WO2023236202A1

WO2023236202A1 - Pharmaceutical formulations of cinacalcet, methods of administration, and uses thereof

Info

Publication number: WO2023236202A1
Application number: PCT/CN2022/098200
Authority: WO
Inventors: Likun WANG; Haoru SHI
Original assignee: Nanjing Haiwei Pharmaceutical Technologies Co., Ltd.
Priority date: 2022-06-10
Filing date: 2022-06-10
Publication date: 2023-12-14

Abstract

The present disclosure provides certain pharmaceutical compositions comprising cinacalcet and/or a pharmaceutically acceptable salt thereof, methods of administering the pharmaceutical compositions, and uses thereof.

Description

Pharmaceutical Formulations of Cinacalcet, Methods of Administration, and Uses thereof

FIELD OF THE DISCLOSURE

SUMMARY

Cinacalcet and its salts are calcimimetic agents that can increase the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Cinacalcet and its salts are used to treat diseases that are related to decreased serum calcium concentration, such as chronic kidney disease (CKD) . Pharmaceutical formulations of cinacalcet or a salt thereof currently available on the market are for oral administration. Oral administration of cinacalcet or a salt thereof often leads to some side effects in the gastrointestinal tract. Other side effects of pharmaceutical formulations of cinacalcet or a salt thereof currently available on the market include, but are not limited to, nausea, vomiting, diarrhea, abdominal pain, myalgia, dyspnea, cough, hypotension, headache, hypocalcemia, muscle spasms, and anorexia. The gastrointestinal side effects can be alleviated by administering cinacalcet and its salts via a non-oral route. Side effects from cinacalcet and its salts can also be alleviated by lowering systemic exposure, which is achieved by, for example, a lower drug dose or a shorter drug half-life. Side effects can also be alleviated by lowering drug administration frequency.

The present disclosure provides novel pharmaceutical compositions and methods for transdermal administration of a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof onto the skin near the subject’s thyroid gland. The present disclosure discloses an unexpected finding that transdermal administration of cinacalcet and/or a pharmaceutically acceptable salt thereof onto the skin near the subject’s thyroid gland can achieve similar or even better pharmacodynamic effects compared to oral administration or transdermal administration at other areas of the subject’s body. Transdermal administration of cinacalcet and/or a pharmaceutically acceptable salt thereof onto the skin near the subject’s thyroid gland can achieve lower systemic exposure, higher parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof compared to oral administration or transdermal administration at other areas of the subject’s body. These favorable pharmacodynamic and pharmacokinetic effects of transdermal administration near the subject’s thyroid gland enable lower drug dose and/or lower administration frequency of the drug, which contribute to alleviating or minimizing those side effects as set forth above.

In an aspect, the present disclosure provides a pharmaceutical composition for external use near a subject’s thyroid gland, comprising cinacalcet and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch.

In some embodiments, the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL

In some embodiments, the at least one pharmaceutically acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.

In another aspect, the present disclosure provides a method, comprising administering a pharmaceutical composition comprising cinacalcet and/or a pharmaceutically acceptable salt thereof to a subject, wherein the pharmaceutical composition is applied onto the skin near the subject’s thyroid gland.

In another aspect, the present disclosure provides a method for lowering parathyroid hormone (PTH) level in a subject, comprising administering an effective amount of a pharmaceutical composition comprising cinacalcet and/or a pharmaceutically acceptable salt thereof to the subject, wherein the pharmaceutical composition is applied onto the skin near the subject’s thyroid gland.

In another aspect, the present disclosure provides a method for treating a subject diagnosed of having a chronic kidney disease, comprising lowering parathyroid hormone (PTH) level in the subject using the method disclosed herein.

In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising cinacalcet and/or a pharmaceutically acceptable salt thereof has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch.

In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising cinacalcet or a pharmaceutically acceptable salt thereof further comprises at least one pharmaceutically acceptable excipient and the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL.

In some embodiments of the methods disclosed herein, the at least one pharmaceutical acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.

