COMPOSITION AND METHOD FOR BUCCAL ADMINISTRATION OF GnRH AGONISTS

Abstract

Provided herein is an optimized method of enhancing endogenous gonadotropins and testosterone/estrogen production and concentrations comprising administration of a therapeutically effective amount of at least one GnRH agonist to a patient in need of such treatment. A method and dosing regimen is also described for delivery across the mucosa of the oral cavity for maximizing absorption and delivery, limiting systemic exposure and unwanted side effects, effectuating a sustained increase in concentrations of sex hormones and providing a non-invasive delivery that does not require inpatient visits. The method described benefits conditions such as hypogonadism in men due to aging or disease and symptoms related to menopause in women.

Claims

1. A method of increasing the endogenous production of at least one of the endogenous gonadotropins, as well as testosterone or estrogen in a human in need thereof comprising administering a composition consisting of a GnRH agonist formulated for buccal delivery that permits 1-5 μg of absolute bioavailability.

2. A method of increasing the endogenous production of at least one of the endogenous gonadotropins, as well as testosterone and/or estrogen in a human in need thereof comprising administering a composition consisting of a GnRH agonist formulated for buccal delivery in an amount, which corresponds to 25 μg or less of the subcutaneous equivalent dose.

3. The method according to claim 1 wherein the composition further comprises a permeability enhancer.

4. The method according to claim 1 wherein the human is a male having hypogonadism as a result of aging or disease.

5. The method according to claim 1 wherein the human is a menopausal woman having decreased estrogen levels.

6. A method of increasing the endogenous production of at least one of the endogenous gonadotropins, as well as testosterone or estrogen comprising administering a composition consisting of a GnRH agonist formulated for oral, sublingual, buccal or nasal delivery and resulting in a minimum blood plasma concentration of 30 pg/ml and a maximum blood plasma concentration of 150 pg/ml.

7. A composition for increasing at least one of the endogenous gonadotropins, as well as testosterone or estrogen comprising 300 μg or less of a GnRH agonist in a pharmaceutically acceptable formulation for buccal delivery sufficient to deliver 50 μg to 300 μg of GnRH daily.

8. A composition according to claim 15 wherein the composition further comprises a permeability enhancer.

9. A composition according to claim 1 such that the Cmax is reduced by half in less than 2 hours.

10. A composition according to claim 1 such that testosterone levels are increased by 50% or more within 30 min of administration.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1a is a testosterone blood level test chart after administration of a compound of the invention.

[0035] FIG. 1b is a second testosterone blood level test chart.

[0036] FIG. 2a is a chart of exposure values of leuprolide administration following administration of a compound of the invention.

[0037] FIG. 2b is a second chart of exposure values of leuprolide administration following administration of a compound of the invention.

[0038] FIG. 2c is a third chart of exposure values of leuprolide administration following administration of a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0039] While this invention is susceptible to embodiment in many different forms, there is shown in the drawings, and will herein be described in detail, specific embodiments, with the understanding that the present disclosure of such embodiments is to be considered as an example of the principles and not intended to limit the invention to the specific embodiments shown and described. In the description below, like reference numerals are used to describe the same, similar or corresponding parts in the several views of the drawings. This detailed description defines the meaning of the terms used herein and specifically describes embodiments in order for those skilled in the art to practice the invention.

Definitions

[0040] The terms “about” and “essentially” mean±10 percent.

[0041] The terms “a” or “an”, as used herein, are defined as one or as more than one. The term “plurality”, as used herein, is defined as two or as more than two. The term “another”, as used herein, is defined as at least a second or more. The terms “including” and/or “having”, as used herein, are defined as comprising (i.e., open language). The term “coupled”, as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically.

[0042] The term “comprising” is not intended to limit inventions to only claiming the present invention with such comprising language. Any invention using the term comprising could be separated into one or more claims using “consisting” or “consisting of” claim language and is so intended.

[0043] References throughout this document to “one embodiment”, “certain embodiments”, and “an embodiment” or similar terms means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of such phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments without limitation.

[0044] The term “or” as used herein is to be interpreted as an inclusive or meaning any one or any combination. Therefore, “A, B or C” means any of the following: “A; B; C; A and B; A and C; B and C; A, B and C”. An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0045] The drawings featured in the figures are for the purpose of illustrating certain convenient embodiments of the present invention, and are not to be considered as limitations thereto. The term “means” preceding a present participle of an operation indicates a desired function for which there is one or more embodiments, i.e., one or more methods, devices, or apparatuses for achieving the desired function, and that one skilled in the art could select from these or their equivalent in view of the disclosure herein and use of the term “means” is not intended to be limiting.

