myristic/stearic fatty acid triglycerides (Softisan 378), capylic/capric/succinic fatty acid triglycerides (Miglyol 829), caprylic/capric triglycerides with stearalkonium benonite and propylene carbonate (Migyol Gel T), caprylic/capric triglycerides with stearalkonium hectorite and propylene carbonate (Migyol Gel B)
• said lipid based carrier includes at least one or a combination of coco-glycerides or coco triglycerides.
• the coco-glycerides or coco triglycerides would comprise 10-18 carbon atoms; for example Softisan 100, 133, 134, 138, 142, 154 which are commercially available.
• said lipid based carrier comprises or consists of myristic acid triglyceride.
• said lipid based carrier comprises or consists of palmitic acid triglyceride.
• said lipid based carrier comprises or consists of stearic acid triglyceride.
• said lipid based carrier comprises a combination of a triglyceride and a polyalkylene polyol.
• said polyalkylene polyol is selected from the group consisting of: polyoxyethylated apricot kernel oil, polyoxyethylated corn oil or polyoxyethylated coconut oil.
• said lipid based carrier comprises a propylene glycol fatty acid.
• said propylene glycol fatty acid is monoester.
• said monoester is propylene glycol monolaurate or propylene glycol monomyristate.
• said monoester is propylene glycol monolaurate.
• said composition comprises at least 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% w/w propylene glycol monolaurate.
• said propylene glycol fatty acid is a diester.
• said diester is selected from the group consisting of: dicaprylate/dicaprate, prolylene glycol dicaprylate/dicaprate and propylene glycol dicaprylate/dicaprate.
• compositions of the invention are administered in effective amounts.
• An "effective amount” is that amount of a composition that alone, or together with further doses, produces the desired response.
• testosterone production rate in men is approximately 3 to 6 mg/day and in women 0.2 to 0.4 mg/day and an effective treatment would deliver this amount of testosterone in to the blood stream in a circadian rhythm with higher levels of testosterone first thing in the morning.
• estradiol the daily production rate is approximately 20 to 60 ug per 24 hours and in pubertal girls there is a distinct circadian rhythm with higher levels of estradiol over night peak first thing in the morning.
• Such amounts will depend, of course, on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size and weight, the duration of the treatment, the nature of concurrent therapy (if any), and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
• hormone replacement therapy should replace the normal level and rhythm of the hormone.
• testosterone that can be assessed by measuring testosterone levels through the 24 hours and in the case of estradiol replacement in measuring 17-beta estradiol over 24 hours.
• estradiol replacement in measuring 17-beta estradiol over 24 hours.
• the impact of hormone replacement can also be assessed by measuring the feedback on the pituitary hormones
• compositions used in the foregoing methods preferably are non- sterile and contain an effective amount of a steroid hormone for producing the desired response in a unit of weight or volume suitable for oral administration to a patient.
• the response can, for example, be measured by determining decrease of disease symptoms. .
• the doses of the steroid hormone administered to a subject can be chosen in accordance with different parameters. Factors include the desired period of treatment. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits.
• the lipid compositions When administered, the lipid compositions are applied in pharmaceutically-acceptable amounts and in pharmaceutically-acceptable compositions.
• pharmaceutically acceptable means physiologically or toxicologically tolerable. Such preparations may routinely contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents. Such agents may be presented or encased within a suitable polymeric capsule dosage form, wherein the capsule can be made from gelatine, hydroxypropylmethyl cellulose (HMPC) or other cellulosic polymer derivatives.
• HMPC hydroxypropylmethyl cellulose
• typical additives include ethanol, benzyl alcohol, glycerol, propylene glycol, propylene carbonate, diethylene glycol monoethyl ether, cremaphor, polysorbate (Tween 80), or combinations thereof.
• said solubilizing agent is ethanol, and/or benzyl alcohol.
• said composition comprises: testosterone, sesame oil, lauroglycol, ethanol and benzyl alcohol.
• said composition comprises at least 1%, 2%, 3%, 4% or 5% w/w/ ethanol.
• said composition comprises at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% w/w benzyl alcohol.
• composition consists essentially of:
• said composition consists of testosterone, sesame oil, lauroglycol, ethanol and benzyl alcohol as described in table 2.
• compositions may be combined, if desired, with additional pharmaceutically-acceptable carriers to preserve the steroid hormone and protect the lipid based carrier.
• pharmaceutically-acceptable carrier means one or more compatible solid or liquid fillers, diluents or encapsulating substances which are suitable for administration into a human and compatible with a steroid hormone and lipid based carrier.
• pharmaceutically-acceptable carrier in this context denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application or protect the active agent.
• Such pharmaceutically acceptable material may include: butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), mixed tocopherols, aromatic phenols, lignans, etc.