In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising cinacalcet and/or a pharmaceutically acceptable salt thereof is administered to the subject no more than twice per day.

In some embodiments of the methods disclosed herein, the total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours ranges from 15μg to 180 mg.

In some embodiments of the methods disclosed herein, the bioavailability of cinacalcet and/or a pharmaceutically acceptable salt thereof in the subject’s serum is lower than 50%.

In some embodiments of the methods disclosed herein, the serum concentration of parathyroid hormone (PTH) in the subject after the treatment is lower than 300pg/mL.

In some embodiments of the methods disclosed herein, the maximum serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof after administration is not higher than 50 ng/mL.

In some embodiments of the methods disclosed herein, the half-life of cinacalcet and/or a pharmaceutically acceptable salt thereof is not shorter than 3 hours.

In some embodiments of the methods disclosed herein, the ratio of parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof to serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof is higher than 5: 1, at the time of 4 hours post the administration.

In some embodiments of the methods disclosed herein, the pharmaceutical composition comprising cinacalcet and/or a pharmaceutically acceptable salt thereof has a modified-release effect.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1. depicts cinacalcet concentrations in blood at different time for the 8mg dose group. Cinacalcet was administered to skin at the thyroid site to SD rats at dose of 8 mg/rat. Fig. 1 shows the mean of cinacalcet concentration in plasma (ng/mL) relative to time (hr) .

Fig. 2. depicts concentrations (ng/g) of cinacalcet in thyroid gland (including parathyroid glands) of SD rats at different time (hr) .

Fig. 3. depicts concentrations (ng/g) of cinacalcet in administration site skin of SD rats at different time (hr) .

Fig. 4. depicts the mean of cinacalcet concentration in plasma (ng/mL) relative to time (hr) for the three administration routes. Cinacalcet was administered in three different routes to SD rats at dose of 2 mg/rat, .

DETAILED DESCRIPTION

Definitions

In the present disclosure, unless otherwise specified, the scientific and technical terms used herein have the meanings generally understood by a person skilled in the art. Accordingly, the terms defined herein are more fully described by reference to the Specification as a whole.

As used herein, the singular terms “a, ” “an, ” and “the” include the plural reference unless the context clearly indicates otherwise.

As used herein, “and/or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative ( “or” ) . Moreover, the present disclosure also contemplates that in some embodiments of the disclosure, any feature or combination of features set forth herein can be excluded or omitted.

Unless the context requires otherwise, the terms “comprise, ” “comprises, ” and “comprising, ” or similar terms are intended to mean a non-exclusive inclusion, such that a recited list of elements or features does not include those stated or listed elements solely, but may include other elements or features that are not listed or stated.

It is to be understood that this disclosure is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context in which they are used by those of skills in the art.

As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of a therapeutic compound, and is relatively nontoxic, i.e., the material may be administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained. Pharmaceutically acceptable components include those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the term “solubility” refers to the maximum amount of a substance that can be dissolved in a solvent at a given temperature. For the purpose of this application, solubility is measured at room temperature.

As used herein, the term “transdermal, ” “transdermal administration, ” or “transdermal delivery” refers to administering a pharmaceutical composition to the skin of a subject for systemic distribution. Transdermal administration is external.

As used herein, an “effective amount” refers to an amount of a pharmaceutical composition which is sufficient to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response) . The effective amount of a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the particular composition being employed, the particular pharmaceutically-acceptable excipient (s) and/or carrier (s) utilized, and like factors with the knowledge and expertise of the attending physician.

As used herein, a “disease” or “disorder” refers to a condition in which treatment is needed and/or desired.

As used herein, the term “treat, ” “treating, ” or “treatment” refers to ameliorating a disease or disorder, e.g., slowing or arresting or reducing the development of the disease or disorder or reducing at least one of the clinical symptoms thereof. For example, in some embodiments, ameliorating a disease or disorder can include obtaining a beneficial or desired clinical result that includes, but is not limited to, any one or more of: alleviation of one or more symptoms, diminishment of extent of disease, preventing or delaying spread of disease, preventing or delaying recurrence of disease, delay or slowing of disease progression, amelioration of the disease state, inhibiting the disease or progression of the disease, inhibiting or slowing the disease or its progression, arresting its development, and remission (whether partial or total) .

