US20170246187A1 - (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE - Google Patents
(17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE Download PDFInfo
- Publication number
- US20170246187A1 US20170246187A1 US15/507,754 US201515507754A US2017246187A1 US 20170246187 A1 US20170246187 A1 US 20170246187A1 US 201515507754 A US201515507754 A US 201515507754A US 2017246187 A1 US2017246187 A1 US 2017246187A1
- Authority
- US
- United States
- Prior art keywords
- oxoandrost
- tridecanoate
- substantially pure
- composition
- less
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Images
Classifications
-
- 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
- A61K31/5685—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 having an oxo group in position 17, e.g. androsterone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
- C07J1/0025—Esters
Definitions
- compositions having or made from pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate for administration to mammals, e.g., humans, in need thereof.
- API active pharmaceutical ingredient
- API also known as drug or a prodrug of an API (also referred to herein as API) and its content. It is also critical that pure drug or prodrug is used in preparation of compositions or dosage forms of drugs or prodrugs to enable safe and effective use in treatment of appropriate disease conditions. Moreover, it is also important to limit all drug or prodrug related materials (starting impurities in the drug or prodrug, degradation product(s) derived from aging through chemical interaction between components of a composition or dosage form upon storage) to acceptable levels that are safe and do not limit shelf life of the composition or dosage form to an unacceptably short time.
- (17- ⁇ )-hydroxy-4-androsten-3-one also known as testosterone
- (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is a novel ester prodrug of (17- ⁇ )-hydroxy-4-androsten-3-one that has demonstrated promise in early testing in treating mammals in need of (17- ⁇ )-hydroxy-4-androsten-3-one, a critical hormone useful for treating numerous conditions in males and females.
- (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is particularly prone to decomposition as a result of reactions such as oxidation, reduction, cleavage of the ester moiety; oxidation of the steroid ring system; cleavage of one or more rings of the steroid ring system; rearrangement of the steroid ring; dealkylation of the steroid ring; dealkylation of the ester; or a combination thereof.
- androstenedione (having a steroid core ring system similar to that of (17- ⁇ )-hydroxy-4-androsten-3-one but having the hydroxyl group as a keto group) induces albnorm alities in morphology and tion of e eloping oocytes in female mice, (Fertil Steril. 2012 Feb;97(2):469-76. doi: 10.1016/j stert.2011.11.040) and androstenedione is carcinogenic in male and female mice Food Chem Toxicol. 2011 Sep;49(9):2116-24. doi: 10.1016/j.fct,2011,05.026. Epub 2011 May 30,
- compositions e.g., bulk drug substance, pharmaceutical, or unit dosage forms
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate which can be stored for prolonged periods without deterioration in their quality, decrease in potency below a specified limit, as well as an increase of the concentration of decomposition products above acceptable limits.
- compositions and dosage forms that are stable upon storage for up to two years (or more) and are safe, with adequate potency (e.g., at least 80%) and acceptable (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate related substances in the compositions independent of using substantially pure starting (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate prodrug.
- (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has the propensity to degrade or decompose.
- (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has the propensity to convert to (17- ⁇ )-Hydroxy-4-androsten-3-one (or otherwise decompose) due to hydrolysis upon storage or interaction with components of the composition or dosage forms that are acidic, hygroscopic, have an unsaturated moiety in their structure and contaminants or catalyst in the prodrug or excipients. Loss of potency of these compositions, especially those containing lipid additives (with associated free radicals) could compromise product performance.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and compositions containing substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in one embodiment, can have greater than 80% potency.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate includes (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurities, decomposition impurities, or both,
- an API or composition that is substantially free of impurities can have less than 20% of total impurities (know and unknown).
- compositions of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate include substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient, pharmaceutical compositions comprised of or prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and a pharmaceutically acceptable carrier, and unit dosage forms comprised of or prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and a pharmaceutically acceptable carrier.
- Substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is useful for administration to a subject (e.g., mammalian; human) to provide safe and effective levels of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and (17- ⁇ )-hydroxy-4-androsten-3-one.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can be used to treat a subject having hypogonadism or any other disorder, disease or conditions associated with low levels of (17- ⁇ )-hydroxy-4-androsten-3-one or that can be improved or prevented with (17- ⁇ )-hydroxy-4-androsten-3-one.
- Substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is useful in pharmaceutical applications and has exceptional safety characteristics as well as stability.
- FIG. 1A shows a non-limiting example of a synthetic scheme for (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 1B shows non-limiting examples of crystallization of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 2 shows general classification of potential impurities in (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate samples.
- FIG. 3 shows a classification of potential impurities in (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate samples.
- FIG. 4 shows a classification of potential impurities related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate samples.
- FIG. 5 shows a classification of potential impurities related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate samples.
- FIG. 6 shows a classification of potential impurities related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 7 shows the structures of several potential impurities related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 8 shows the structures of several potential impurities related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 9 shows a differential scanning calorimtery first heat cycle plot for a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample.
- FIG. 10 shows a differential scanning calorimtery first cool cycle plot for a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample.
- FIG. 11 shows a differential scanning calorimtery second heat cycle plot for a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample.
- FIG. 12 shows a differential scanning calorimtery second cool cycle plot for a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample.
- FIG. 13 shows a portion on an HPLC trace of a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities.
- FIG. 14 shows a portion on an HPLC trace of a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities.
- FIG. 15 shows a portion on an HPLC trace of a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities.
- FIG. 16 shows the two mass spectrum from LCMS traces of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate sample from kept at elevated temperatures for 24 hours (lower trace) and 48 hours (upper trace). See example 6.
- the mass spectra of compounds corresponding to some of these peaks are shown in FIG. 18 through FIG. 28 .
- the retention times are listed about the peaks in the traces.
- FIG. 17 shows a mass spectrum of peaks corresponding to a retention time 29.58-79.92 from the 48 hour sample.
- FIG. 18 shows a mass spectrum of peaks corresponding to a retention time 23.12-23.24 from the 48 hour sample.
- FIG. 19 shows a mass spectrum of peaks corresponding to a retention time 21.45-21.60 from the 48 hour sample.
- FIG. 20 shows a mass spectrum of peaks corresponding to a retention time 20.57-20.59 from the 48 hour sample.
- FIG. 21 shows a mass spectrum of peaks corresponding to a retention time 29.78-29.78 from the 24 hour sample.
- FIG. 22 shows a mass spectrum of peaks corresponding to a retention time 20.99-21.25 from the 2.4 hour sample.
- FIG. 23 shows a mass spectrum of peaks corresponding to a retention time 21.37-21.54 from the 2.4 hour sample.
- FIG. 24 shows a mass spectrum of peaks corresponding to a retention time 18.47-18.76 from the 2.4 hour sample.
- FIG. 25 shows a mass spectrum of peaks corresponding to a retention time 17.77-18.07 from the 24 hour sample.
- FIG. 26 shows a mass spectrum of peaks corresponding to a retention time 16.01-16.23 from the 24 hour sample.
- FIG. 27 shows a mass spectrum of peaks corresponding to a retention time 21.37-21.43 from the 24 hour sample.
- FIG. 28 shows the release profile stability of a pharmaceutical composition having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. See Examples 8 and 9.
- FIG. 29 shows the release profile stability of a pharmaceutical composition having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. See Example 8 and 9.
- substantially pure compositions of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate are provided that are free of synthetic impurities, decomposition impurities, or both.
- the substantially pure compositions of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate described herein include bulk prodrug, pharmaceutical compositions having substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and nit dosage forms having substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the compositions described herein may further include a stabilizing agent or are stored under stabilizing conditions.
- compositions of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate are described, including methods of treatment (e.g., treating a disease, disorder or condition in an individual), and methods of producing or preparing compositions.
- the pharmaceutical compositions described herein have substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- Unit dosage forms can be formed from the pharmaceutical compositions e.g., tablet or capsule (soft gel or hard gel).
- active pharmaceutical ingredient refers to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the biological active metabolite of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is (17- ⁇ )-Hydroxy-4-Androsten-3-one which is produced in vivo by de-esterification.
- Another important biologically active metabolite is (17- ⁇ )-hydroxy-5 ⁇ -androstan-3-one with an IUPAC name of (5S,8R.,9S,1.0S,13S,14S,17S)-17-hydroxy-10,13-dimethyl-11,2,4,5,6,8,9,11,12,14,15,116,17-tetradecahydrocyclopenta[a]phenanthren-3-one (CAS No. 521-18-6) .
- (17- ⁇ )-Hydroxy-4-Androsten-3-one refers to a chemical having IUPAC name of (8R,9S,10R,13S,14S,17S)-17-Hydroxy-10,13-dimethyl-1,2,6,711,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one and a CAS number of 58-22-0.
- (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate refers to a compound having the (17- ⁇ )-Hydroxy-4-Androsten-3-one core structure but the hydroxyl group is esterified with tridecanoic acid e.g., (17- ⁇ )-Hydroxy-4-Androsten-3-one esterified with a straight chain saturated 13 carbon long alkarioic acid called tridecanoic acid.
- Tridecanoic acid is the IUPAC name fir the alkanoic acid having CAS nu giber 638-53-9.
- impurity refers to a chemical or chemical that is not (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate but is derived from the synthesis, preparation, processing, degradation or decomposition of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the impurity is a synthetic impurity or a decomposition impurity.
- Impurities typically can be derived from decomposition, degradation or the chemical reaction of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate which can be referred to as related compounds or “RC” or “RCs”.
- impurities can be present as described herein and are typically synthetic by-products, solvents, etc., derived from the manufacturing or processing of the API. Although synthetic and decomposition impurities are used to categorize classes described herein, they are not mutually exclusive and it is not always certain where or how a particular impurity arises.
- substantially pure refers to a composition having an active pharmaceutical ingredient which meets applicable regulatory requirements in terms of potency.
- potency refers to the comparison of a reference standard deemed to be 100% potent by any number of techniques including NMR, elemental analysis, IR, chromatography (e.g., HPLC) and the such.
- potency is defined in terms of the definition provided by a compendium e.g., the United States Pharmacopeia, European Pharmacopeia or other national or regional Pharmacopeia. Potency can be determined by one of ordinary skill in the art in view of the definition in the compendium or as described herein.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate or related compositions has greater than 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% potency.
- substantially free of impurities refers to a composition having active pharmaceutical ingredient which meets applicable regulatory requirements for levels of impurities (e.g., below a specific level).
- substantially free of impurities can refer to all impurities or a specific impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of active pharmaceutical ingredient and the specific impurity or impurities (or total impurities).
- percent impurity is calculated as the (total weight of a specific impurity or impurities)/(total weight of API +weight of specific impurity or impurities)*100. In some instances, other methods beside weight are used to characterize impurities, like area under the curves of HPLC traces or NMR signals which can be used to calculate percent impurities also.
- the impurities can be decomposition impurities, synthetic impurities, or any other impurity.
- the synthetic impurities in some aspects, refers to those identified in the examples, figures, or elsewhere herein.
- substantially free of synthetic impurities refers to a composition having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate which meets applicable regulatory requirements for levels of impurities (e.g., below a specific level) where the impurity is related to synthesis and/or processing of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- substantially free of synthetic impurities can refer to all synthetic impurities or a specific synthetic impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and the specific synthetic impurity or impurities.
- the synthetic impurities in some aspects, refer to those identified in the examples, figures, or elsewhere herein.
- Synthetic impurities of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, starting materials, by-products (from reactions of reagents or other materials), side-products (from reaction of impurities in reagents or other materials), intermediates, degradation (or decomposition) products, reagents, ligands, catalysts, residual solvents (e.g., from the synthesis, purification or processing of API).
- Specific synthetic impurities include, 17- ⁇ -Hydroxy-4-Androsten-3-one, tridecanoic acid (or a salt form thereof), tridecanoyl chloride, etc. or a non-API compound derived therefrom, pyridine, heptane, heptanes, etc.
- substantially free of decomposition impurities refers to a composition having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate which meets applicable regulatory requirements for levels of impurities related to the decomposition (including degradation) of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., below a specific level).
- decomposition impurities can refer to all decomposition impurities or a specific synthetic impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and the specific or known decomposition impurity or unknown or unspecified impurities.
- the decomposition impurities in some aspects, refer to those identified in the examples, figures, or elsewhere herein.
- Decomposition impurities include, but are not limited to (17- ⁇ )-hydroxy-4-androsten-3-one, an oxidation product of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, an oxidation product of 17- ⁇ -Hydroxy-4-Androsten-3-one, or other decomposition products.
- the impurity is 3-Oxoandrost-1,4-dien-17 ⁇ -yl tridecanoate, 3-Oxoandrost-4,6-dien-17 ⁇ -yl tridecanoate, 17 beta-hydroxy androst-4-en-3-one tridecylenate (e.g., tridec-12-enoate), 3-Oxoandrost-4-en-17 ⁇ -yl tridecanoate , 4-Androstene-3,17-dione, 17 ⁇ -hydroxyandrost-4-en-3one , 4-Androstene-313,17f3-diol, androsta-1,4-dien-3,17-dione, 17 ⁇ -hydroxyandrosta-4,6-dien-3-one, 17 ⁇ -hydroxy-5 ⁇ -androstan-3-one, or 17 ⁇ -hydroxyandrost-1,4-dien-3-one.
- 3-Oxoandrost-1,4-dien-17 ⁇ -yl tridecanoate 3-Oxoandrost-4
- the impurity is as shown in any of the Figures.
- compositions containing substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can be substantially free of impurities.
- Impurities of compositions containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, synthetic impurities, decomposition impurities, or both.
- the substantially pure (17 ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition is provided that is at least 80%, 85% or 90% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the composition comprises at least 95% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the composition comprises at least 97% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the composition comprises at least 98% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99.5% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In a specific aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is a white crystalline or amorphous powder.