[0046] Those skilled in the art to which the present invention pertains may make modifications resulting in other embodiments employing principles of the present invention without departing from its spirit or characteristics, particularly upon considering the foregoing teachings. Accordingly, the described embodiments are to be considered in all respects only as illustrative, and not restrictive, and the scope of the present invention is, therefore, indicated by the appended claims rather than by the foregoing description or drawings. Consequently, while the present invention has been described with reference to particular embodiments, modifications of structure, sequence, materials and the like apparent to those skilled in the art still fall within the scope of the invention as claimed by the applicant.

[0047] As used herein, the terms “GnRH agonists” are well known and include, but are not limited to, leuprolide acetate, buserelin, naferelin, deslorein, histerelin, goserelin and cetrorelix. The GnRH agonists can be dispersed in a variety of well-known formulations using permeabilizers, co-solvents or surfactants and administered into the buccal cavity, maximizing absorption, increasing pulsatile delivery, limiting systemic exposure and thus improving safety/tolerability profile and resulting in a sustained increase in sex hormones compared to parenteral administration. The dosage in one embodiment is limited to 1-5 μg of bioavailable dose.

[0048] As used herein, “compositions for buccal administration” refers to liquid dosage forms, which include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

[0049] As used herein, “permeability enhancers” include, but are not limited to, 1) Anionic Surfactants like Sodium lauryl sulfate, Sodium laurate, Laureth-9, Sodium dodecyl sulfate(SDS), Dioctyl Sodium sulfosuccinate, 2) Non ionic surfactants like Polyoxyethylene-9-lauryl ethe(PLE), Tween80, Nonylphenoxypolyoxyethylene(NPPOE), Polysorbates, Sodium glycocholate Cationic Surfactants like cetylpyridinium chloride, Chitosan, trimethyl chitosan, Poly-L-arginine, L-lysine, 3) Fatty acids and derivatives like Oleic acid Caprylic acid Mono(di)glycerides, Lauric acid Linoleic acid, Acylcholines, Acylcarnitine, Sodium caprate, Oleic acid Bile Salts and derivatives like Sodium deoxycholate, Sodium taurocholate, Sodium taurodihydrofusidate(STDHF), Sodium glycodihydrofusidate, Sodium glycocholate Sodium deoxycholate, 4) Sulfoxides like Dimethyl sulfoxide(DMSO), Decylmethyl sulfoxide, 5) Chelating agents like EDTA, Citric acid Salicylates, 6) Monohydric alcohols like Ethanol, Isopropanol, 7) Polyols like Propylene glycol, Polyethylene glycol, Glycerol, Propanediol and 8) Non Surfactants like Urea and derivative, Unsaturated cyclic urea, Azone(1-dodecylazacycloheptan-2-one) (laurocapram) and Cyclodextrin.

Examples

Example 1: Evidence of Lack of Desensitization with an Optimized Dosing Regimen

[0050] The objectives of this study were to assess the pharmacokinetics, safety profile and hormonal response of fixed (5 mg daily, 5 mg twice a day and 10 mg daily) oral leuprolide acetate administered for 28 days to healthy male volunteers. This was a phase 1, single center, fixed-dose open label study where three doses of oral leuprolide acetate were administered to 60 healthy male volunteers for 28 days. Twenty subjects were assigned to each dosing group. Dosing groups were dosed sequentially, beginning with 5 mg daily group (Group A). Dosing for the 5 mg twice a day group (Group B) commenced 2 weeks after the initiation of Group A and the dosing for the 10 mg daily group (Group C) began 2 weeks after initiation of the 5 mg twice a day group. The formulation used for dosing the patients consisted of water, ethanol, oleic acid, leuprolide acetate 5 mg/ml and tween 80. The final formulation to be dosed was prepared at the investigational site by a pharmacist. For all measurements, the final value obtained before the start of the study drug administration was used as the baseline value for that variable. When applicable, only pre-dose (prior to morning dose for the leuprolide acetate 5 mg twice a day group) hormone values were used. The observed plasma testosterone levels during the first 10 days of the study are shown in Table 1.