As used herein, the term “subject” refer to an animal. For example, in some embodiments, the animal is a mammal. In some embodiments, the animals are humans, rodents, simians, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian laboratory animals, mammalian farm animals, mammalian sport animals, or mammalian pets. The animal can be male or female and can be at any suitable age, including infant, juvenile, adolescent, adult, and geriatric. In some examples, an “individual” or “subject” refers to an animal in need of treatment for a disease or disorder. In some embodiments, the animal to receive the treatment can be a “patient, ” designating the fact that the animal has been identified as having a disorder of relevance to the treatment, or being at adequate risk of contracting the disorder. In particular embodiments, the animal is a human, such as a human patient.

As used herein, the term “transdermal, ” “transdermal administration, ” or “transdermal delivery” are used interchangeably with “percutaneous, ” “percutaneous administration, ” or “percutaneous delivery. ”

Cinacalcet and Uses thereof

Cinacalcet and its salts are calcimimetic agents that can increase the sensitivity of the calcium-sensing receptor to activation by extracellular calcium. Cinacalcet’s empirical formula is C ₂₂H ₂₂F ₃N, with a molecular weight of 357.4 g/mol. It has the formula described chemically as (R) -N- (1- (Naphthalen-1-yl) ethyl) -3- (3- (trifluoromethyl) phenyl) propan-1-amine, and has the following structural formula:

Cinacalcet hydrochloride is one of the pharmaceutically acceptable salts of cinacalcet. Its empirical formula is C ₂₂H ₂₂F ₃N·HCl, with a molecular weight of 393.9 g/mol. Its formula is described chemically as N- [ (1R) -1-naphthalen-1-ylethyl] -3- [3- (trifluoromethyl) phenyl] propan-1-amine hydrochloride.

Parathyroid hormone (PTH) , also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates the serum calcium concentration. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. The calcium-sensing receptor on the surface of the primary cell of the parathyroid gland is the principal regulator of PTH synthesis and secretion. Cinacalcet can lower the PTH level by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium.

Cinacalcet and its salts are used to treat diseases that are related to decreased serum calcium concentration. In some embodiments, a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is used to treat a chronic kidney disease (CKD) . In some embodiments, a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is used to treat secondary hyperparathyroidism (HPT) in a subject with CKD. In some embodiments, a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is used to treat secondary hyperparathyroidism in an adult subject with CKD on dialysis. In some embodiments, a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is used to treat parathyroid carcinoma. In some embodiments, a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is used to treat primary hyperparathyroidism.

Some pharmaceutical properties of cinacalcet are listed in Table 1.

Administration and Dosage Form of Cinacalcet

Pharmaceutical formulations of cinacalcet or a salt thereof currently available on the market are for oral administration. Oral administration of cinacalcet or a salt thereof often leads to some side effects in the gastrointestinal tract. It has been shown in clinical trials that about 20%patients had gastrointestinal side effects during cinacalcet treatment. Cases of gastrointestinal bleeding, mostly upper gastrointestinal bleeding, have occurred in patients using cinacalcet hydrochloride. Other side effects of pharmaceutical formulations of cinacalcet or a salt thereof currently available on the market include, but are not limited to, nausea, vomiting, diarrhea, abdominal pain, myalgia, dyspnea, cough, hypotension, headache, hypocalcemia, muscle spasms, and anorexia. See SENSIPAR prescribing information at, https: //www. accessdata. fda. gov/drugsatfda_docs/label/2017/021688s023lbl. pdf

The gastrointestinal side effects can be alleviated by administering cinacalcet and its salts via a non-oral route. Side effects from cinacalcet and its salts can also be alleviated by lowering systemic exposure, which is achieved by, for example, a lower drug dose or a shorter drug half-life. Side effects can also be alleviated by lowering drug administration frequency.