- at least 1 g, 10 g, 50 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 500 kg, 1000 kg, 5000 kg 10,000 kg, 50,000 kg of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- a pharmaceutical composition which comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 80%, 85% or 90% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 95% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 97% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 98% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99.5% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the pharmaceutical composition comprises or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is a white crystalline or amorphous powder.
- Pharmaceutical compositions of this embodiment are suitable for any form of administration.
- the pharmaceutical formulations can be formulated for enteral, parenteral, or topical administration.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- a unit dosage form which comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 80%, 85% or 90% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and that is at least 95% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 97% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 98% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99.5% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- the unit dosage form comprises or is prepared from pharmaceutical ingredient, (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, that is a white crystalline or amorphous powder.
- Unit dosage forms of this embodiment are suitable for any form of administration.
- the unit dosage form of the compositions of this invention can be formulated for enteral, parenteral, or topical administration.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises at least 95% (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In a more specific aspect, the composition comprises at least 97% (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 98% (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the composition comprises at least 99.5% (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the active pharmaceutical ingredient is a white crystalline or amorphous powder.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 20%, 15% or 10% impurities (e.g., total impurities (known +unknown)).
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5% total impurities.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3% total impurities. In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2% total impurities. In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1% total impurities. In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5% 17- ⁇ -Hydroxy-4-Androsten-3-one.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3% 17- ⁇ -Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2% 17- ⁇ -Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1% 17- ⁇ -Hydroxy-4-Androsten-3-one.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 0.5% 17- ⁇ -Hydroxy-4-Androsten-3-one. In another specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 20000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 10000 ppm of a solvent (e.g., ethanol).
- a solvent e.g., ethanol
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2000 ppm ethanol.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1500 ppm of a solvent (e.g., ethanol).
- a solvent e.g., ethanol
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is a white crystalline or amorphous powder.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 3% or 2% of a single unknown impurity.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 1% of a single unknown impurity.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.5% of a single unknown impurity. In one specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.1% of a single unknown impurity. In one specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 5% of a single known impurity. In one specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 3% of a single known impurity.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 2% of a single known impurity. In one specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 1% of a single known impurity. In one specific aspect, the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.5% of a single known impurity. In one aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- an impurity is “known” if its structure or chemical identity is known and an impurity is “unknown” if its structure or chemical identity is known.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient or composition or dosage form comprising (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate which is useful for dosing of 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1900-2000, 2000-2500, 2500-3000, 3000-3500, 3500-4000, or 5000 or more mg per day to an individual, has greater than 80%, 85%, 90%, 95%, 98%, or 99% potency is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate of having less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of total impurities (known+unknown) is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate having less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of total unknown impurities is also provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of any single known impurity is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate having less than 10, 5, 2, 1, or 0.5% of any single known impurity is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of any single unknown impurity is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate having less than 5, 4, 3, 2, 1, 0.5 or 0.2% or less of any single unknown impurity is provided.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate safe for administration to a human subject is provided (e.g., male or female).
- the substantial pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is safe for chronic administration (e.g., more than 1, 2, 3, or 4 weeks; more than 1, 2, 3, 4, 6, 9, 12 months; more than 1, 2, 3, 4, or 5 years) at daily doses of 300 mg to 1500 mg (e.g., 300 to 1000 mg or 400 mg to 900 mg) to a human.
- the substantial pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is safe for administration as a testosterone replacement therapy to a hypogonadal male.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is stable.
- stable refers to a composition meeting one or more of the purity or impurity profiles described herein.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate having less than 20, 15, 10, 5 or 2% or less decomposition product of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has less than 20, 15, 10, 5 or 2% or less decomposition product of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate at 90 days at 20-25° C. is provided.
- the substantially pure comprises more than 80, 85, 90, 95, 98, 99, 99.5 or 99.8% substantially (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 10, 5, 4, 3, 2, 1, or 0.5% 17- ⁇ -Hydroxy-4-Androsten-3-one.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprising less than 50,000, 25000, or 15000 PPM of residual solvent (e.g., ethanol).
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the pharmaceutical composition is stable or total impurities, total unknown impurities, any single known impurity, or any single unknown impurity does not increase above acceptable levels after 1 month, 3 months, 6 months, 9 months, one year, or two years at a specified temperature (e.g., 20, 25, 37, 40 or 60° C.) with no more than 10% or 20% decomposition or 10 or 20% loss in potency of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the pharmaceutical composition comprises a stabilizing agent.
- the pharmaceutical composition comprises a pharmaceutically acceptable stabilizing agent which is an antioxidant, bufferant, complexing agent or dessicant.
- the pharmaceutical composition is formulated for topical, enteral or parenteral administration.
- the pharmaceutical composition is formulated for oral, buccal, sublingual, or sublabial administration.
- the pharmaceutical composition is formulated for nasal, rectal or vaginal administration.
- the pharmaceutical composition is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal, or intra-arterial administration.
- the pharmaceutical composition is a liquid, solution, suspension, dispersion, solid, semi-solid, a gel, a lotion, paste, foam, spray, emulsion, syrup, or ointment.
- the pharmaceutical composition is formulated as a tablet or capsule.
- the pharmaceutical composition is formulated as a tincture, patch, injectable, tablet, capsule, sprinkle, aggregate, granule, drink, or powder.
- a unit dosage form comprising a pharmaceutically acceptable carrier and the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate described herein which is useful for dosing up to 2000 mg per day to an individual, has greater than 80%, 85%, 90%, 95%, 98%, or 99% potency and a pharmaceutically acceptable carrier is provided.
- the unit dosage form comprises a stabilizing agent.
- the unit dosage form comprises a pharmaceutically acceptable stabilizing agent which is an antioxidant, bufferant, complexing agent or desiccant.
- the unit dosage form is formulated for topical, parenteral or enteral administration.
- the unit dosage form is a solid, a semi-solid, a gel, a lotion, a paste, tincture, foam, spray, suspension, dispersion, syrup, patch, or ointment.
- the unit dosage form is formulated for an oral route of administration.
- the unit dosage form is a tablet or capsule.
- the unit dosage form comprises or is prepared from at least 3, 5, 10, 15, 30, 25, 30, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- compositions containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurities include, but are not limited to, residual solvents, unreacted reactants, unreacted impurities in reactants, reaction products of impurities in reactants, and impurities created during synthesis, work up, or both. See FIG. 3 ,
- a composition having substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl comprises at least 95% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In a more specific aspect, the composition comprises at least 97% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 98% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% substantially (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the composition comprises at least 99.5% substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the API is a crystalline or amorphous powder.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (A): 17- ⁇ -Hydroxy-4-Androsten-3-one or a synthetic reaction by-product thereof is provided.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (B): tridecanoic acid, tridecanoate, tridecanoyl chloride or a non-API synthetic reaction by-product thereof is provided.
- B tridecanoic acid, tridecanoate, tridecanoyl chloride or a non-API synthetic reaction by-product thereof
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (C): Ethanol, pyridine, heptanes, heptanes, or a combination thereof is provided.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (D): (17- ⁇ )-3-Oxoandrost-4-en-17-yl undecanoate is provided.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (E): (17- ⁇ )-3-Oxoandrost-4-en-17-yl decanoate is provided.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (F): (17- ⁇ )-3-Oxoandrost-4-en-17-yl dodecanoate is provided.
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (E): (17- ⁇ )-3-Oxoandrost-4-en-17-yl tetradecanoate is provided.
- substantially free of an impurity in this paragraph refers to less than 10%, 7%, 5%, 3%, 3%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of any specific impurity referred to this paragraph or their xnnbined total,
- the sum total of all these Impurities (Synthetic Impurity A, B, C, D, or E) compared to the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g.
- the total of any one of these synthetic impurity A, B, C, D, or E as described above as compared to the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC is no more than 2%, 1.5%, 1.0%, 0.50%, 0.40%, 0.30%, 0.20%, 0.10%. 0.075%, 0.050%, 0.025%, 0.020%, 0.010%, or 0.0050%.
- compositions containing substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of decomposition impurities include, but are not limited to, decomposition of (17 ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in e.g., bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, pharmaceutical compositions or formulations, or in unit dosage forms.
- Decomposition impurities include, but are not limited to impurities resulting from cleavage of the ester moiety, oxidation of functional groups on the steroid polycyclic core, dealkylation of the ester, etc.
- stabilized compositions are provided herein. Such stabilized compositions can be e.g., compositions stored under specific environmental conditions, have stabilizing agents (e.g., an antioxidant), or both.
- the stabilized composition can be (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, a composition such as a pharmaceutical composition comprising (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, a unit dosage form having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier and the such.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided substantially free of Decomposition Impurity (1): (17- ⁇ )-Hydroxy-4-Androsten-3-one.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is substantially free of Decomposition Impurity (2): hydroxylated at position 6 (out of the plane) of the FIG. 6 .
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is substantially free of Decomposition Impurity (3): hydroxylated at position 6 (in the plane) of the FIG. 6 .
- a substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of Decomposition Impurity (1), (2), or (3) or a combination thereof as described above is provided.
- the sum total of all these Decomposition Impurities (Decomposition Impurity 1, 2, and 3) compared to the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g., at about 240 or 242 nm or another appropriate wavelength) is no more than 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.50%, 0,25%, 0,20%, 0.10%, or 0.50%.
- HPLC e.g., at about 240 or 242 nm or another appropriate wavelength
- the total of any one of Decomposition impurities (1), (2), and (3) described above as compared to the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC is no more than 2%, 1.5%, 1.0%, 0.50%, 0,40%, 0,30%, 0.20%, 0.10%, 0.075%, 0.050%, 0.025%, 0,020%, 0.010%, or 0.0050%.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of related compound (RC) impurity 1, 2, 3, 4, 5, 6, 7, 8, 9 10, or 11 as identified in Example 5 (see e.g. FIGS. 13-15 ).
- the sum total of all these impurities compared to the amount of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC is no more than 20%, 15%, 10%, 5%, 2%, 1%, 0.75 , 0.50%, 0.25%, 0.20%, 0,10%, or 0.50%,
- the total of any one of these impurities e.g., RC impurity 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11
- Example 5 see e.g., FIGS.
- Impurities in the composition can be determined by any method suitable for identifying such impurities. Typical methods for determining impurities depend on the nature of the starting composition. For example, techniques suitable for examining bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate may be different or involve different condition as compared to examining impurities in a pharmaceutical composition or unit dosage form. The potency of bulk API, pharmaceutical compositions or unit dosage forms may also be determined via some of these techniques. Exemplary, non-limiting techniques are described in more detail below.
- HPLC is a technique commonly used to identify impurities or levels thereof in substances (and may also be used to determine potency).
- HPLC can be used to quantitatively or to qualitatively assess impurities in samples (e.g., bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate or a composition containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate) and potency.
- HPLC methods can also be used for assessing the potency of a particular sample. The ordinary skilled artisan is familiar with and capable of performing HPLC techniques. Typically, a chromatogram from known standard samples is compared to that of an unknown sample.
- the purity of the unknown can be estimated by comparing the area under the curve for the peak that corresponds to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate to other peaks in the chromatogram.
- HPLC techniques are described in the Examples. Other methods can be adapted to analyze purity or impurities of the compositions described herein. (See e.g., Gonzalo-Lumbreras, et al. J. Pharm. Biomed. Anal. Volume 38, Issue 4,15 July 2005, Pages 757-762; Pozo et al. Biomed. Chrom. Volume 23, Issue 8, pages 873-880, August 2009).
- NMR is a technique commonly used to identify impurities or levels thereof in substances and potency. NMR can be used to quantitatively or to qualitatively assess impurities in samples (e.g., bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate or a composition containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate) and potency. NMR methods can also be used for assessing the potency of a particular sample. The ordinary skilled artisan is familiar with and capable of performing NMR techniques.
- Stabilized compositions are provided herein. Instability of bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and composition containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can result in undesirable changes in performance (e.g., dissolution or bioavailability), changes in physical appearance, product failures, safety, toxicity, etc. Stabilization of compositions having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate depends on the nature of the composition and the nature of what type of stabilization is desired.
- stabilization of bulk (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate may involve a specific set of conditions (“stabilizing condition”) e.g., storage and handling conditions that are different (although not necessarily) than for a pharmaceutical composition or a unit dosage form.
- stabilization of certain compositions can involve preventing or mitigating certain things in one composition whereas those same certain things may be desirable in another composition.
- crystalline substantially pure and substantially free of impurity (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate may be desirable for stabilization of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, whereas in other compositions like a pharmaceutical compositions or unit dosage forms crystalline (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate may not be desirable.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is stabilized.
- the stabilized substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is stabilized by its high degree of purity in solid form (e.g., crystalline, amorphous, or a combination thereof).
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solvent.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solve which is an alcohol, alkane, oil, fatty acid or other solvent.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solvent which is an alcohol, alkane, oil, fatty acid or other solvent to provide substantially pure stabilized (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is stabilized in a composition e.g., pharmaceutical composition or unit dosage form that has a stabilizing agent.
- the stabilizing agent is an antioxidant.
- the stabilizing agent is ascorbate or a derivative thereof
- the stabilizing agent is a fatty acid ester of ascorbate.
- the stabilizing agent is ascorbyl palmitate.
- compositions are provided (e.g., pharmaceutical composition, formulation or unit dosage form) having or prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and ascorbyl palmitate.
- the stabilized substantial pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- the pharmaceutical compositions are substantial free of iodine or peroxides.
- the pharmaceutical composition or components from which it is prepared have a peroxide of less than 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10 or 5.
- Bulk API can also be stabilized by maintaining the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate under stabilizing conditions which include, but are not limited to, temperature (e.g., less than 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60° C.). ; relative humidity (e.g., less than 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5%); light (e.g., controlling or minimizing exposure to light including UV, visible, or IR light); and oxidation (e.g., preventing or minimizing exposure to oxidizing agents or oxidizing conditions).
