Controlled release nasal testosterone gels, methods and pre-filled multi-dose applicator systems for pernasal administration

A testosterone, gel technology, applied in the field of controlled-release nasal testosterone gel, for nasal administration and pre-filled multi-dose applicator system, can solve the problem of high testosterone protein binding, unnecessary, short hormone elimination half-life and other problems, to achieve the effect of good tolerance, safe use and easy mass production

Inactive Publication Date: 2014-05-21
ACERUS PHARMA SRL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Again, this rate is unnecessary for sex hormone replacement therapy and is undesirable given the short elimination half-life of hormones
[0016] In addition to the above "release / absorption" issues related to sex hormones and bioavailability and almost exclusively critical hepatic metabolism and short half-life issues, there is also the issue of protein binding of high testosterone in circulating plasma in both men and women

Method used

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  • Controlled release nasal testosterone gels, methods and pre-filled multi-dose applicator systems for pernasal administration
  • Controlled release nasal testosterone gels, methods and pre-filled multi-dose applicator systems for pernasal administration
  • Controlled release nasal testosterone gels, methods and pre-filled multi-dose applicator systems for pernasal administration

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0119] The preparation of intranasal testosterone gel is carried out by thickening oil mixture and blow-fill-seal technology packaging.

[0120] Introduce a lipophilic vehicle, e.g., castor oil, and a supersolvent, e.g., DMI, (step 1) into a mixing vessel (e.g., FrymaKoruma Vacuum-Mixing, Dispersing and Homogenising machine type Dinex700). The support and supersolvent mixture is blanketed with nitrogen (step 2) to vent oxygen and preheated, eg, to about 40°C to about 50°C.

[0121] The sieved (mesh size about 2 mm) testosterone (step 3) was added to the vehicle and supersolvent mixture and processed to obtain the following intermediate products.

[0122] Controlling the temperature of the vehicle and supersolvent mixture is necessary in the following steps to prevent a significant increase in temperature due to the shear strength applied to dissolve the testosterone.

[0123]

[0124] Homogenization of the intermediate product is carried out by controlling the temperature ...

preparation Embodiment

[0164] Examples of testosterone gels of the present invention are exemplified in Tables 1-3 below.

[0165] Table 1

[0166]

[0167] * Applied micronization

[0168] Table 2

[0169]

[0170]

[0171] *Preferably applied micronization

[0172] table 3

[0173]

[0174] *Preferably applied micronization

[0175] Intranasal testosterone gel formulations 14-21 are further examples (per 100 parts) of gel formulations contemplated by the present invention. Testosterone in micronized form is preferred.

[0176] gel 14

[0177]

[0178] gel 15

[0179]

[0180] gel 16

[0181]

[0182] gel 17

[0183]

[0184] gel 18

[0185]

[0186] gel 19

[0187]

[0188] gel 20

[0189]

[0190] gel 21

[0191]

[0192] Italicized is "surfactant"

[0193] gel 22

[0194]

[0195] gel 23

[0196]

[0197] gel 24

[0198]

[0199] gel 25

[0200]

[0201] gel 26

[0202]

[0203] gel 27

[0204]

[0205] gel 2...

Embodiment 2

[0219] Two dosage levels of an intranasal testosterone gel formulation, Trimel, in healthy adult male subjects Biopharma, Inc., Compleo of Canada TM Bid opening, balanced, random selection, crossover, double group, Dual therapy (dose levels 1 and 2), two-phase pharmacokinetic study

[0220] Test product for: Testosterone gel for nasal administration.

[0221] Profile Level 1:

[0222] Syringes, prefilled with 4.5% testosterone gel, delivering 6.75 mg of testosterone per nostril (manufactured by Trimel Biopharma, Inc. Canada). The formulation is as follows:

[0223] 4.5% Testosterone

[0224] 4% M1944

[0225] 3% (SiO 2 )

[0226] 88.5% castor oil.

[0227] Profile Level 2:

[0228] Compleo TM Syringe, prefilled with 6.5% testosterone gel, delivering 9.75 mg of testosterone per nostril (manufactured by Trimel Biopharma, Inc. Canada), based on 150 mg of Compleo TM Gel prefill weight. Compleo TM The gel formulation is as follows:

[0229]

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Abstract

The present invention relates to intranasal testosterone gels for the controlled release of testosterone into the systemic circulation of males and females for providing constant effective testosterone blood levels, without inducing undesired testosterone spike in blood levels, following pernasal administration. The intranasal testosterone gels of the present invention are safe, convenient to use, well tolerated, stable and easily and reproducibly manufactured on scale up. Moreover, because supra- normal and sub-normal testosterone blood levels are believed to be essentially kept to a minimum or avoided and the testosterone serum levels are believed to remain essentially constant during dose life, i.e., the intranasal testosterone gels of the present invention mimic or restore testosterone blood levels to normal physiologic daily rhythmic testosterone levels, the novel intranasal testosterone gels of the present invention are uniquely suited for testosterone replacement or supplemental therapy and effective for treating males diagnosed with, for example, male testosterone deficiency, such as, low sexual libido, low sexual drive, low sexual activity, low fertility, low spermatogenesis, aspermatogenesis, depression and/or hypogonadism, and females who are diagnosed with, for example, female sexual dysfunction, such as, low sexual libido, low sexual drive, low sexual activity, low amygdala reactivity, low sexual stimulation, hypoactive sexual desire disease ("HSDD"), female sexual arousal disorder and/or anorgasmia. The present invention also relates to methods and pre- filled multi-dose airless applicator systems for pernasal administration of the nasal testosterone gels of the present invention.

Description

technical field [0001] The present invention relates to intranasal testosterone gels for the controlled release of testosterone into the systemic circulation in men and women after nasal administration, providing constant effective testosterone blood levels over the life of the dose without causing unwanted Peak testosterone blood levels, which are indicated for testosterone replacement or supplementation therapy and are effective in treating men and women in need of testosterone replacement or supplementation therapy, for example, testosterone deficiency in men or sexual dysfunction in women. The present invention also relates to methods and prefilled multi-dose applicator systems for nasal administration of nasal testosterone gel. Background technique [0002] Nasal drug delivery offers multiple advantages, including rapid absorption due to multiple capillaries, fast onset of action, avoidance of hepatic first-pass metabolism, chronic drug applicability, and ease of admini...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/00A61K9/06A61K31/568A61K47/34A61K47/44A61P5/26
CPCA61K9/0043A61K31/568A61K47/34A61K47/44A61M31/00A61P15/00A61P15/02A61P15/08A61P15/10A61P25/24A61P5/24A61P5/26A61K9/06A61K47/02
Inventor W·克雷普聂S·福加尔蒂W·奥别瑞吉尔P·J·P·M·梅斯
Owner ACERUS PHARMA SRL
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