The present disclosure provides novel pharmaceutical compositions and methods for transdermal administration of a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof onto the skin near the subject’s thyroid gland. The present disclosure discloses an unexpected finding that transdermal administration of cinacalcet and/or a pharmaceutically acceptable salt thereof near thyroid gland can achieve similar or even better pharmacodynamic effect compared to oral administration and compared to transdermal administration at other area of the body. Transdermal administration of cinacalcet and/or a pharmaceutically acceptable salt thereof near thyroid gland can achieve lower systemic exposure, higher parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof compared to oral administration and compared to transdermal administration at other area of the body. These favourable pharmacodynamic and pharmacokinetic effects of transdermal administration near thyroid gland enable lower drug dose and/or lower administration frequency of the drug, which contribute to alleviation of those side effects as set forth above.

Thyroid gland, or thyroid, is an endocrine gland in vertebrates. In humans, it is in the neck and consists of two connected lobes. The thyroid is located at the front of the neck, below the Adam's apple. Parathyroid glands are small endocrine glands. In humans, there are usually four parathyroid glands, located on the back of the thyroid gland in variable locations. The parathyroid gland produces and secretes parathyroid hormone in response to a low blood calcium.

In an aspect, the present disclosure provides a pharmaceutical composition for external use near a subject’s thyroid gland, comprising cinacalcet and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable salt of cinacalcet is cinacalcet hydrochloride. In some embodiments, the concentration of cinacalcet or its pharmaceutically acceptable salt thereof in the pharmaceutical composition ranges from 15 μg /mL to 500 mg/mL. In some embodiments, the concentration of cinacalcet or its pharmaceutically acceptable salt thereof in the pharmaceutical composition is 15 μg/mL, 100 μg/mL, 200 μg/mL, 500 μg/mL, 800 μg/mL, 1 mg/ml, 10 mg/ml, 50 mg/ml, 100 mg/ml, 200 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml.

In some embodiments, the pharmaceutical composition disclosed herein has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch. In some embodiments, the pharmaceutical composition has a dosage form of spray.

As used herein, a skin area that is “near thyroid gland” refers to a skin area that covers the thyroid gland, or a skin area that is no more than 3 cm away from the skin area covering the thyroid gland. A skin area near thyroid gland is also near parathyroid gland.

As used herein, “pharmaceutically acceptable excipient” includes without limitation, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, surfactant, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. Exemplary pharmaceutically acceptable carriers include, but are not limited to, to sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; tragacanth; malt; gelatin; talc; cocoa butter; waxes; animal and vegetable fats; paraffins; silicones; bentonites; silicic acid; zinc oxide; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate, and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffer solutions; and any other compatible substances employed in pharmaceutical formulations.

In some embodiments, the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL. In some embodiments, the pharmaceutically acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.

In another aspect, the present disclosure provides a method, comprising administering a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof to a subject, wherein the pharmaceutical composition of cinacalcet is applied onto the skin near the subject’s thyroid gland.

In some embodiments, the pharmaceutically acceptable salt of cinacalcet is cinacalcet hydrochloride.

In some embodiments, the concentration of cinacalcet and/or its pharmaceutically acceptable salt thereof in the pharmaceutical composition is within range of 15μg/mL –500 mg/mL. In some embodiments, the concentration of cinacalcet and/or its pharmaceutically acceptable salt thereof in the pharmaceutical composition is 15 μg/mL, 100 μg/mL, 200 μg/mL, 500 μg/mL, 800 μg/mL, 1 mg/ml, 10 mg/ml, 50 mg/ml, 100 mg/ml, 200 mg/ml, 300 mg/ml, 400 mg/ml, 500 mg/ml.

In some embodiments, the pharmaceutical composition has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch. In some embodiments, the pharmaceutical composition has a dosage form of spray.

In some embodiments, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient. In some embodiments, the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL. In some embodiments, the pharmaceutically acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.