- stabilizing conditions include, but are not limited to, temperature (e.g., less than 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60° C.). ; relative humidity (e.g., less than 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5%); light (e.g., controlling or minimizing exposure to light including UV
- bulk substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in an amount of greater than 1 g, 5 g, 10 g, 50 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 500 kg, 1000 kg, 5000 kg, or 10,000 kg is maintained under stabilizing conditions.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is crystalline API.
- methods of stabilizing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate are also provided herein.
- the method can depend on the composition (e.g., bulk substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, pharmaceutical composition, formulation, or unit dosage form) that is to be stabilized,
- the method comprises storing substantially pure (17- ⁇ )-3-Oxoandrost-4-en17-17-yl tridecanoate under conditions that prevent decomposition of the (17- ⁇ )-3-Oxoandrost-4-en17-17-yl tridecanoate.
- the condition is high purity (e.g., greater than 95%, greater than 98% or greater than 99% by total weight of the composition), maintaining the composition at a temperature of less than 60° C., less than 50° C., less than 40° C., less than 30° C., less than 20° C., less than 15° C., less than 10° C., less than 5° C., or less than 0° C., maintaining the composition in a non-oxidizing environment or minimal oxidizing environment.
- the method of stabilizing comprises combining tridecanoate with a carrier or agent (e.g., fatty acid ester of ascorbate (i.e., ascorbyl palmitate)) that prevents or minimizes decomposition of (17- ⁇ )-3-Oxoandrost-4-en17-17-yl tridecanoate.
- a carrier or agent e.g., fatty acid ester of ascorbate (i.e., ascorbyl palmitate)
- compositions prepared from or comprising (17- ⁇ )-3-Oxoandrost-4-en17-17-yl tridecanoate wherein there is less than 5%, 2%, or 1% total API related impurities after storage for a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, or 30 months or longer.
- the composition has a potency of 100% or 99.5% or more, 99% or more, 98% or more, 97% or more, 95% or more, or 90% or or or 80% or more after storage for a period of time.
- the composition has a purity of 100% or 99.5% or more, 99% or more, 98% or more, 97% or more, 95% or more, or 90% or more after storage for a period of time.
- Injectable Composition e.g. Parenteral Composition or Subcutaneous
- Method of Use e.g.
- a pharmaceutical composition which is an injectable composition (e.g., for parenteral or subcutaneous administration) which comprises or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en17-17-yl tridecanoate and a pharmaceutically acceptable carrier. Associated methods of employing the composition are provided. For the treatment or prevention of a disease, disorder or a condition hypogonadism). in one aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- the composition and method relate to a depot or depot injection.
- a number of parameters influence the pharmacokinetic profile of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that is injected intramuscularly as a depot.
- a depot effect is achieved with substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that slowly degrades (e.g., is de-esterified) into 17- ⁇ -Hydroxy-4-Androsten-3-one once it has entered into circulation.
- the diffusion rate of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate from the site of injection to the circulatory system is thought to affect the diffusion rate.
- the type of vehicle injected together with substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can influence the rate of diffusion of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate from the vehicle into the surrounding tissues and the rate of absorption into the blood circulation.
- the partition coefficient (n-octanol-water partition coefficient) of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in the vehicle as well as the viscosity of the vehicle can be considered for adapting a depot effect folio intramuscular injection of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is dissolved in a vehicle.
- a depot effect in vivo with of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is provided by injecting intramuscularly the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in a vehicle comprising an oil (e.g., castor oil) and optionally a suitable co-solvent.
- a vehicle comprising an oil (e.g., castor oil) and optionally a suitable co-solvent.
- the co-solvent may lover the viscosity of the castor oil and then solve the problem with high viscosity of the castor oil when being injected, although the co-solvent may increase the diffusion rate of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, resulting in a lower depot effect following intramuscular injection.
- careful selection of the co-solvent and amounts is an important consideration.
- the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- composition comprising substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate; and an oil vehicle (e.g., castor oil) comprising and a co-solvent.
- oil vehicle e.g., castor oil
- the composition is formulated for parenteral administration, preferably intramuscular injection.
- the composition is formulated for subcutaneous injection.
- castor oil is meant to encompass castor oil refined for injectable (e.g., parenteral) use. It should also be understood that the castor oil are not hydrogenated or at least in part not hydrogenated. In some embodiments, some of the double bonds may be hydrogenated. For example, less than 20% w/w of the double bonds are hydrogenated. In one aspect, less than 10% w/w of the double bonds are hydrogenated, less than 5% w/w, less than 2% w/w, less than 1% w/w of the double bonds are hydrogenated.
- Co-solvent(s) can be defined by the capability of reducing the viscosity of the oil (e.g., castor oil), as determined by a floppier viscosimeter.
- oil e.g., castor oil
- the viscosity of an injection solution is below 100 mPas.
- the viscosity of a final product, ready to be injected, such as a re-constituted product is, e.g., less than 100 mPas, such as 90 mPas, 80 mPas, 70 mPas at room temperature.
- the viscosity of the vehicle is less than 60 mPas, 50 mPas, 40 mPas or 30 mPas at room temperature.
- some embodiments relate to those wherein the co-solvent is selected from those that when being mixed with castor oil in an oil:co-solvent volume ratio of between 1:0.2 to 1:3, the viscosity drops from 950-1100 mPas to 20 mPas at room temperature.
- the co-solvent is selected from those, wherein the viscosity drops from 950-1100 mPas to about 80-100 mPas, when the co-solvent is being mixed with castor oil in an oil:co-solvent volume ratio of about 1:11 to 1:3.
- the viscosity of the vehicle can be determined with a Hoppler type viscometer. The viscosity is measured at a fixed temperature, often room temperature such as 20° C. or 25° C.
- the co-solvent can be characterized by its ability to reduce the viscosity of a vehicle, such as castor oil, of the solvent in a ratio dependent manner.
- the viscosity of a mixture of castor oil arid a co-solvent in a volume ratio of 1:0.1 to 1:1.7 is reduced from 60% to 5% of that of castor oil alone.
- the viscosity of a mixture of castor oil and a co-solvent is in a ratio of 1:0.02 by volume and is reduced by about 10% relatively to the viscosity of castor oil.
- the ratio between the oil and co-solvent is 1:0.04 by volume the viscosity is reduced by 20% relatively to the viscosity of castor oil
- the ratio is of 1:0.08 by volume the viscosity is reduced by 25%
- the ratio is of 1:0.1 by volume the viscosity is reduced by 40%
- when the ratio is of 1:0.2 by volume the viscosity is reduced by 50% when the ratio is 1:0.35 by volume the viscosity is reduced by 75%
- the ratio is of 1:0.5 by volume the viscosity is reduced by 80% when the ratio is of 1:1 by volume the viscosity is reduced by 90%, or when the ratio is 1:1.6 by volume the viscosity is reduced by 95%.
- the viscosity of the composition is below 100 mPas.
- the viscosity of vehicle such as the mixture of castor oil and a co-solvent, such as benzyl benzoate is below 90 mPas, the viscosity of the vehicle is about 60-100 mPas, 70 to 100 mPas, or 80-90 mPas at room temperature (20° C. to 25° C.).
- the viscosity of the injected vehicle may dictate to a certain extent the pharmacokinetic profile of an injected substance.
- the castor oil and co-solvent in some aspects, is in a volume ratio ranging between 1:0.2 to 1:3, between 1:0.5 to 1:3, or between 1:0.75 to 1:2.5. In one aspect, the volume ratio is in the range from 1:1 to 1:2.
- the co-solvent is benzyl benzoate.
- Other types of co-solvents are applicable for use in combination with the oil (e.g., castor oil), fur example ethanol or benzyl alcohol.
- co-solvents are those which are capable of dissolving the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and is miscible with castor oil.
- Co-solvents suitable for dissolving about 100-500 mg, such as 250 mg of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in 1 mL of the co-solvent within 50 minutes at 40° C. or within 20 minutes at 60° C. are useful in some aspects.
- the solubility of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can be affected upon adding a co-solvent to the oil (e.g., castor oil) vehicle. In one aspect, the solubility may be improved.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is completely dissolved in the composition (vehicle with co-solvent(s)), and in other embodiments the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is partly dispersed in the composition.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is fully dissolved in the vehicle.
- no particles of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate are detected by X-ray diffraction analysis of the composition comprising (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and vehicle.
- compositions wherein the co-solvent is present in the vehicle at concentrations ranging from 10 to 90 volume % (“v %”).
- concentration of the co-solvent in the vehicle ranges between 15 to 85 v %, between 20 to 80 v %, such as between 45 to 85 v % or 55 to 85 v %.
- the vehicle comprises a plant oil (e.g., castor oil) in a volume concentration ranging between 20 to 85 v %. In one aspect, the concentration of castor oil in the vehicle ranges between25 to 60 v % or 25 to 55 v %. In some aspects, the concentration of castor oil in the vehicle ranges between 25 to 50 v %, 25 to 45 v % or 25 to 40 v %.
- a plant oil e.g., castor oil
- the composition does not comprise another plant oil, e.g., tea seed oil.
- the only plant oil present in the composition is castor oil or that castor oil is at least 50% by volume of the total content of the plant oil in the vehicle, e.g., at least 60%, 70%, 80% or 90% by volume.
- the selection of a co-solvent depends on a number of factors, such as i) the amount (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in the injection vehicle, ii) the required reduction of viscosity and iii) the release properties of the injection vehicle with respect to the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate at the site of injection (diffusion rate).
- the co-solvent is at least 10 v % of the vehicle, at least 15 v %, at least 40 v %, or at least 50 v %.
- the co-solvent is in an amount ranging from about 40 to 80 v % of the vehicle, 50 to 70 v %, or 55 to 65 v % of the vehicle.
- the concentration of the co-solvent in the vehicle is chosen to reduce the diffusion rate of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, for instance at the site of injection. Therefore in some aspects, the concentration of co-solvent in the vehicle is less than 90 v %, less than 85 v %, less than 80 v %, or less than 75 v %.
- the volume injected intramuscularly is chosen to affect the release rate of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate from the vehicle.
- an injection volume of 5 mi. is provided for administration by one single intramuscular injection to one injection site. If an intramuscular injection of a volume greater than 5 mL is required, the injection volume can be divided into two or more separate injections to different injection sites. In one aspect, the injection volume is 4-5 mL or less, 3-4 mL or less, 2-3 mL or less, 1-2 mL or less, or 1 mL or less.
- a single dose to one injection site offers advantages in controlling the release rate of an active principle, rather than multiple injections of divided single doses.
- an injection scheme wherein a single dose of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is divided into no more than two separate injections to one or more injection sites is provided.
- a single dose of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is injected as one single injection to one injection site.
- the dose of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is administered as a single injection to one injection site, wherein the injected volume is from 1 to 5 mL, of 1 to 4 mL, or 1.5 to 4 mL.
- Suitable injection volumes for ensuring reproducible administration volumes and uniform release of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is lower than 5 mL, e.g., about 5 mL, about 4 mL, about 3 mL, about 2 mL and about 1 mL.
- the concentration of the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate in the compositions can be relatively high.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is in a concentration of 50 mg to 1000 mg per mL of the vehicle.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is in a concentration of 100 to 750 mg per mL of the vehicle, 150 to 500 mg per mL, 175 to 400 mg per mL, or about 250 mg/mL of the vehicle.
- composition in some aspects, is formulated as a unit dose form such as a unit dose for injection as one single dose.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is in a dose of 500 to 4000 mg, 500 mg to 3000 mg, 750 mg to 2000 mg, 750 mg to 1500 mg, or about 250 mg, about 500 mg, about 750 mg or about 1000 mg.
- the injectable compositions can further comprise another therapeutically active agent, such as a progestin and/or a further gonadotropin suppressive agent other than (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- another therapeutically active agent such as a progestin and/or a further gonadotropin suppressive agent other than (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- compositions some embodiments are chemically stable with respect to the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- degradation products are not detected after long term storage (such as after 7 weeks, 10 leeks or 17 weeks or even longer) at conditions normally known to accelerate degradation processes, such as variations in temperatures, high and low temperatures and various relative humidity.
- less than 1% by weight of degradation products of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is present after storage of the composition for at least 7 weeks, such as for 16 or 17 weeks, for 6 months, or for 9 or 12 months at 40° C. and 25% r.h.
- compositions and dosage forms e.g. capsule or tablet
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can include a variety of pharmaceutically acceptable carriers or additives known in the art.
- Non-limiting examples of components that can be included as components of the pharmaceutical carrier include lipophilic surfactants, hydrophilic surfactants, triglycerides, fatty acid (C8 to C22), fatty acid glycerides (mono-, di-, tri-, or a combination thereof), or a combination thereof.
- the pharmaceutical composition or dosage form comprises, or is prepared with, substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate as described herein.
- the pharmaceutical composition or unit dosage form is characterized by its dissolution or release profile (e.g., at least 75% in 4 hours).
- the oral pharmaceutical composition or unit dosage form can be formulated as a tablet or capsule (e.g., hard gel or soft gel).
- a pharmaceutical composition or unit dosage form having a particular amount of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more).
- the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate that does not change substantially as a function of storage time using a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0° C. ( ⁇ 0.5)) at 100 rpm.
- a release profile e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point
- a release profile e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart
- the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one aspect, the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months.
- the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate using a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0° C.
- a release profile e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point
- the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate using a USP type 2 apparatus in about 1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0 ° C.
- a release profile e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point
- the pharmaceutically acceptable carrier of the composition can include a lipophilic additive.
- the lipophilic additive can comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95 wt % of the pharmaceutically acceptable carrier.
- Non-limiting examples of lipophilic additives can include lipophilic surfactants, triglycerides, tocopherol, tocopherol derivatives and combinations thereof.
- the lipophilic additive can include a fatty acid or fatty acid glyceride.