TABLE-US-00001 TABLE 1 Testosterone levels ng/dL Leuprolide acetate Dose Baseline Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Group A 453.25 452.45 406.25 384.70 430.55 434.55 413.75 405.85 358.8 369.80 Group B 485.00 563.5 541.35 527.40 502.85 493.25 484.75 449.10 427.65 428.95 Group C 458.85 495.85 501.00 492.20 463.90 412.65 435.50 409.00 428.05 405.95

[0051] The testosterone levels for Group B were higher than the baseline until Day 7 of the study. Testosterone levels for Group C were higher than the baseline until Day 6 of the study. When leuprolide acetate administered at a dose of 5 mg daily (Group A) failed to raise the levels of testosterone above the baseline, 5 mg twice a day (Group B) administration resulted in more significant elevation of plasma testosterone in comparison with 10 mg daily dose (Group C). In Groups B and C, the testosterone levels declined below baseline on Day 7 and Day 6 onwards. This was probably due to the exhausted pituitary responsiveness subsequent to multiple stimuli.

Example 2

[0052] About 36 mg deoxycholate, and 50 mg trihydroxy oxocholanyl glycine (sodium glycocholate) were added to 9.0 mL of SWI (Sterile water for injection) with gentle stirring. 250 mg of glycerine was then added in small aliquots while rapidly stirring the solution. To this was added 1 mL of a solution containing leuprolide acetate (5 mg/mL), benzyl alcohol (9 mg/mL) and sodium chloride USP (6.3 mg/mL) slowly with gentle stirring. This solution was stored under refrigerated conditions. This solution can be used for dosing animals and humans. A propellant like HFA-134 can be used to aid the buccal spray dispersion of this solution.

Example 3

[0053] Two Formulations were Prepared and can be Used for Dosing Through the Buccal Route in Animals and Humans.

[0054] First, 10 mL of stock solutions of the excipients were prepared in de-ionized water, for each of the excipients as shown below:

Sorbitol: 40 mg/mL
Sodium glycocholate: 12 mg/mL
Poloxamer 124: 400 mg/mL
Glycerin: 50 mg/mL

[0055] The formulations with and without Leuprolide were then prepared using the above excipient solutions. Leuprolide (4 mg) was weighed as required for each formulation and was dissolved in 500 μL of de-ionized water, in a 4 mL vial. The required volumes of excipient stock solutions were then sequentially added, as per the required amount for each formulation, and vortexed for 30 sec after which pH was checked. The solutions were then adjusted (as needed) to pH 5.56 or 7.5 using 1M NaOH or glacial acetic acid (99%) or 1M HCl, and volumes used were noted. The solutions were then brought to a total volume of 1 mL with de-ionized water.

TABLE-US-00002 Formulation 1 (1 mL; pH 5.5) Formulation 2 (1 mL; pH 5.5) Leuprolide (4 mg) Leuprolide (4 mg) Glycerin (2.5 mg) Sorbitol (2 mg) Sorbitol (20 mg) Sodium Glycocholate (0.6 mg) Poloxamer 124 (20 mg) Poloxamer 124 (20 mg) De-ionized Water (1 mL) De-ionized Water (1 mL) HCl 1M (as required) Acetic acid (99%) (as required) NaOH 1M (as required) NaOH 1M (as required)

Example 4

[0056] The GnRH analogue leuprorelin acetate (leuprolide acetate) which is available as an injectable, was reformulated as described in Example 3. This spray was administered to male beagle dogs at a dose of 0.5 mg suspended in 140 μl and dispensed in a single spray to the inner cheek of male beagle dogs (studies 1 and 2). In addition, formulation 2 was sprayed to the mucosae at the back of the throat in a separate study to determine if this would alter the absorption characteristics (study 3). The two formulations were administered with a one week washout period. Drug was dispensed in a single spray with a volume of 140 μl (studies 1 and 2) or three consecutive sprays (study 3). The aim of the study was to determine if leuprolide could be delivered as an oralmucosal spray and to determine the minimum exposure required to increase levels of testosterone.

[0057] The blood levels for leuprolide were monitored 15 minutes before the start of the study and at time “0” (immediately after drug administration), then at 15, 30 minutes and at 1, 2, 3 and 5 hours (postdosing; studies 1 and 2). In addition, for study 3, two additional time points were included at 5 and 10 min post dosing. The blood samples were drawn (3 ml at each time point) via a cephalic catheter.

[0058] The study was conducted by the University Health Network in Toronto and specifically at the Toronto Western Hospital. Serum samples were analysed at Inventiv Health in Quebec City.

Results

[0059] The drug induced a peak testosterone increase of almost 200% compared to baseline (FIGS. 1a, b). Moreover, this testosterone increase occurred at exposure levels of at least 30 pg/ml. Lastly, the pharmacokinetic curve for leuprolide demonstrated a rapid rise and fall, thus predicting a low risk for accumulation after multiple dosing (FIGS. 2a, b, c).