In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is administered to the subject no more than twice per day. In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is administered to the subject every 12 hours, twice a day, once a day, once every two days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, or once every 7 days. It would be understood that a skilled person in the art is able to determine the suitable frequency of administration for a subject in light of the considerations including, but not limited to, the health condition of the subject and the concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in the pharmaceutical composition.

In some embodiments, the total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours ranges from 15μg to 180 mg. In some embodiments, the total amount of pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours is 15 μg, 16 μg, 17 μg, 18 μg, 19 μg, 20 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, or 180 mg. Total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours is calculated by the following formula: D ₂₄ = C _V*V*T, wherein D ₂₄ refers to the total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours, C _V refers to the volume concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in the applied pharmaceutical composition, V refers to the volume of the pharmaceutical composition applied to the subject, and T refers to the times of administration within the 24 hours. Alternatively, total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours is calculated by the following formula: D ₂₄ = C _M*M*T, wherein D ₂₄ refers to the total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours, C _M refers to the mass concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in the applied pharmaceutical composition, M refers to the mass of the pharmaceutical composition applied to the subject, and T refers to the times of administration within the 24 hours.

In some embodiments, the serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in the subject is not higher than 50ng/mL. In some embodiments, the maximum serum concentration (C _max) of cinacalcet or a salt thereof after administration is not higher than 50ng/mL. As used herein, the term “C _max” refers to the maximum value of blood concentration shown on the curve that represents changes in blood concentrations of an active pharmaceutical ingredient (e.g., cinacalcet) , or a metabolite of the active pharmaceutical ingredient, over time. It would be understood that a person skilled in the art is able to select the suitable methods and conditions for measuring serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in a subject and determining the C _max.

In some embodiments, the bioavailability of cinacalcet and/or a pharmaceutically acceptable salt thereof in the subject’s serum is lower than 50%. As used herein, bioavailability (F) describes the percentage of an administered dose of a drug that reaches the systemic circulation. Its meaning is as defined in 21 C.F.R. § 320.1 (a) . For the purpose of the present disclosure, F(AUC _0-t) = (AUC _0-t, _Transdermal/Dose _Transdermal) / (AUC _0-t, _iv/Dose _iv) × 100%. As used herein, AUC refers to area under the curve, which is the area under the curve defined by changes in the blood concentration of an active pharmaceutical ingredient (e.g., cinacalcet) , or a metabolite of the active pharmaceutical ingredient, over time following the administration of a dose of the active pharmaceutical ingredient. “AUC _0-∞” is the area under the concentration-time curve extrapolated to infinity following the administration of a dose. “AUC _0-t” is the area under the concentration-time curve from time zero to time t following the administration of a dose, wherein t is the last time point with a measurable concentration.

In some embodiments, the serum concentration of PTH after treatment in the subject is lower than 300pg/mL. It would be understood that a person skilled in the art is able to select the suitable methods and conditions for measuring serum concentration of PTH in a subject. In some embodiments, the serum concentration of PTH is measured 24 hours after treatment. In some embodiments, the serum concentration of PTH is measured 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 2 weeks, 3 weeks, 4 weeks, 5 weeks or 6 weeks after treatment.

In some embodiments, the half-life (t _1/2) of cinacalcet and/or a pharmaceutically acceptable salt thereof is not shorter than 3 hours. As used herein, half-life (t _1/2) refers to the length of time required for the concentration of a particular substance (typically a drug) to decrease to half of its starting dose in the body. It would be understood that a person skilled in the art is able to select the suitable methods and conditions for measuring the half-life (t _1/2) of cinacalcet and/or a pharmaceutically acceptable salt thereof.

In some embodiments, wherein the ratio of parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof to serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof is higher than 5: 1 at the time of 4 hours post administration. It would be understood that a person skilled in the art is able to select the suitable methods and conditions for measuring parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof and serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof. The ratio is calculated with the formula: R = C _parathyroid/C _serum, wherein C _parathyroid refers to the parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof to serum concentration of cinacalcet in a subject, and C _serum refers to the serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof in the same subject.