- lipophilic additive can include the fatty acid glyceride, and the fatty acid glyceride can be a monoglyceride, a diglyceride, or mixtures thereof.
- the fatty acid is oleic acid, stearic acid or a combination thereof.
- the fatty acid glyceride is glyceryl palmitostearate.
- Non-limiting examples of fatty acid glycerides that can be used in the oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and/or diglycerides derived from sources such as maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, and mixtures thereof.
- the pharmaceutical composition or dosage form thereof comprises 50%, 40%, 30%, 20%, 15%, 10%, 5% by weight or less of a triglyceride.
- the pharmaceutical composition or dosage form thereof comprises less than 50% by weight of castor oil.
- the composition includes 10 wt % or less of triglycerides.
- the composition includes 5 wt % or less of triglycerides. In a still a further embodiment, the composition includes about 3 wt % or less of triglycerides. In still a further embodiment, the composition includes about 1 wt % or less of triglycerides. In another embodiment, the composition is free or substantially free of triglycerides. In another embodiment, the composition and dosage forms are free of phytosterols and phytosterol fatty acid esters.
- the lipophilic additive can include a lipophilic surfactant.
- a surfactant is considered to be a lipophilic surfactant when it has an HLB value of 10 or less.
- Various lipophilic surfactants can be used including, but not limited to mono-, di- glycerides of fatty acids like glyceryl monolinoleate (e.g. Maisine® 35-1), mono- and di-glycerides of caprylic, capric acid (e.g.
- Capmul® MCM glyceryl monooleate, reaction mixtures of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g. Labrafil® M 2125 CS), PEG-6 almond oil (e.g. Labrafil®M 1966 CS), PEG-6 apricot kernel oil (e.g. Labrafil®M 1944 CS), PEG-6 olive oil (e.g. Labrafil®M 1980 CS), PEG-6 peanut oil (e.g. Labrafil®M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. Labrafil®.
- natural and/or hydrogenated oils such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g. Labrafil® M 2125 CS), PEG-6 almond oil (e.g.
- PEG-6 palm kernel oil e.g. Labrafil® M 2130 CS
- PEG-6 triolein e.g. Labrafil® M 2735 CS
- PEG-8 corn oil e.g. Labrafil® WL 2609 BS
- PEG-20 corn glycerides e.g. Crovol® M40
- PEG-20 almond glycerides e.g. Crovol® A40
- lipophilic polyoxyethylene-polyoxypropylene block co-polymers e.g. Pluronic® L92, L101, L121 etc.
- propylene glycol fatty acid esters such as propylene glycol monolaurate (e.g.
- Lauroglycol FCC propylene glycol ricinoleate (e.g. Propymuls), propylene glycol monooleate (e.g. Myverol P-O6), propylene glycol dicaprylate/dicaprate (e.g. Captex® 200), and propylene glycol dioctanoate (e.g. Captex® 800), propylene glycol mono-caprylate (e.g. Capryol® 90); propylene glycol oleate (e.g.
- Lutrol OP2000 propylene glycol myristate; propylene glycol mono stearate; propylene glycol hydroxy stearate; propylene glycol ricinoleate ; propylene glycol isostearate; propylene glycol mono-oleate; propylene glycol dicaprylate/dicaprate; propylene glycol dioctanoate; propylene glycol caprylate-caprate; propylene glycol dilaurate; propylene glycol distearate; propylene glycol dicaprylate; propylene glycol dicaprate; mixtures of propylene glycol esters and glycerol esters such as mixtures composed of the oleic acid esters of propylene glycol and glycerol (e.g.
- Arlacel® 186 sterol and sterol derivatives such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol, and the like; glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or a combination thereof; sorbitan fatty acid esters such as sorbitan monolaurate (e.g. Arlacel 20), sorbitan monopalmitate (e.g. Span-40), sorbitan monooleate (e.g.
- sorbitan monolaurate e.g. Arlacel 20
- sorbitan monopalmitate e.g. Span-40
- sorbitan monooleate e.g.
- Span-80 sorbitan monostearate, and sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate, and the like; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidyl choline, bile salts, and the like, and mixtures thereof. It is important to note that some lipophilic surfactants may also function as the solubilizer component of the compositions and oral dosage forms.
- the lipophilic surfactant can be selected from the group consisting of glyceryl monolinoleate (e.g. Maisine® 35-1), mono- and di glycerides of caprylic, capric acid (e.g. Capmul® MCM), glyceryl monooleate, propylene glycol mono caprylate, propylene glycol oleate, propylene glycol monostearate, propylene glycol monolaurate, propylene glycol mono-oleate, propylene glycol dicaprylate/dicaprate, sorbitan monooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, sorbitan monolaurate (e.g.
- the lipophilic surfactants can comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95 wt % of the total pharmaceutically acceptable carrier. It should be noted that the combinations of two or more lipophilic surfactants from the same or different classes therein are also within the scope of this invention and are together can be referred to as the lipophilic surfactant, unless otherwise stated.
- the oral pharmaceutical compositions or dosage forms can include a hydrophilic additive.
- hydrophilic additive is a selected from the group consisting of hydrophilic surfactant, celluloses—such as hydroxypropyl celluloses low molecular weight, low viscosity types (e.g. Methocel® E5, E6, El° E15, LV100 etc. grades) and hydroxypropyl celluloses having higher molecular weight, medium to high viscosity (e.g. Methocel® K4M, Kl5M, K100M etc); polyvinylpyrrolidones (e.g. Kollidon k17, K30 etc); polyvinyl acetates and combinations thereof.
- hydrophilic surfactant celluloses—such as hydroxypropyl celluloses low molecular weight, low viscosity types (e.g. Methocel® E5, E6, El° E15, LV100 etc. grades) and hydroxypropyl celluloses having higher molecular weight, medium
- the hydrophilic additive can be a hydrophilic surfactant.
- a surfactant is considered to be a hydrophilic surfactant when it has an HLB value of greater than 10.
- hydrophilic surfactants include non-ionic surfactants, ionic surfactants and zwitterionic surfactants.
- hydrophilic surfactants suitable for the current invention include, but not limited to alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulphate salts, dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters; polyethylene glycol fatty acids mono- and di- ester mixtures; polysorbates, polyethylene glycol derivatives of tocopherol and the like
- the hydrophilic additive can be a hydrophilic surfactant.
- Non-limiting examples of hydrophilic surfactants can include PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acids mono- and di-ester mixtures, polysorbate 80, polysorbate 20, polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof.
- surfactants utilized in the pharmaceutical compositions described herein include sterols and derivatives of sterols.
- these surfactants are hydrophilic or lipophilic.
- hydrophilic sterol surfactants are lanosterol PEG-24 cholesterol ether (e.g. Solulan C-24, Amerchol), PEG-30 soya sterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g. Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, from Nikko).
- Lipophilic Sterol Surfactants are Cholesterol, sitosterol, Phytosterol (e.g. GENEROL series from Henkel), PEG-5 soya sterol (e.g. Nikkol BPS-S, from Nikko), PEG-10 soya sterol (e.g. Nikkol BPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol BPS-20 from Nikko).
- the oral pharmaceutical composition or the dosage form comprises or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or dosage form.
- the compositions or the dosage form of the current invention includes substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or dosage form, and wherein the carrier includes at least 50 wt % of the composition or the dosage form and wherein the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature. In one aspect, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel). In one aspect, the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- the compositions or the dosage forms includes or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and wherein the carrier includes about 50 wt % to about100 wt % of lipophilic surfactant and 0 wt % to about 50 wt % of hydrophilic surfactant.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature.
- the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel).
- the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- the composition or the dosage form includes or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and the carrier includes about 50 wt % to about 95 wt % a lipophilic surfactant and a hydrophilic surfactant 5 wt % to about 30 wt %.
- the lipophilic additive is a C16 to C18 fatty acid (saturated or having 1, 2, or 3 unsaturations), or a mono-, di-, or triglyceride thereof In one aspect, mono-, di-, or tri-glyceride is glyceryl palmitostearate.
- the hydrophilic component is a hydrogenated oil. In one aspect, the hydrophilic component is a polyoxylated hydrogenated oil. In a further more specific embodiment, the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C.
- the ester is not fully dissolved in the carrier at human body temperature.
- the composition or the dosage form can optionally contain about 10 wt % or less of ethyl alcohol.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature.
- the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel).
- the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- the hydrophilic surfactant can comprise at least about 20% of the total pharmaceutical carrier. In another embodiment, the hydrophilic surfactant can comprise at least about 5 wt % of the carrier. In another embodiment, the hydrophilic surfactant can comprise less than 5, 4, 3, 2, or 1 wt % of the carrier.
- the composition or the dosage form includes or is prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate, wherein the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and wherein the composition includes about 50 wt % to about 100 wt % of lipophilic additive and 0 wt % to about 50 wt % of hydrophilic additive.
- the lipophilic additive can be lipophilic surfactant and the hydrophilic additive can be hydrophilic surfactant.
- the lipophilic additive is a C16 to C18 fatty acid (saturated or having 1, 2, or 3 unsaturations), or a mono-, di-, or triglyceride thereof.
- mono-, di-, or tri-glyceride is glyceryl palmitostearate.
- the hydrophilic component is a hydrogenated oil.
- the hydrophilic component is a polyoxylated hydrogenated oil.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the lipophilic additive or the composition at human body temperature.
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature.
- the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel).
- the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10).
- the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg.
- substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175
- the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- the hydrophilic surfactant can comprise at least about 20% of the composition. In another embodiment, the hydrophilic surfactant can comprise at least about 5 wt % of the composition. In another embodiment, the hydrophilic surfactant can comprise less than 5 wt % of the composition.
- the oral pharmaceutical composition or the dosage form can include both a lipophilic surfactant and hydrophilic surfactant.
- the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2:1.
- the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2.5:1.
- the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 3.5:1. In still another embodiment, the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is at least 6.5:1.
- Subjects that can be treated by pharmaceutical compositions and unit dosage forms of the present disclosure can be any man (e.g., male or female) in need thereof.
- the human male is at least 14, 16, or 18 years of age.
- the human male is at least age 20. 21, 25 or 30.
- the subject is an adult male of at least age 40 or 50.
- the subject can be an adult male of at least age 60.
- Subjects that can be treated by pharmaceutical compositions and unit dosage forms of the present disclosure can be any human male in need thereof.
- the human female may be at least 14 years of age.
- the human subject is a female.
- the human female is an adult of at least 20 or 30 years of age.
- the subject can be an adult female of at least age 40 or 50.
- the subject can be an adult female who is deficient in the endogenous serum testosterone levels.
- the subject can be an adult female who has undergone unilateral or bilateral oophorectomy. In yet a further embodiment, the subject can be an adult female who has undergone unilateral or bilateral oophorectomy, In yet another embodiment, subject can be a post-menopausal woman.
- a method of treating a human subject in need of testosterone therapy is provided.
- the method can include the steps of administering any of the pharmaceutical compositions or dosage forms (e.g., capsule or tablet) disclosed herein.
- the pharmaceutical compositions and the dosage forms of the present invention can be used to treat any condition associated with testosterone deficiency, including complete absence, of endogenous testosterone in male or female subjects.
- Examples of conditions associated with testosterone deficiency that can be treated using the dosage forms (e.g., capsule or tablet) or compositions described herein include, but are not limited to congenital or acquired primary hypogonadism, hypogonadotropic hypogonadism, cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism, endocrine impotence, infertility due to spermatogenic disorders, impotence, male sexual dysfunction (MSD) including conditions such as premature ejaculation, erectile dysfunction, decreased libido, and the like, micropenis and constitutional delay, penile enlargement, appetite stimulation, testosterone deficiency associated with chemotherapy, testosterone deficiency associated with toxic damage from alcohol, testosterone deficiency associated with toxic damage from heavy metal, osteoporosis associated with androgen deficiency, or a combination thereof
- compositions and dosage forms disclosed herein include idiopathic gonadotropin, LURE deficiency, or pituitary hypothalamic injury - from tumors, trauma, or radiation. Typically, these subjects have low serum testosterone levels but have gonadotropins in the normal or low range.
- the composition or oral dosage form can be used to stimulate puberty in carefully selected males with clearly delayed puberty not secondary to pathological disorder, in another embodiment, the composition or oral dosage form can be used in female-to-male transsexuals in order to maintain or restore male physical and sexual characteristics including body muscle mass, muscle tone, bone density, body mass index (BMI), enhanced energy, motivation and endurance, restoring psychosexual activity etc.
- BMI body mass index
- pharmaceutical composition or unit dosage form of the present disclosure e.g., prepared from or comprising substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities
- the pharmaceutical composition or unit dosage form of the present disclosure e.g., prepared from or comprising substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities
- the pharmaceutical composition or unit dosage form of the present disclosure can be used to treat and/or improve the patient related outcomes including the quality of life or wellbeing a subject suffering from deficiency of endogenous testosterone or who can otherwise benefit from the treatment
- the pharmaceutical composition or unit dosage form of the present disclosure e.g., prepared from or comprising (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities
- certain biomarkers such as for example, increased SHBG levels, can be used to diagnose a subject who may be in need of testosterone therapy.
- These biomarkers can be associated with conditions/disease :states such as anorexia nervosa, hyperthyroidism, hypogonadism, androgen insensitivity/ deficiency, alcoholic hepatic cirrhosis, primary biliary cirrhosis, and the like.
- a pharmaceutical composition prepared by synthesizing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate to produce substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate solid and mixing the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate with one or more pharmaceutically acceptable carriers to provide a pharmaceutical composition which is substantially free of impurities.
- a pharmaceutical composition is prepared by providing substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate solid and mixing the substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate with one or more pharmaceutically acceptable carriers to provide a pharmaceutical composition which is substantially free of impurities.
- compositions and unit dosage forms can be prepared by any suitable method known to the skilled artisan or developed in view of the teachings herein.