• BHA butylated hydroxyanisole
• BHT butylated hydroxytoluene
• the components of the pharmaceutical compositions also are capable of being co- mingled with the molecules of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
• compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well-known in the art of pharmacy. All methods include the step of bringing the active agent into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active compound into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.
• compositions suitable for oral administration may be presented as discrete units, such as capsules, tablets, lozenges, each containing a predetermined amount of the active compound.
• Carrier formulation suitable for oral administrations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA.
• composition according to the invention in hormone therapy.
• said hormone therapy is testosterone hormone therapy.
• testosterone therapy is the treatment of male hypogonadism both primary and secondary.
• Conditions associated with male hypogonadism include, the treatment of fertility, lack of libido, osteoporosis, increase muscle growth, anaemia, insulin resistance and depression.
• said hormone therapy is oestrogen therapy.
• oestrogen therapy is female hypogonadism.
• Conditions associated with female hypogonadism include; hormone replacement therapies in pre-menopausal and post-menopausal women and also to replace hormones lost as a consequence of surgically induce menopause, osteoporosis, vaginal atrophy, amenorrhea and dysmenorrhoea.
• a method to treat a condition that would benefit from steroid replacement therapy comprising administering an effective amount of the composition according to the invention to a subject in need of hormone replacement wherein the composition is administered in accordance with the circadian secretion of said steroid to provide physiological replacement of said steroid.
• Physiological testosterone levels show a distinct circadian rhythm with low levels in the evening and levels rising overnight and peaking in the early hours of the morning.
• oestrogen also shows a circadian pattern of secretion specifically at the onset and during puberty. It would therefore be desirable to provide native 17-beta-oestradiol for oral HRT and especially during puberty this as a circadian therapy.
• said steroid is an androgen.
• said androgen is testosterone or dihydrotestosterone.
• said androgen is a functional variant of testosterone.
• said functional variant is selected from the group consisting of: testosterone propionate, testosterone enanthate, testosterone cypionate, testosterone undecanoate, testosterone buciciate, methyltestosterone, fluoxymesterone or mesterolone.
• composition is administered prior to sleep; preferably between 20:00 and 24:00.
• said steroid replacement therapy is the treatment of male hypogonadism.
• said steroid is an oestrogen.
• said oestrogen is selected from the group consisting of: oestradiol, estriol and estrone.
• said steroid replacement therapy is the treatment of female hypogonadism.
• composition is administered prior to sleep; preferably between 20:00 and 24:00.
• a pharmaceutical composition adapted for oral delivery of a steroid comprising: a steroid, a lipid based carrier wherein said carrier includes at least one triglyceride fatty acid wherein the fatty acid is at least 10 carbon atoms in length and at least one agent that enhances the solubility of the steroid in the composition
• said steroid hormone is an oestrogen.
• said oestrogen is selected from the group consisting of: oestradiol, estriol and estrone.
• Figure 1 illustrates pharmacokinetic profiles for testosterone lipidic formulation B2 and testosterone control formulation dosed at 40mg to female beagle dogs under fed state;
• Figure 2 illustrates pharmacokinetic profiles for testosterone lipidic formulation B3 and testosterone control formulation dosed at 40mg to female beagle dogs under fed state;
• Figure 3 illustrates pharmacokinetic profiles for testosterone lipidic formulation B2 dosed at 40mg and ⁇ Omg to female beagle dogs under fed state
• Figure 4 illustrates pharmacokinetic profiles for testosterone lipidic formulation B2 dosed at 40mg to female beagle dogs under fasted and fed states.
• the lipid system for use the delivery of testosterone may be selected from natural edible oils, specific distilled fractions thereof or synthetically modified derivatives.
• Such systems include:
• Edible oils derived from vegetable or animal sources with triglycerides containing fatty acids with (predominantly) chain lengths in excess of 10-carbon units i.e., almond oil, arachis (ground-nut) oil, canola oil, cod liver oil, corn (maize) oil, cotton seed oil, flaxseed oil, grape seed oil, peanut oil, safflower oil sesame oil, soybean oil, sunflower oil and walnut oil, see Table 1.
• caprylic/capric triglycerides such as caprylic/capric triglycerides (Migyol 810 and 812), caprylic/Capric/Linoleic triglycerides (Miglyol 818), Caprylic/ Capric/Myristic/Stearic triglycerides (Softisan 378), Capylic/Capric/Succinic triglycerides (Miglyol 829), Caprylic/Capric triglycerides (and) stearalkonium benonite (and) propylene carbonate (Migyol Gel T), Caprylic/Capric triglycerides (and) stearalkonium hectorite (and) propylene carbonate (Migyol Gel B), see Table 2.