In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof has a modified-release effect. In some embodiments, the modified-release effect is delayed-release, extended-release, controlled-release, sustained-release, or targeted-release.

In another aspect, the present disclosure provides a method for lowering parathyroid hormone (PTH) level in a subject comprising administering an effective amount of a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof to the subject using the method described herein.

In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is co-administered with other drugs to lower PTH level. In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is co-administered with at least one of calcitriol, calcium carbonate, pantoprazole, sevelamer HCl, vitamin D sterols, and phosphate binders.

In another aspect, the present disclosure provides a method for treating a subject diagnosed of having a secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) on dialysis, hypercalcemia in patients with parathyroid carcinoma., comprising lowering PTH level in the subject using the method described herein.

In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is co-administered with other drugs for treating a subject diagnosed of having a chronic kidney disease by lowering PTH level. In some embodiments, the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is co-administered with at least one of ketoconazole, calcium carbonate, pantoprazole, sevelamer HCl, vitamin D sterols, and phosphate binders.

Examples

Example 1: Cinacalcet Tissue Distribution Study

The purpose of the tissue distribution study was to compare cinacalcet distribution in thyroid (including parathyroid) of transdermal formulation (2mg/rat and 8mg/rat) and oral formulation (2mg/rat) in healthy rats.

Transdermal formulation (2mg/rat and 8mg/rat) : cinacalcet free form was prepared as liquid formulation (solution, cinacalcet dissolved in a mixture of 50%isopropyl alcohol (IPA) and 50%isopropyl myristate (IPM) ) .

Oral formulation (2 mg/rat) : cinacalcet free form was prepared as liquid formulation (solution, cinacalcet dissolved in a mixture of 5%DMSO + 10%polyethylene glycol-15 hydroxystearate + 85% (20%2-hydroxypropyl-beta cyclodextrin) .

Rats were dosed according to the schemes set forth in Table 2.

Table 2. Experimental design for tissue distribution study (healthy rats)

Route of administration: Gavage for cinacalcet oral administration group. Cinacalcet was administered percutaneously for the cinacalcet low dose group and high dose group at thyroid site skin with a fixed administration area of 2 × 2 cm ² covering thyroids on both sides. Hair was shaved before administration and 0.2 mL of the solution was pipetted and evenly applied to the administration site. A collar was provided to prevent the animals from licking after administration. The animals were fasted for solids for more than 12 h before administration and were given foods at the same time after administration.

Sample Processing and Storage: Approximately 0.3 mL (0.15-0.2 mL) of blood was collected from the eye socket plexus into a tube containing potassium EDTA (anticoagulant) . The tube was shaken immediately to ensure adequate mixing of the blood with the anticoagulant. The whole blood was centrifuged at 12,000 rpm for 2 min, and the plasma was transferred into a centrifuge tube and stored in a refrigerator at -20℃. Tissue samples were stored in a refrigerator at -20℃ for no more than 1 h after collection.

Table 3. UPLC Analytical procedure for cinacalcet

Table 4. Analytical procedure for cinacalcet : Mass spectrometry conditions

Pretreatment of plasma samples: A volume of 40 μL of plasma sample was transferred into a 1.5-mL polyethylene centrifuge tube, before adding 20 μL internal standard solution and mixing. A volume of 190 μL acetonitrile was then added before being vortexed for 30 s and centrifuged at 14,000 rpm for 6 min. The supernatant was then collected for analysis. Linearity range of plasma: 0.5-1,000 ng/mL was obtained.

Pretreatment of tissue samples: Tissue samples were added with methanol/water (5: 95, v/v) to a volume of mixed solution 4 times of skin weight (1: 4, w/v) , or 10 times of thyroid gland (including parathyroid glands) weight (1: 10, w/v) . Samples were homogenized before further treatment. A volume of 20 μL of homogenized sample was transferred into a 1.5-mL polyethylene centrifuge tube, added with 20 μL of internal standard solution before mixing. A volume of 200 μL acetonitrile was then added before being vortexed for 30 s and centrifuged at 14,000 rpm for 6 min. The supernatant was collected for LC-MS analysis. Good linearity was observed for homogenized tissues within the range of 0.2-1,000 ng/mL.