- the carrier(s) and API are brought to or maintained at a temperature at which they are flowable (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.).
- the mixture of carrier and API is a clear solution at a specified temperature (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.).
- the mixture of carrier and API is a cloudy or hazy solution at a specified temperature (e.g., below 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.).
- the composition is prepared by weighing all of the components, except the API into a clean stainless steel container and mixed together at ambient temperature or at elevated temperatures e.g., at about 25° C. to about 30° C., at about 30° C. to about 35° C., at about 35° C. to about 40° C., at about 40° C. to about 45° C., at about 45° C. to about 45° C., or 50° C. to about 70° C., using a stirrer.
- the API is added and stirred into the mixture of other components until the API dissolves.
- a predetermined quantity of this “liquid fill material” is disposed into a capsule (for example, hard gelatin capsule) to get the required API dose per dosage unit.
- the capsules are allowed to cool at room temperature, banded (if required) and packaged in a HDPE bottle and tightly closed with an appropriate lid.
- various capsule sizes e.g., hard gel or soft gel
- soft gel capsules for oral administration have fill volumes of less than 1.5 mL, 1.3 mL or 1.25 mL with numerous incremental fill volumes in these ranges.
- hard gel capsules typically have fill volumes of less than 1.25 mL, 1.10 mL or 1 mL. Due to the nature of some hard gel capsules, the total fill volume may not be useable.
- any pharmaceutical composition described herein e.g., a can be prepared by (i) combining and heating all ingredients until a molten mixture is obtained (e.g., 50-70° C.); and (ii) encapsulating an amount of molten mixture comprising a select dose (e.g., a therapeutically effective amount or a partial dose of a therapeutically effective amount) API to obtain an oral dosage form.
- a select dose e.g., a therapeutically effective amount or a partial dose of a therapeutically effective amount
- the molten mixture is spray-congealed to obtain beads.
- the molten mixture is sprayed onto inert cores (e.g., sugar spheres) to obtain coated cores.
- such beads, cores, or similar forms are encapsulated or otherwise formulated to provide an oral dosage form.
- the molten mixture is admixed, uniformly dispersed, or granulated over a carrier and compressed into a tablet dosage form.
- the molten mixture/carrier composition is further mixed with one or more pharmaceutical aid including, by way of non-limiting example, glidants, lubricants, binders, or the like.
- the carrier is a therapeutically inert carrier such as, by way of non-limiting example, microcrystalline cellulose, starch, lactose, or the like.
- compositions described herein are formulated as oral dosage forms.
- Oral dosage forms are prepared by any suitable process including one or more steps of, by way of non-limiting example, agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, encapsulation, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or the like.
- a pharmaceutical composition described herein is formulated with a substrate to form an oral dosage form.
- substrates useful for formulating pharmaceutical compositions described herein as oral dosage forms include or comprise, by way of non-limiting example, a powder or a multiparticulate (e.g., one or more granule, one or more pellet, one or more bead, one or more spherule, one or more beadlet, one or more microcapsule, one or more millisphere, one or more mini capsule, one or more microcapsule, one or more nanocapsule, one or more nanosphere, one or more microsphere, one or more minitablet, one or more tablet, one or more capsule, or one or more combinations thereof).
- a powder or a multiparticulate e.g., one or more granule, one or more pellet, one or more bead, one or more spherule, one or more beadlet, one or more microcapsule, one or more millisphere, one or more mini capsule, one or more
- a powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and/or additives.
- reaction mixture is transferred to a large separatory funnel and diluted with heptane (1000 mL) (Note: Thin layer chromatography (“TLC”) can be used to monitor the reaction e.g., after one hour);
- a reaction mixture of Example 1 can be transferred to water, ethanol, or methanol (or any other suitable solvent) and allowed to crystallize.
- the crystalline mass can be filtered by suction, washed with water, dried over phosphorous pentoxide and re-crystallized from another solvent e.g., oleic acid, hexane, heptanes, etc.
- Liquid chromatography can be used to purify or analyze the purity of samples having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- One exemplary liquid chromatographic method is as follows.
- Dissolve sample in mobile phase e.g., 20 mg in 50 mL).
- Run time twice the retention time of (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- these impurities can be analyzed and identified.
- mass spectrometry in conjunction with liquid chromatography can be used to assess or identify impurities in a sample having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 10 and FIG. 12 show the first and cycle cooling cycles respectively.
- Impurities in (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate or composition containing (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can be separated and/or identified according to the following procedure
- Detector Wavelength about 240 nm (e.g., 242 nm)
- the sample used in this example was derived from a (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate (89.9 mg) formulation/composition stored at 40° C. for 17 months.
- FIGS. 13-15 show different portions of the HPLC trace. Placebo labeled peaks were identified from a similar formulations not having (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. RC peaks are impurities believed to be related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- FIG. 13 shows the trace from about time zero to about 12 minutes with RC 1 identified as testosterone.
- FIG. 13 shows the trace from about time zero to about 12 minutes with RC 1 identified as testosterone.
- FIG. 14 shows the trace from 8-105 minutes with RC 2-11 (from shortest to longest RRT) identified and the API.
- FIG. 15 shows trace from 8 minutes to 210 minutes with RC 2-11 shown and (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate.
- RRT refers to the relative retention time to API.
- formulations without a stabilizing agent e.g., antioxidant e.g., ascorbyl palmitate
- a stabilizing agent e.g., antioxidant (e.g., ascorbyl palmitate) had the buildup over time of the impurities putatively identified as hydroxylated at position 6 of the compound in FIG. 6 in the “out of the plane”, “in the plane”, or both.
- antioxidant e.g., ascorbyl palmitate
- Samples related to (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate can be analyzed by LC/MS.
- substantial pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate was exposed to elevated temperatures for 24 hours or 48 hours.
- the samples were dissolved in a solvent after exposure to elevated temperatures.
- the samples were then prepared for the LC/MS experiments by a 1:10,000 dilution into (20:80 acetonitrile:distilled/deionized water) by first dilution into the acetonitrile and then by bringing the volume up to the final volume by dilution with the distilled/deionized water.
- FIG. 16 shows the result trace from the column (C18 Atlantis; injection volume).
- FIGS. 17-27 show the mass spectra corresponding to peaks from the HPLC trace.
- composition (A) Weight Percent Quantity Fill Quantity Fill of Fill Material per Material per Pharmaceutical Hard Gel Soft Gel Composition Capsule Capsule ( ⁇ 1%) ( ⁇ 1%) ( ⁇ 1%) Ingredient Name % w/w mg mg API 24 183 300 Oleic Acid, NF 41 308 513 Peppermint Oil, NF 18 136 225 Polyoxyl 40 Hydrogenated 4 30 50 Castor Oil, NF Ascorbyl Palmitate, NF 0.2 1.5 2.5 Glyceryl Palmitostearate 12 90 150 (Glyceryl Distearate, NF) Total 100 750 1241
- RRT stands for relative retention time compared to API when analyzed by HPLC.
- Exemplary HPLC conditions are a C18 column (5 ⁇ m), 150 ⁇ 3.9 mm, 90% methanol: 10% deionized water at a flow rate of 1.0 mL/min with the column at 25° C.
- compositions, dosage forms described herein containing API can subjected to in vitro dissolution (release) testing using USP type 2 apparatus in about 1000 mL aqueous medium.
- the composition e.g., dosage form
- USP type 2 apparatus is subjected to in vitro dissolution testing using USP type 2 apparatus in about e.g., 1000 mL 8% Triton X100 solution in water at a specific temperature (e.g., 37° C.) at 100 rpm for a specific time (e.g., 1, 2, 3, 4, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180, or 240 minute time point where a sample is withdrawn and analyzed for API content (e.g., via HPLC)).
- a specific temperature e.g., 37° C.
- a specific time e.g., 1, 2, 3, 4, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180, or 240 minute time point where a sample is withdrawn and analyzed for API content (e.
- compositions, dosage forms described herein containing API can subjected to in vitro dissolution (release) testing using USP type 2 apparatus in about 1000 mL aqueous medium as described in the above example after storage for particular amounts of time under specific conditions.
- FIG. 28 shows the release profile stability of composition (B) composition (e.g., unit dosage form of composition (B) described herein.
- the diamonds with solid line labeled 1 represents time point 0; the diamond with dotted line represents 1 month storage at 25° C. and 60% relative humidity (labeled 2); the square with long dashed line represents 1 month storage at 40° C. and 75% relative humidity (labeled 3); the square with dash dot line represents 3 month storage at 25° C.
- the X-axis represents time in hours with measurements made at 15 min, 30 min, 45 min, 1 hour, 2 hours and 4 hours.
- the Y-axis represents percent API released in 1000 mL 8% Triton X-100 media at 37° C. with a USP Type 2 Apparatus at 100 RPM.
- FIG. 29 shows the release profile stability for composition (A) at time 0 (1), 1 month stored at either 25° C. 60% RH (2) or 40° C. 75% RH (3), 2 months stored at either at either 25° C. 60% RH (4) or 40° C. 75% RH (5), and 3 months stored at either at either 25° C. 60% RH (6) or 40 ° C. 75% RH (7).
- RH is relative humidity.
- the X-axis represents time in hours with measurements made at 15 min, 30 min, 45 min, 1 hour, 2 hours and 4 hours.
- the Y-axis represents percent API released in 1000 mL 8% Triton X-100 media at 37° C. with a USP Type 2 Apparatus at 100 RPM.
- compositions described herein comprising or prepared from substantially pure (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate were administered to human subjects as a single dose of the esters to subjects.
- the C max , C avg t1-t2 , T max and AUC t1-t2 are calculated for testosterone in the serum of the subjects.
- Pharmacokinetic and statistical analyses are performed on the data obtained from the subjects. The pharmacokinetic parameters are defined as follows:
- compositions Composition No. 12 13 14 Components (17- ⁇ )-3-Oxoandrost-4-en-17-yl 10-30 10-30 10-30 tridecanoate
- Lipophilic additive e.g. surfactant 55-80 55-80 55-80 of HLB ⁇ 10 such as mono- or di- or tri- glyceride of fatty acid or fatty acid
- Hydrophilic additive e.g. Surfactant 0-20 0-20 0-20 0-20 with HLB >10 such as Cremophor RH40
- Adjuvant q.s. q.s q.s.s.
- Serum T pharmacokinetic results PK parameter Daily dose as mg T Equivalent 250-400 250-500 250-400 % of T-ester not dissolved in 0 >12 >40 lipophilic additive at body temperature % of T-ester not dissolved in 0 >15 >50 lipophilic additive at 20° C. No. of capsules/daily T dose 4-5 3-7 1-3 Mean serum T C avg t0-t24 /mg T 1.65 1-2-2.2 1.86 equivalent [ng/dL/mg]
- compositions 12-14 can be formulated as a capsule or tablet dosage form. Further, each of the capsule dosage forms can be formulated to contain from about 50 mg to about 450 mg of the ester (or more or less). For instance, the Compositions 12-14 can be formulated as a capsule or tablet dosage form.
- Total daily ester dose administered is 300 to 1500 mg for Compositions 12-14. Specifically, for Compositions 12-14 the total daily (17- ⁇ )-3-Oxoandrost-4-en-17-yl dose administered is from about 3000 mg to about 1500. However, it is notable that unlike Composition 12 that has no “not dissolved” ester, Compositions 13 and 14 require fewer dosage units per administration.
- Table 2 shows that the higher the fraction of the lipobalanced ester not dissolved or not solubilized, the fewer the number of daily dosage form units (e.g., capsules) that need to be administered to achieve the desirable serum testosterone levels when treating hypogonadism in a male with (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate. It should be noted that to provide the total daily dose of about 420 mg 850 mg of the (17- ⁇ )-3-Oxoandrost-4-en-17-yl tridecanoate for a hypogonadal subject, no more than four oral dosage form units are required; even more preferred is that no more than two oral dosage form units per day are required for administration.
- Compositions 12-14 can be prepared with the lipophilic surfactant and hydrophilic surfactant in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2:1. Specifically, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 2.5:1. Further, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 3.5:1. Even further, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 6.5:1.
- Compositions 12-14 can be prepared with hydrophilic surfactant present at 20 wt % or more of the total carrier. Compositions 12-14 can be prepared with hydrophilic surfactant present at 5 wt % or less of the total carrier.
- the lipophilic additives, the hydrophilic additives, and the adjuvant for the representative inventive compositions shown in Table 7 can be similar to those described for compositions in Table 2.
- the pharmacokinetic (PK) evaluation procedure is given under Example 2.
- the PK results for the Compositions 13 and 14 or related capsule dosage forms thereof, following oral administration of single dose, two consecutive doses or steady state to a group of subjects, for example, hypogonadal males, along with a meal, are summarized in Table 3A, 3B and 3C.
- compositions 13 and 14 are not fully dissolved nor solubilized in the composition or dosage form thereof. Further, Compositions 13 and 14 provide, upon single administration with a meal to a human subject, a serum T mean C avg t0-t24 /mg of T equivalent dose administered in a range between the 1.2 to 2.2 ng/dL/mg. Additionally, Compositions 13 and 14 enable a patient-friendly dosing regimen, for instance via fewer dosage units per administration.
- compositions, dosage forms and/or modes of applications are only illustrative of preferred embodiments of the present invention.
Abstract
Description
- This application claims the benefit of U.S. Provisional Application No. 62/043,343 filed Aug. 28, 2014 which is incorporated herein by reference in its entirety.
- Disclosed herein are pharmaceutical compositions having or made from pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate for administration to mammals, e.g., humans, in need thereof.
- Worldwide marketing authorizations for pharmaceutical products set forth strict requirements for the stability and purity of pharmaceutical products regarding an active pharmaceutical ingredient (API) also known as drug or a prodrug of an API (also referred to herein as API) and its content. It is also critical that pure drug or prodrug is used in preparation of compositions or dosage forms of drugs or prodrugs to enable safe and effective use in treatment of appropriate disease conditions. Moreover, it is also important to limit all drug or prodrug related materials (starting impurities in the drug or prodrug, degradation product(s) derived from aging through chemical interaction between components of a composition or dosage form upon storage) to acceptable levels that are safe and do not limit shelf life of the composition or dosage form to an unacceptably short time.