• Propylene glycol mono- and/or di-esters of fatty acids propylene glycol monolaurate (Lauroglycol), propylene glycol monomyristate (Mipryl) propylene glycol dicaprylate/dicaprate (Capex 200), prolylene glycol dicaprylate/dicaprate (Miglyol 840) and propylene glycol dicaprylate/dicaprate (Neobee M-20), see Table 6.
• the formulation systems as detailed in Table 1 all show significant solubilization capacity for testosterone (>50mg/ 1 ) which is at least 100-fold higher than that achievable in aqueous media ( ⁇ 0.3mg/g 1 ) and at least 5-fold higher than that achievable in single component lipidic vehicles alone (max. ⁇ 10mg/g).
• Tables 2 and 3 show lipidic formulations for testosterone based on formulation system B and D respectively (see Table 1) wherein the overall concentration of testosterone can be changed in order to meet therapeutic requirements and for optimising the formulation dispersion stability along the gastrointestinal tract.
• Dispersion stability in gastrointestinal environment The dispersion stability of lipidic formulations of testosterone as described in Tables 2-4 were evaluated under simulated gastric (pH1) and intestinal (pH6.8) conditions. Samples were evaluated by placing the testosterone formulation (filled in gelatin capsule) in 250ml of media maintained at 37°C in a Caleva dissolution bath. Gentle agitation was provided using paddle apparatus at 50rpm. The dispersibility was monitored visually for precipitation and the time formulations remained in solution. Solution systems were monitored at 15, 30 and 60 minutes, if any precipitation occurred further testing was stopped. If no change was observed the test was continued and monitored every hour up to 7 hours, and left overnight for 24 hours.
• lipidic formulations of testosterone as described in Tables 2-3, were evaluated at room temperature (20-25 0 C) and under accelerated temperature condition (50 0 C) over a period of 2-weeks.
• Lipidic formulations of testosterone were filled into size 00 gelatin capsules and placed on stability at each of the specified storage conditions. The capsules were stored upright (and horizontally) in glass vials. All samples were monitored daily over a period of two weeks for discolouration, precipitation, separation and leakage (from capsules).
• Blood samples were collected up to 24 h post-dose in 4 female dogs following oral administration (6 phases). Blood samples (ca 0.5 ml_) were removed from the jugular vein into uniquely-labelled tubes with clot activator gel (BD Vacutainer ® gold top), at the following target times: pre-dose, 0.5, 1, 2, 3, 4, 6, 10, 12 and 24 h post dosing.
• clot activator gel BD Vacutainer ® gold top
• FIG. 1-4 The pharmacokinetic profiles for representative lipidic formulations of testosterone in female beagle dogs are shown in Figures 1-4. All lipidic formulations were profiled against a control formulation containing testosterone suspension in sesame oil. Figures 1 and 2 show the pharmacokinetic profiles for the lipidic formulations versus the control formulation, all dosed under fed state. The overall extent of absorption, characterised by the maximal serum concentration for testosterone (Cmax) and the area under the curve (AUC) was significantly higher (11-77%) for the lipidic formulations (B2 and B3) than for the control formulation at an equivalent dose.
• Cmax maximal serum concentration for testosterone
• AUC area under the curve
• Figure 3 shows that by increasing the total administered dose from 40mg to 80mg, the level of exposure (as reflected by the AUC) increased disproportionately with dose to over 3-fold (Table 6).
• Figure 4 shows that dosing of formulation B2 to the animals under fasted state resulted in a reduction in AUC of only c. 30%, which is significantly less than that observed for testosterone related oral formulations wherein the reduction in bioavailability under fasted state can exceed 20-fold 1

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  • 2009-04-27 EP EP09738382.2A patent/EP2273984B1/en active Active
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  • 2009-04-27 CA CA2722408A patent/CA2722408C/en active Active
  • 2009-04-27 WO PCT/GB2009/001068 patent/WO2009133352A2/en not_active Ceased
  • 2009-04-27 PL PL09738382T patent/PL2273984T3/pl unknown
  • 2009-04-27 JP JP2011506766A patent/JP5727925B2/ja active Active
  • 2009-04-27 DK DK09738382.2T patent/DK2273984T3/da active
  • 2009-04-27 KR KR1020107025087A patent/KR101617811B1/ko active Active
  • 2009-04-27 ES ES09738382.2T patent/ES2502242T3/es active Active
  • 2009-04-27 PT PT97383822T patent/PT2273984E/pt unknown
  • 2009-04-27 CN CN2009801149913A patent/CN102083421B/zh active Active
  • 2009-04-27 EP EP13186572.7A patent/EP2722038A3/en not_active Withdrawn
• 2010
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  • 2010-10-25 ZA ZA2010/07612A patent/ZA201007612B/en unknown
• 2014
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• 2015
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