Cinacalcet concentration in plasma v.s. time is shown in Table 5. It was observed that at 8mg dose, after percutaneous administration of cinacalcet in SD rats via skin near thyroid, T _max was 2 h, and t _1/2 was approximately 14 h. (Fig. 1)

Cinacalcet concentration in thyroid (including parathyroid) and in skin near thyroid relative to time is shown in Table 6. It was observed that at 2mg dose, transdermal delivery through skin near thyroid resulted in much higher cinacalcet concentration in thyroid (including parathyroid) at 4 hours, 24 hours, and 48 hours after dosing, than oral administration, respectively. Higher transdermal dose (8 mg/rat) resulted in much higher cinacalcet concentration at 4 hours and 24 hours, but not at 48 hours compared with 2mg/rat transdermal delivery. Thus, transdermal delivery of cinacalcet through skin near thyroid is a more effect approach: resulting in higher concentrations in the target tissue and lasting a much longer time compared with that oral administration.

Table 5. Results from thyroid site skin administration of cinacalcet

Table 6. Results from tissue distribution study

The results of this study are also depicted in Fig. 1-3.

Example 2: Pharmacokinetics (PK) comparison between oral, transdermal through skin near thyroid, transdermal through skin in the back

Healthy rats were used to compare the PK differences among Cinacalcet delivery through oral route, transdermal through skin near thyroid, and transdermal through skin in the back. As PTH can be considered as biomarker of Cinacalcet (pharmacodynamically, Cinacalcet lowers PTH level in blood) , PTH level was also measured.

Transdermal formulation (2mg/rat) : cinacalcet free form was prepared as liquid formulation (solution, cinacalcet dissolved in a mixture of 50%isopropyl alcohol (IPA) and 50%isopropyl myristate (IPM) ) .

Oral formulation (2mg/rat) : cinacalcet free form was prepared as liquid formulation (solution, cinacalcet dissolved in a mixture of 5%DMSO + 10%polyethylene glycol-15 hydroxystearate + 85% (20%2-hydroxypropyl-beta cyclodextrin) .

Rats were dosed according to the schemes set forth in Table 7.

Table 7. Experimental design for PK study

Route of administration: Gavage for cinacalcet oral administration group. Cinacalcet was administered percutaneously for the cinacalcet transdermal group 1 at thyroid site skin, and cinacalcet transdermal group 2 at dorsal skin, with a fixed administration area of 2 × 2 cm ² covering both thyroids. Hair was shaved before administration and 0.2 mL of the solution was pipetted and evenly applied to the administration site. A collar was provided to prevent the animals from licking dosed drug after administration. The animals were fasted for solids for more than 12 h before administration and were given foods at the same time after administration.

Sample Processing and Storage: At the scheduled collection time points, approximately 0.15 mL of whole blood was collected from the eye socket plexus into a tube containing potassium EDTA (anticoagulant) . Immediately after collection of each tube of blood, the tube was gently shaken to ensure adequate mixing of the blood with the anticoagulant. Within 1 h after collection, the sample was centrifuged at 12,000 rpm for 2 min and plasma was collected to an centrifuge tube and stored in a refrigerator at -20℃. Approximately 0.3 mL of whole blood was collected at each sample time point.

Table 8. UPLC Analytical procedure for cinacalcet

Table 9. Analytical procedure for cinacalcet: Mass spectrometry conditions

Pretreatment of plasma samples: A volume of 40 μL of plasma sample was transferred into a 1.5-mL polyethylene centrifuge tube, adding 20 μL internal standard solution before mixing well. A volume of 190 μL of acetonitrile was then added before being vortexed for 30 s and centrifuged at 14,000 rpm for 6 min. The supernatant was then collected for further analysis. Linear range of plasma: 0.5-1,000 ng/mL was obtained.