- A study recently found a number of (17-β)-hydroxy-4-androsten-3-one (also known as testosterone) replacement therapy products on the market that have problems with impurities (Baert et al. Volume 72,
Issue 1, May 2009, Pages 275-281). (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is a novel ester prodrug of (17-β)-hydroxy-4-androsten-3-one that has demonstrated promise in early testing in treating mammals in need of (17-β)-hydroxy-4-androsten-3-one, a critical hormone useful for treating numerous conditions in males and females. - Due to its unique structure, (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is particularly prone to decomposition as a result of reactions such as oxidation, reduction, cleavage of the ester moiety; oxidation of the steroid ring system; cleavage of one or more rings of the steroid ring system; rearrangement of the steroid ring; dealkylation of the steroid ring; dealkylation of the ester; or a combination thereof. Thus, the preparation and identification of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and stable compositions and methods associated with use of stable (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is challenging. Furthermore, (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has a unique dosing regimen with a different unit dosage form and daily dose requirement for effectiveness as compared to conventional prodrugs of (17-β)-hydroxy-4-androsten-3-one reported to date. Therefore, a significant challenge that is unique to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate relates to absolute levels of allowable impurities and degradation products for safe use in therapeutic settings.
- Impurities in (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can pose a number of problems to patients receiving (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate for therapy. Since (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate possesses a steroid core ring system, alteration of this molecule by decomposition or failure to remove synthetic by-products may result in exposing patients to potentially harmful agents. Compounds with steroid ring cores are often biologically active. For example, androstenedione (having a steroid core ring system similar to that of (17-β)-hydroxy-4-androsten-3-one but having the hydroxyl group as a keto group) induces albnorm alities in morphology and tion of e eloping oocytes in female mice, (Fertil Steril. 2012 Feb;97(2):469-76. doi: 10.1016/j stert.2011.11.040) and androstenedione is carcinogenic in male and female mice Food Chem Toxicol. 2011 Sep;49(9):2116-24. doi: 10.1016/j.fct,2011,05.026. Epub 2011 May 30,
- Thus, there is a need for substantially pure (17-β)-3-Oxoandrost-4-en-17-yl ltridecanoate and compositions (e.g., bulk drug substance, pharmaceutical, or unit dosage forms) containing substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, which can be stored for prolonged periods without deterioration in their quality, decrease in potency below a specified limit, as well as an increase of the concentration of decomposition products above acceptable limits. Moreover, there is even more critical need to prepare compositions and dosage forms that are stable upon storage for up to two years (or more) and are safe, with adequate potency (e.g., at least 80%) and acceptable (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate related substances in the compositions independent of using substantially pure starting (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate prodrug. (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has the propensity to degrade or decompose. For example, (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has the propensity to convert to (17-β)-Hydroxy-4-androsten-3-one (or otherwise decompose) due to hydrolysis upon storage or interaction with components of the composition or dosage forms that are acidic, hygroscopic, have an unsaturated moiety in their structure and contaminants or catalyst in the prodrug or excipients. Loss of potency of these compositions, especially those containing lipid additives (with associated free radicals) could compromise product performance.
- Thus, there is a need for (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate products having acceptable levels of impurities, especially since this molecule has not yet received market authorization. Moreover, methods of stabilizing and inclusion of stabilizing agents that limit loss of potency of the compositions made with substantially (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate prodrug is particularly needed for compositions (and dosage forms) for safe and effective human use. Ensuring safe levels of impurities and maintaining potency and stability of compounds like (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is no small task given the daily dose requirements and the chronic therapeutic use of such agents.
- Provided herein is substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and compositions containing substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one embodiment, a substantially pure API or composition can have greater than 80% potency. Substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate includes (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurities, decomposition impurities, or both, In one embodiment an API or composition that is substantially free of impurities can have less than 20% of total impurities (know and unknown). The compositions of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate include substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient, pharmaceutical compositions comprised of or prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and a pharmaceutically acceptable carrier, and unit dosage forms comprised of or prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient and a pharmaceutically acceptable carrier. Substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is useful for administration to a subject (e.g., mammalian; human) to provide safe and effective levels of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and (17-β)-hydroxy-4-androsten-3-one. For example, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be used to treat a subject having hypogonadism or any other disorder, disease or conditions associated with low levels of (17-β)-hydroxy-4-androsten-3-one or that can be improved or prevented with (17-β)-hydroxy-4-androsten-3-one. Substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is useful in pharmaceutical applications and has exceptional safety characteristics as well as stability.
-
FIG. 1A shows a non-limiting example of a synthetic scheme for (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. -
FIG. 1B shows non-limiting examples of crystallization of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. -
FIG. 2 shows general classification of potential impurities in (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate samples. -
FIG. 3 shows a classification of potential impurities in (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate samples. -
FIG. 4 shows a classification of potential impurities related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate samples. -
FIG. 5 shows a classification of potential impurities related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate samples. -
FIG. 6 shows a classification of potential impurities related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. -
FIG. 7 shows the structures of several potential impurities related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. -
FIG. 8 shows the structures of several potential impurities related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. -
FIG. 9 shows a differential scanning calorimtery first heat cycle plot for a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample. -
FIG. 10 shows a differential scanning calorimtery first cool cycle plot for a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample. -
FIG. 11 shows a differential scanning calorimtery second heat cycle plot for a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample. -
FIG. 12 shows a differential scanning calorimtery second cool cycle plot for a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample. -
FIG. 13 shows a portion on an HPLC trace of a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities. -
FIG. 14 shows a portion on an HPLC trace of a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities. -
FIG. 15 shows a portion on an HPLC trace of a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample having impurities. -
FIG. 16 shows the two mass spectrum from LCMS traces of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate sample from kept at elevated temperatures for 24 hours (lower trace) and 48 hours (upper trace). See example 6. The mass spectra of compounds corresponding to some of these peaks are shown inFIG. 18 throughFIG. 28 . The retention times are listed about the peaks in the traces. -
FIG. 17 shows a mass spectrum of peaks corresponding to a retention time 29.58-79.92 from the 48 hour sample. -
FIG. 18 shows a mass spectrum of peaks corresponding to a retention time 23.12-23.24 from the 48 hour sample. -
FIG. 19 shows a mass spectrum of peaks corresponding to a retention time 21.45-21.60 from the 48 hour sample. -
FIG. 20 shows a mass spectrum of peaks corresponding to a retention time 20.57-20.59 from the 48 hour sample. -
FIG. 21 shows a mass spectrum of peaks corresponding to a retention time 29.78-29.78 from the 24 hour sample. -
FIG. 22 shows a mass spectrum of peaks corresponding to a retention time 20.99-21.25 from the 2.4 hour sample. -
FIG. 23 shows a mass spectrum of peaks corresponding to a retention time 21.37-21.54 from the 2.4 hour sample. -
FIG. 24 shows a mass spectrum of peaks corresponding to a retention time 18.47-18.76 from the 2.4 hour sample. -
FIG. 25 shows a mass spectrum of peaks corresponding to a retention time 17.77-18.07 from the 24 hour sample. -
FIG. 26 shows a mass spectrum of peaks corresponding to a retention time 16.01-16.23 from the 24 hour sample. -
FIG. 27 shows a mass spectrum of peaks corresponding to a retention time 21.37-21.43 from the 24 hour sample. -
FIG. 28 shows the release profile stability of a pharmaceutical composition having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. See Examples 8 and 9. -
FIG. 29 shows the release profile stability of a pharmaceutical composition having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. See Example 8 and 9. - As described herein, substantially pure compositions of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate are provided that are free of synthetic impurities, decomposition impurities, or both. The substantially pure compositions of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate described herein include bulk prodrug, pharmaceutical compositions having substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and nit dosage forms having substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. The compositions described herein may further include a stabilizing agent or are stored under stabilizing conditions. Additionally, methods of using substantially pure compositions of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate are described, including methods of treatment (e.g., treating a disease, disorder or condition in an individual), and methods of producing or preparing compositions. The pharmaceutical compositions described herein have substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. Unit dosage forms can be formed from the pharmaceutical compositions e.g., tablet or capsule (soft gel or hard gel).
- It should be noted that, the singular forms “a,” “an,” and, “the” include plural references unless the context clearly dictates otherwise. Thus, for example, reference to “an excipient” includes reference to one or more of such excipients, and reference to “the carrier” includes reference to one or more of such carriers.
- Concentrations, amounts, levels and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges or decimal units encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described. In this specification, “comprises,” “comprising,” “comprised of,” “containing” and “having” and the like can have the meaning ascribed to them in U.S. Patent law and can mean “includes,” “including,” and the like, and are generally interpreted to be open ended terms. The terms “consisting of” or “consists of” are closed terms, and include only the components, structures, steps, or the like specifically listed in conjunction with such terms, as well as that which is in accordance with U.S. Patent law. “Consisting essentially of” or “consists essentially of” have the meaning generally ascribed to them by U.S. Patent law. In particular, such terms are generally closed terms, with the exception of allowing inclusion of additional items, materials, components, steps, or elements, that do not materially affect the basic and novel characteristics or function of the item(s) used in connection therewith. For example, trace elements present in a composition, but not affecting the compositions nature or characteristics would be permissible if present under the “consisting essentially of” language, even though not expressly recited in a list of items following such terminology. When using an open ended term in the specification, like “comprising” or “including,” it is understood that direct support should be afforded also to “consisting essentially of” language as well as “consisting of” language as if stated explicitly and vice versa.
- As used herein, “active pharmaceutical ingredient” refers to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. The biological active metabolite of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is (17-β)-Hydroxy-4-Androsten-3-one which is produced in vivo by de-esterification. Another important biologically active metabolite is (17-β)-hydroxy-5α-androstan-3-one with an IUPAC name of (5S,8R.,9S,1.0S,13S,14S,17S)-17-hydroxy-10,13-dimethyl-11,2,4,5,6,8,9,11,12,14,15,116,17-tetradecahydrocyclopenta[a]phenanthren-3-one (CAS No. 521-18-6) .
- As used herein, the term “(17-β)-Hydroxy-4-Androsten-3-one” refers to a chemical having IUPAC name of (8R,9S,10R,13S,14S,17S)-17-Hydroxy-10,13-dimethyl-1,2,6,711,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one and a CAS number of 58-22-0. (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate refers to a compound having the (17-β)-Hydroxy-4-Androsten-3-one core structure but the hydroxyl group is esterified with tridecanoic acid e.g., (17-β)-Hydroxy-4-Androsten-3-one esterified with a straight chain saturated 13 carbon long alkarioic acid called tridecanoic acid. Tridecanoic acid is the IUPAC name fir the alkanoic acid having CAS nu giber 638-53-9.
- As used herein, “impurity” or “impurities” refer to a chemical or chemical that is not (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate but is derived from the synthesis, preparation, processing, degradation or decomposition of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. Typically, the impurity is a synthetic impurity or a decomposition impurity. Impurities typically can be derived from decomposition, degradation or the chemical reaction of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate which can be referred to as related compounds or “RC” or “RCs”. Other impurities can be present as described herein and are typically synthetic by-products, solvents, etc., derived from the manufacturing or processing of the API. Although synthetic and decomposition impurities are used to categorize classes described herein, they are not mutually exclusive and it is not always certain where or how a particular impurity arises.
- As used herein, “substantially pure” refers to a composition having an active pharmaceutical ingredient which meets applicable regulatory requirements in terms of potency. In this context, potency refers to the comparison of a reference standard deemed to be 100% potent by any number of techniques including NMR, elemental analysis, IR, chromatography (e.g., HPLC) and the such. In one definition, potency is defined in terms of the definition provided by a compendium e.g., the United States Pharmacopeia, European Pharmacopeia or other national or regional Pharmacopeia. Potency can be determined by one of ordinary skill in the art in view of the definition in the compendium or as described herein. In one embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate or related compositions has greater than 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% potency.
- As used herein, “substantially free of impurities” refers to a composition having active pharmaceutical ingredient which meets applicable regulatory requirements for levels of impurities (e.g., below a specific level). Depending on the context, substantially free of impurities can refer to all impurities or a specific impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of active pharmaceutical ingredient and the specific impurity or impurities (or total impurities). Unless otherwise specified percent impurity is calculated as the (total weight of a specific impurity or impurities)/(total weight of API +weight of specific impurity or impurities)*100. In some instances, other methods beside weight are used to characterize impurities, like area under the curves of HPLC traces or NMR signals which can be used to calculate percent impurities also. The impurities can be decomposition impurities, synthetic impurities, or any other impurity. The synthetic impurities, in some aspects, refers to those identified in the examples, figures, or elsewhere herein.
- As used herein, “substantially free of synthetic impurities” refers to a composition having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate which meets applicable regulatory requirements for levels of impurities (e.g., below a specific level) where the impurity is related to synthesis and/or processing of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. Depending on the context, substantially free of synthetic impurities can refer to all synthetic impurities or a specific synthetic impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and the specific synthetic impurity or impurities. The synthetic impurities, in some aspects, refer to those identified in the examples, figures, or elsewhere herein. Synthetic impurities of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, starting materials, by-products (from reactions of reagents or other materials), side-products (from reaction of impurities in reagents or other materials), intermediates, degradation (or decomposition) products, reagents, ligands, catalysts, residual solvents (e.g., from the synthesis, purification or processing of API). Specific synthetic impurities include, 17-β-Hydroxy-4-Androsten-3-one, tridecanoic acid (or a salt form thereof), tridecanoyl chloride, etc. or a non-API compound derived therefrom, pyridine, heptane, heptanes, etc.
- As used herein, “substantially free of decomposition impurities” refers to a composition having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate which meets applicable regulatory requirements for levels of impurities related to the decomposition (including degradation) of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., below a specific level). Depending on the context, free of decomposition impurities can refer to all decomposition impurities or a specific synthetic impurity which is 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, 5% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.3% or less, 0.2% or less, or 0.1% or less by total weight of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and the specific or known decomposition impurity or unknown or unspecified impurities. The decomposition impurities, in some aspects, refer to those identified in the examples, figures, or elsewhere herein. Decomposition impurities include, but are not limited to (17-β)-hydroxy-4-androsten-3-one, an oxidation product of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, an oxidation product of 17-β-Hydroxy-4-Androsten-3-one, or other decomposition products.
- In one embodiment, the impurity is 3-Oxoandrost-1,4-dien-17β-yl tridecanoate, 3-Oxoandrost-4,6-dien-17β-yl tridecanoate, 17 beta-hydroxy androst-4-en-3-one tridecylenate (e.g., tridec-12-enoate), 3-Oxoandrost-4-en-17α-yl tridecanoate , 4-Androstene-3,17-dione, 17α-hydroxyandrost-4-en-3one , 4-Androstene-313,17f3-diol, androsta-1,4-dien-3,17-dione, 17β-hydroxyandrosta-4,6-dien-3-one, 17β-hydroxy-5α-androstan-3-one, or 17β-hydroxyandrost-1,4-dien-3-one.
- In one embodiment, the impurity is as shown in any of the Figures.
- Reference will now be made in detail to preferred embodiments of the invention. While the invention will be described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to those preferred embodiments. To the contrary, it is intended to cover alternatives, variants, modifications, and equivalents as may be included within the spirit and scope of the invention as defined by the appended claims.
- Provided herein are compositions containing substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. The substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be substantially free of impurities. Impurities of compositions containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, synthetic impurities, decomposition impurities, or both. In one aspect, the substantially pure (17β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In one embodiment, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition is provided that is at least 80%, 85% or 90% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. According to an aspect of this embodiment, the composition comprises at least 95% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a more specific aspect, the composition comprises at least 97% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 98% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99.5% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a specific aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one embodiment, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is a white crystalline or amorphous powder. In one aspect, at least 1 g, 10 g, 50 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 500 kg, 1000 kg, 5000 kg 10,000 kg, 50,000 kg of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In another embodiment, a pharmaceutical composition is provided which comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 80%, 85% or 90% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. According to an aspect of this embodiment, the pharmaceutical composition comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 95% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In a more specific aspect, the pharmaceutical composition comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 97% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In another more specific aspect, the pharmaceutical composition comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 98% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In another more specific aspect, the pharmaceutical composition comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In another more specific aspect, the pharmaceutical composition comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99.5% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In a specific aspect, the pharmaceutical composition comprises or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is a white crystalline or amorphous powder. Pharmaceutical compositions of this embodiment are suitable for any form of administration. For example, the pharmaceutical formulations can be formulated for enteral, parenteral, or topical administration. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In yet another embodiment, a unit dosage form is provided which comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 80%, 85% or 90% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. According to an aspect of this embodiment, the unit dosage form comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and that is at least 95% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In a more specific aspect, the unit dosage form comprises or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 97% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In another more specific aspect, the unit dosage form comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 98% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In another more specific aspect, the unit dosage form comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier.
- In another more specific aspect, the unit dosage form comprises or is prepared from (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is at least 99.5% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier. In a specific aspect, the unit dosage form comprises or is prepared from pharmaceutical ingredient, (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, that is a white crystalline or amorphous powder. Unit dosage forms of this embodiment are suitable for any form of administration. For example, the unit dosage form of the compositions of this invention can be formulated for enteral, parenteral, or topical administration. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In one embodiment, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition is provided. According to this embodiment, the composition comprises at least 95% (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a more specific aspect, the composition comprises at least 97% (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 98% (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99.5% (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a specific aspect, the active pharmaceutical ingredient is a white crystalline or amorphous powder. According to one aspect of this embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 20%, 15% or 10% impurities (e.g., total impurities (known +unknown)). In a more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5% total impurities. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3% total impurities. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2% total impurities. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1% total impurities. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5% 17-β-Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3% 17-β-Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2% 17-β-Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1% 17-β-Hydroxy-4-Androsten-3-one. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 0.5% 17-β-Hydroxy-4-Androsten-3-one. In another specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 20000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 10000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 5000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 3000 ppm of a solvent (e.g., ethanol). In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 2000 ppm ethanol. In another more specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 1500 ppm of a solvent (e.g., ethanol). In a specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is a white crystalline or amorphous powder. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 3% or 2% of a single unknown impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 1% of a single unknown impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.5% of a single unknown impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.1% of a single unknown impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 5% of a single known impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 3% of a single known impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 2% of a single known impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 1% of a single known impurity. In one specific aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate composition comprises less than 0.5% of a single known impurity. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- As used herein, an impurity is “known” if its structure or chemical identity is known and an impurity is “unknown” if its structure or chemical identity is known.
- Thus, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient or composition or dosage form comprising (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate which is useful for dosing of 300-400, 400-500, 500-600, 600-700, 700-800, 800-900, 900-1000, 1000-1100, 1100-1200, 1200-1300, 1300-1400, 1400-1500, 1500-1600, 1600-1700, 1700-1800, 1900-2000, 2000-2500, 2500-3000, 3000-3500, 3500-4000, or 5000 or more mg per day to an individual, has greater than 80%, 85%, 90%, 95%, 98%, or 99% potency is provided. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities is provided. In another aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate of having less than 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of total impurities (known+unknown) is provided. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% of total unknown impurities is also provided. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of any single known impurity is provided. In another aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having less than 10, 5, 2, 1, or 0.5% of any single known impurity is provided. In another aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of any single unknown impurity is provided. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having less than 5, 4, 3, 2, 1, 0.5 or 0.2% or less of any single unknown impurity is provided. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate safe for administration to a human subject is provided (e.g., male or female). In one aspect, the substantial pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is safe for chronic administration (e.g., more than 1, 2, 3, or 4 weeks; more than 1, 2, 3, 4, 6, 9, 12 months; more than 1, 2, 3, 4, or 5 years) at daily doses of 300 mg to 1500 mg (e.g., 300 to 1000 mg or 400 mg to 900 mg) to a human. In one aspect, the substantial pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is safe for administration as a testosterone replacement therapy to a hypogonadal male. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is stable. In some aspects, stable refers to a composition meeting one or more of the purity or impurity profiles described herein. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having less than 20, 15, 10, 5 or 2% or less decomposition product of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has less than 20, 15, 10, 5 or 2% or less decomposition product of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at 90 days at 20-25° C. is provided. In a related aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate of the previous sentence wherein the decomposition product of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate results from oxidation, reduction, cleavage of the ester moiety; oxidation of the steroid ring system; cleavage of one or more rings of the steroid ring system; rearrangement of the steroid ring; dealkylation of the steroid ring; dealkylation of the ester; or a combination thereof is provided. In one aspect, the substantially pure comprises more than 80, 85, 90, 95, 98, 99, 99.5 or 99.8% substantially (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises less than 10, 5, 4, 3, 2, 1, or 0.5% 17-β-Hydroxy-4-Androsten-3-one. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprising less than 50,000, 25000, or 15000 PPM of residual solvent (e.g., ethanol). In one aspect, a pharmaceutical composition comprising a pharmaceutically acceptable carrier and substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided. In one aspect, the pharmaceutical composition is stable or total impurities, total unknown impurities, any single known impurity, or any single unknown impurity does not increase above acceptable levels after 1 month, 3 months, 6 months, 9 months, one year, or two years at a specified temperature (e.g., 20, 25, 37, 40 or 60° C.) with no more than 10% or 20% decomposition or 10 or 20% loss in potency of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the pharmaceutical composition comprises a stabilizing agent. In one aspect, the pharmaceutical composition comprises a pharmaceutically acceptable stabilizing agent which is an antioxidant, bufferant, complexing agent or dessicant. In one aspect, the pharmaceutical composition is formulated for topical, enteral or parenteral administration. In one aspect, the pharmaceutical composition is formulated for oral, buccal, sublingual, or sublabial administration. In one aspect, the pharmaceutical composition is formulated for nasal, rectal or vaginal administration. In one aspect, the pharmaceutical composition is formulated for intravenous, subcutaneous, intramuscular, intradermal, intraspinal, intrathecal, or intra-arterial administration. In one aspect, the pharmaceutical composition is a liquid, solution, suspension, dispersion, solid, semi-solid, a gel, a lotion, paste, foam, spray, emulsion, syrup, or ointment. In one aspect, the pharmaceutical composition is formulated as a tablet or capsule. In one aspect, the pharmaceutical composition is formulated as a tincture, patch, injectable, tablet, capsule, sprinkle, aggregate, granule, drink, or powder. In one aspect, a unit dosage form comprising a pharmaceutically acceptable carrier and the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate described herein which is useful for dosing up to 2000 mg per day to an individual, has greater than 80%, 85%, 90%, 95%, 98%, or 99% potency and a pharmaceutically acceptable carrier is provided. In one aspect, the unit dosage form comprises a stabilizing agent. In one aspect, the unit dosage form comprises a pharmaceutically acceptable stabilizing agent which is an antioxidant, bufferant, complexing agent or desiccant. In one aspect, the unit dosage form is formulated for topical, parenteral or enteral administration. In one aspect, the unit dosage form is a solid, a semi-solid, a gel, a lotion, a paste, tincture, foam, spray, suspension, dispersion, syrup, patch, or ointment. In one aspect, the unit dosage form is formulated for an oral route of administration. In one aspect, the unit dosage form is a tablet or capsule. In one aspect, the unit dosage form comprises or is prepared from at least 3, 5, 10, 15, 30, 25, 30, 40, 50, 60, 75, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- Provided herein are compositions containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurities. Synthetic impurities of compositions containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, residual solvents, unreacted reactants, unreacted impurities in reactants, reaction products of impurities in reactants, and impurities created during synthesis, work up, or both. See
FIG. 3 , - In one embodiment, a composition having substantially pure (17-β)-3-Oxoandrost-4-en-17-yl comprises at least 95% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a more specific aspect, the composition comprises at least 97% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 98% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99% substantially (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In another more specific aspect, the composition comprises at least 99.5% substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. In a specific aspect, the API is a crystalline or amorphous powder. in one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (A): 17-β-Hydroxy-4-Androsten-3-one or a synthetic reaction by-product thereof is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (B): tridecanoic acid, tridecanoate, tridecanoyl chloride or a non-API synthetic reaction by-product thereof is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (C): Ethanol, pyridine, heptanes, heptanes, or a combination thereof is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (D): (17-β)-3-Oxoandrost-4-en-17-yl undecanoate is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (E): (17-β)-3-Oxoandrost-4-en-17-yl decanoate is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (F): (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate is provided. In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of synthetic impurity (E): (17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate is provided. According to some aspect, substantially free of an impurity in this paragraph refers to less than 10%, 7%, 5%, 3%, 3%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of any specific impurity referred to this paragraph or their xnnbined total, In a specific aspect, the sum total of all these Impurities (Synthetic Impurity A, B, C, D, or E) compared to the amount of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g. at about 240 nm or another appropriate wavelength) is no more than 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.75%, 0.50%, 0.25%, 0.20%, 0.10%, or 0.50%. In another specific aspect, the total of any one of these synthetic impurity A, B, C, D, or E as described above as compared to the amount of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g., at about 240 nm or nm another appropriate wavelength) is no more than 2%, 1.5%, 1.0%, 0.50%, 0.40%, 0.30%, 0.20%, 0.10%. 0.075%, 0.050%, 0.025%, 0.020%, 0.010%, or 0.0050%.
- Decomposition or Degradation (17-β)-3-Oxoandrost-4-en-17-yl Tridecanoate or Incompatibility Thereof with Carrier of the Composition or Related Impurities
- Provided herein are compositions containing substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of decomposition impurities. Decomposition impurities of compositions containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate include, but are not limited to, decomposition of (17β)-3-Oxoandrost-4-en-17-yl tridecanoate in e.g., bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, pharmaceutical compositions or formulations, or in unit dosage forms. Decomposition impurities include, but are not limited to impurities resulting from cleavage of the ester moiety, oxidation of functional groups on the steroid polycyclic core, dealkylation of the ester, etc. In some aspects, stabilized compositions are provided herein. Such stabilized compositions can be e.g., compositions stored under specific environmental conditions, have stabilizing agents (e.g., an antioxidant), or both. The stabilized composition can be (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, a composition such as a pharmaceutical composition comprising (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, a unit dosage form having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier and the such. In one embodiment, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided substantially free of Decomposition Impurity (1): (17-β)-Hydroxy-4-Androsten-3-one. In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is substantially free of Decomposition Impurity (2): hydroxylated at position 6 (out of the plane) of the
FIG. 6 . In one aspect, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is substantially free of Decomposition Impurity (3): hydroxylated at position 6 (in the plane) of theFIG. 6 . In one aspect, a substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of Decomposition Impurity (1), (2), or (3) or a combination thereof as described above is provided. In a specific aspect, the sum total of all these Decomposition Impurities (Decomposition Impurity impurity FIGS. 13-15 ). In a specific aspect, the sum total of all these impurities compared to the amount of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g., at about 240 or 242 nm or another appropriate wavelength) is no more than 20%, 15%, 10%, 5%, 2%, 1%, 0.75 , 0.50%, 0.25%, 0.20%, 0,10%, or 0.50%, In another specific aspect, the total of any one of these impurities (e.g.,RC impurity FIGS. 13-15 )) compared to the amount of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in a sample as determined by HPLC (e.g., at about 240 nm or another appropriate wavelength) is no more than 2%, 1. 7 1.0%, 0.50%, 0.40%, 0.30%, 0.20%, 0.10%, 0.075%, 0.050%, 0.025%, 0.020%, 0.010%, or 0.0050%. - Impurities in the composition can be determined by any method suitable for identifying such impurities. Typical methods for determining impurities depend on the nature of the starting composition. For example, techniques suitable for examining bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may be different or involve different condition as compared to examining impurities in a pharmaceutical composition or unit dosage form. The potency of bulk API, pharmaceutical compositions or unit dosage forms may also be determined via some of these techniques. Exemplary, non-limiting techniques are described in more detail below.