Determination of PTH (parathyroid hormone) concentration in serum: Instrument model: Spectra Max i3x multiplate reader/525. Rat parathyroid hormone (PTH) enzyme-linked immunosorbent assay (ELISA) kit: microelisa stripplate, 96T. The absorbance (OD value) was measured using a microplate reader at a wavelength of 450 nm, and the PTH (parathyroid hormone) concentration in the serum sample was calculated according to standard curve. Test range: 62.5-2,000 pg/mL.

Cinacalcet concentration in plasma relative to time is shown in Table 10. (Fig. 4) It was observed that transdermal administration of cinacalcet at 2 mg/rat to the thyroid site skin showed similar AUC compared with oral route but slightly shorter half-life. Compared with transdermal through dorsal skin, transdermal trough skin near thyroid showed faster absorption as well as shorter half-life.

Table 10. Results from different administration methods of cinacalcet (2mg/rat)

The change of PTH concentration in plasma is shown in Table 11. In general, transdermal delivery through skin near thyroid showed lowest PTH level for both at 48 h after dosing; transdermal delivery through skin near thyroid showed lowest level of minimal PTH concentration after dosing. longer time compared with the other two delivery routes (possibly means lower dosing frequency) .

Table 11. Results from different administration of cinacalcet (2mg/rat)

Claims

A pharmaceutical composition for external use near a subject’s thyroid gland, comprising cinacalcet and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipients that are suitable for the external use near the subject’s thyroid gland.
The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch.
The pharmaceutical composition according to any one of claims 1-2, wherein the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL.
The pharmaceutical composition according to claim 3, wherein the at least one pharmaceutically acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.
A method, comprising administering a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof to a subject, wherein the pharmaceutical composition is applied onto the skin near the subject’s thyroid gland.
A method for lowering parathyroid hormone (PTH) level in a subject, comprising administering an effective amount of a pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof to the subject using the method of claim 5.
A method for treating a subject diagnosed of having a chronic kidney disease, comprising lowering parathyroid hormone (PTH) level in the subject using the method of claim 6.
The method according to any one of claims 5-7, wherein the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof has a dosage form of liquid, oil, gel, lotion, cream, ointment, spray, or patch.
The method according to any one of claims 5-8, wherein the pharmaceutical composition of cinacalcet or a pharmaceutically acceptable salt thereof further comprises at least one pharmaceutically acceptable excipient and wherein the solubility of cinacalcet and/or a pharmaceutically acceptable salt in the composition is no less than 0.15 mg/mL.
The method according to claim 9, wherein the at least one pharmaceutical acceptable excipient is selected from ethyl alcohol, isopropyl alcohol (IPA) , glycerinum, propylene glycol, transcutol, labrasol, isopropyl myristate (IPM) , and diisopropyl adipate.
The method according to any one of claims 5-10, wherein the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof is administered to the subject no more than twice per day.
The method according to any one of claims 5-11, wherein the total dose of cinacalcet and/or a pharmaceutically acceptable salt thereof administered to the subject within 24 hours ranges from 15 μg to 180 mg.
The method according to any one of claims 5-12, wherein the bioavailability of cinacalcet and/or a pharmaceutically acceptable salt thereof in the subject’s serum is lower than 50%.
The method according to any one of claims 5-13, wherein the serum concentration of parathyroid hormone (PTH) in the subject after treatment is lower than 300 pg/mL.
The method according to any one of claims 5-14, wherein the maximum serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof after administration is not higher than 50 ng/mL.
The method according to any one of claims 5-15, wherein the half-life of cinacalcet and/or a pharmaceutically acceptable salt thereof is not shorter than 3 hours.
The method according to any one of claims 5-16, wherein the ratio of parathyroid concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof to serum concentration of cinacalcet and/or a pharmaceutically acceptable salt thereof is higher than 5: 1, at the time of 4 hours post administration.
The method according to any one of claims 5-17, wherein the pharmaceutical composition of cinacalcet and/or a pharmaceutically acceptable salt thereof has a modified-release effect.