- HPLC is a technique commonly used to identify impurities or levels thereof in substances (and may also be used to determine potency). HPLC can be used to quantitatively or to qualitatively assess impurities in samples (e.g., bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate or a composition containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) and potency. HPLC methods can also be used for assessing the potency of a particular sample. The ordinary skilled artisan is familiar with and capable of performing HPLC techniques. Typically, a chromatogram from known standard samples is compared to that of an unknown sample. The purity of the unknown can be estimated by comparing the area under the curve for the peak that corresponds to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate to other peaks in the chromatogram. Several appropriate HPLC techniques are described in the Examples. Other methods can be adapted to analyze purity or impurities of the compositions described herein. (See e.g., Gonzalo-Lumbreras, et al. J. Pharm. Biomed. Anal. Volume 38,
Issue Issue 8, pages 873-880, August 2009). - NMR is a technique commonly used to identify impurities or levels thereof in substances and potency. NMR can be used to quantitatively or to qualitatively assess impurities in samples (e.g., bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate or a composition containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate) and potency. NMR methods can also be used for assessing the potency of a particular sample. The ordinary skilled artisan is familiar with and capable of performing NMR techniques. Typically, proton NMR, 13C NMR, or both are used for assessing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate compositions for purity or potency (quantitative NMR). Webster et al. Appl Spectrosc. 2010 May;64(5):537-42.
- Other techniques are also useful for analyzing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate for purity and potency such as x-ray powder diffraction, mass spectrometry, fourier-transform infrared spectroscopy, raman spectroscopy, etc. See Bugay Adv Drug Deliv Rev. 2001 May 16;48(1):43-65.
- Stabilized compositions are provided herein. Instability of bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and composition containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can result in undesirable changes in performance (e.g., dissolution or bioavailability), changes in physical appearance, product failures, safety, toxicity, etc. Stabilization of compositions having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate depends on the nature of the composition and the nature of what type of stabilization is desired. For example, stabilization of bulk (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may involve a specific set of conditions (“stabilizing condition”) e.g., storage and handling conditions that are different (although not necessarily) than for a pharmaceutical composition or a unit dosage form. Furthermore, stabilization of certain compositions can involve preventing or mitigating certain things in one composition whereas those same certain things may be desirable in another composition. For example, crystalline substantially pure and substantially free of impurity (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may be desirable for stabilization of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, whereas in other compositions like a pharmaceutical compositions or unit dosage forms crystalline (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate may not be desirable.
- Thus, in one embodiment, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is provided that is stabilized. In one aspect of this embodiment, the stabilized substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is stabilized by its high degree of purity in solid form (e.g., crystalline, amorphous, or a combination thereof). In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solvent. In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solve which is an alcohol, alkane, oil, fatty acid or other solvent. In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is recrystallized from a solvent which is an alcohol, alkane, oil, fatty acid or other solvent to provide substantially pure stabilized (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate pharmaceutical ingredient. In another aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is stabilized in a composition e.g., pharmaceutical composition or unit dosage form that has a stabilizing agent. In a specific aspect, the stabilizing agent is an antioxidant. In another specific aspect, the stabilizing agent is ascorbate or a derivative thereof In another specific aspect, the stabilizing agent is a fatty acid ester of ascorbate. in another specific aspect, the stabilizing agent is ascorbyl palmitate. In some aspects, compositions are provided (e.g., pharmaceutical composition, formulation or unit dosage form) having or prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and ascorbyl palmitate. In one aspect of this embodiment, the stabilized substantial pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- In certain embodiments, the pharmaceutical compositions are substantial free of iodine or peroxides. For example, in some embodiments the pharmaceutical composition or components from which it is prepared have a peroxide of less than 100, 90, 80, 70, 60, 50, 40, 30, 25, 20, 15, 10 or 5.
- Bulk API can also be stabilized by maintaining the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate under stabilizing conditions which include, but are not limited to, temperature (e.g., less than 0, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60° C.). ; relative humidity (e.g., less than 90, 80, 70, 60, 50, 40, 30, 20, 10 or 5%); light (e.g., controlling or minimizing exposure to light including UV, visible, or IR light); and oxidation (e.g., preventing or minimizing exposure to oxidizing agents or oxidizing conditions). In one aspect, bulk substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in an amount of greater than 1 g, 5 g, 10 g, 50 g, 100 g, 500 g, 1 kg, 5 kg, 10 kg, 50 kg, 100 kg, 500 kg, 1000 kg, 5000 kg, or 10,000 kg is maintained under stabilizing conditions. In an aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is crystalline API. In a related aspect, methods of stabilizing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate are also provided herein. The method can depend on the composition (e.g., bulk substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, pharmaceutical composition, formulation, or unit dosage form) that is to be stabilized, In one aspect, the method comprises storing substantially pure (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate under conditions that prevent decomposition of the (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate. According to a specific aspect, the condition is high purity (e.g., greater than 95%, greater than 98% or greater than 99% by total weight of the composition), maintaining the composition at a temperature of less than 60° C., less than 50° C., less than 40° C., less than 30° C., less than 20° C., less than 15° C., less than 10° C., less than 5° C., or less than 0° C., maintaining the composition in a non-oxidizing environment or minimal oxidizing environment. In yet another aspect, the method of stabilizing comprises combining tridecanoate with a carrier or agent (e.g., fatty acid ester of ascorbate (i.e., ascorbyl palmitate)) that prevents or minimizes decomposition of (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate. These methods are suitable for providing substantially pure (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate or a unit dosage form or pharmaceutical composition prepared from or comprising (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate wherein there is less than 5%, 2%, or 1% total API related impurities after storage for a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 25, or 30 months or longer. According to some aspects, the composition has a potency of 100% or 99.5% or more, 99% or more, 98% or more, 97% or more, 95% or more, or 90% or or 80% or more after storage for a period of time. According to some aspects, the composition has a purity of 100% or 99.5% or more, 99% or more, 98% or more, 97% or more, 95% or more, or 90% or more after storage for a period of time.
- Injectable Composition (e.g. Parenteral Composition or Subcutaneous) and Method of Use
- In one embodiment, a pharmaceutical composition is provided which is an injectable composition (e.g., for parenteral or subcutaneous administration) which comprises or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en17-17-yl tridecanoate and a pharmaceutically acceptable carrier. Associated methods of employing the composition are provided. For the treatment or prevention of a disease, disorder or a condition hypogonadism). in one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- In one embodiment, the composition and method relate to a depot or depot injection. A number of parameters influence the pharmacokinetic profile of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that is injected intramuscularly as a depot. A depot effect is achieved with substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that slowly degrades (e.g., is de-esterified) into 17-β-Hydroxy-4-Androsten-3-one once it has entered into circulation. Another factor contributing to the depot effect is the diffusion rate of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate from the site of injection to the circulatory system. The diffusion rate can depend on the dose and the volume injected in that the concentration gradient of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at the site of administration is thought to affect the diffusion rate. Furthermore, the type of vehicle injected together with substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can influence the rate of diffusion of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate from the vehicle into the surrounding tissues and the rate of absorption into the blood circulation. The partition coefficient (n-octanol-water partition coefficient) of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in the vehicle as well as the viscosity of the vehicle can be considered for adapting a depot effect folio intramuscular injection of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
- Thus in one embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is dissolved in a vehicle.
- In one embodiment, a depot effect in vivo with of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, is provided by injecting intramuscularly the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in a vehicle comprising an oil (e.g., castor oil) and optionally a suitable co-solvent. In one aspect, the co-solvent may lover the viscosity of the castor oil and then solve the problem with high viscosity of the castor oil when being injected, although the co-solvent may increase the diffusion rate of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, resulting in a lower depot effect following intramuscular injection. Thus, careful selection of the co-solvent and amounts is an important consideration. In one aspect, the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities.
- Thus, in one embodiment, a composition comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate; and an oil vehicle (e.g., castor oil) comprising and a co-solvent.
- In one embodiment, the composition is formulated for parenteral administration, preferably intramuscular injection. Alternatively, the composition is formulated for subcutaneous injection.
- The term “castor oil” is meant to encompass castor oil refined for injectable (e.g., parenteral) use. It should also be understood that the castor oil are not hydrogenated or at least in part not hydrogenated. In some embodiments, some of the double bonds may be hydrogenated. For example, less than 20% w/w of the double bonds are hydrogenated. In one aspect, less than 10% w/w of the double bonds are hydrogenated, less than 5% w/w, less than 2% w/w, less than 1% w/w of the double bonds are hydrogenated.
- Co-solvent(s) can be defined by the capability of reducing the viscosity of the oil (e.g., castor oil), as determined by a floppier viscosimeter.
- Injection of viscous vehicles, such as castor oil, is associated with technical limitations to the size of cannula due to the resistance of the vehicle when passing the cannula, In one aspect, the viscosity of an injection solution is below 100 mPas. In certain aspects, the viscosity of a final product, ready to be injected, such as a re-constituted product is, e.g., less than 100 mPas, such as 90 mPas, 80 mPas, 70 mPas at room temperature. In some aspects, the viscosity of the vehicle is less than 60 mPas, 50 mPas, 40 mPas or 30 mPas at room temperature.
- Thus, some embodiments relate to those wherein the co-solvent is selected from those that when being mixed with castor oil in an oil:co-solvent volume ratio of between 1:0.2 to 1:3, the viscosity drops from 950-1100 mPas to 20 mPas at room temperature. In one aspect, the co-solvent is selected from those, wherein the viscosity drops from 950-1100 mPas to about 80-100 mPas, when the co-solvent is being mixed with castor oil in an oil:co-solvent volume ratio of about 1:11 to 1:3. The viscosity of the vehicle can be determined with a Hoppler type viscometer. The viscosity is measured at a fixed temperature, often room temperature such as 20° C. or 25° C.
- The co-solvent can be characterized by its ability to reduce the viscosity of a vehicle, such as castor oil, of the solvent in a ratio dependent manner.
- In one embodiment, the viscosity of a mixture of castor oil arid a co-solvent in a volume ratio of 1:0.1 to 1:1.7 is reduced from 60% to 5% of that of castor oil alone.
- In another embodiment, the viscosity of a mixture of castor oil and a co-solvent is in a ratio of 1:0.02 by volume and is reduced by about 10% relatively to the viscosity of castor oil. In other aspects, when the ratio between the oil and co-solvent is 1:0.04 by volume the viscosity is reduced by 20% relatively to the viscosity of castor oil, when the ratio is of 1:0.08 by volume the viscosity is reduced by 25%, when the ratio is of 1:0.1 by volume the viscosity is reduced by 40%, when the ratio is of 1:0.2 by volume the viscosity is reduced by 50%, when the ratio is 1:0.35 by volume the viscosity is reduced by 75%, when the ratio is of 1:0.5 by volume the viscosity is reduced by 80%, when the ratio is of 1:1 by volume the viscosity is reduced by 90%, or when the ratio is 1:1.6 by volume the viscosity is reduced by 95%.
- In further embodiments, the viscosity of the composition is below 100 mPas. In some aspects, the viscosity of vehicle, such as the mixture of castor oil and a co-solvent, such as benzyl benzoate is below 90 mPas, the viscosity of the vehicle is about 60-100 mPas, 70 to 100 mPas, or 80-90 mPas at room temperature (20° C. to 25° C.).
- The viscosity of the injected vehicle may dictate to a certain extent the pharmacokinetic profile of an injected substance. Thus, in order to obtain a final product with a suitable depot effect in vivo, the castor oil and co-solvent, in some aspects, is in a volume ratio ranging between 1:0.2 to 1:3, between 1:0.5 to 1:3, or between 1:0.75 to 1:2.5. In one aspect, the volume ratio is in the range from 1:1 to 1:2.
- In some embodiments, the co-solvent is benzyl benzoate. Other types of co-solvents are applicable for use in combination with the oil (e.g., castor oil), fur example ethanol or benzyl alcohol. In one aspect, co-solvents are those which are capable of dissolving the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and is miscible with castor oil. Co-solvents suitable for dissolving about 100-500 mg, such as 250 mg of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in 1 mL of the co-solvent within 50 minutes at 40° C. or within 20 minutes at 60° C. are useful in some aspects.
- The solubility of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be affected upon adding a co-solvent to the oil (e.g., castor oil) vehicle. In one aspect, the solubility may be improved. Thus, in some embodiments, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is completely dissolved in the composition (vehicle with co-solvent(s)), and in other embodiments the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is partly dispersed in the composition. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is fully dissolved in the vehicle. In one aspect, no particles of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate are detected by X-ray diffraction analysis of the composition comprising (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and vehicle.
- Provided herein are compositions, wherein the co-solvent is present in the vehicle at concentrations ranging from 10 to 90 volume % (“v %”). In one aspect, the concentration of the co-solvent in the vehicle ranges between 15 to 85 v %, between 20 to 80 v %, such as between 45 to 85 v % or 55 to 85 v %.
- In one embodiment, the vehicle comprises a plant oil (e.g., castor oil) in a volume concentration ranging between 20 to 85 v %. In one aspect, the concentration of castor oil in the vehicle ranges between25 to 60 v % or 25 to 55 v %. In some aspects, the concentration of castor oil in the vehicle ranges between 25 to 50 v %, 25 to 45 v % or 25 to 40 v %.
- In some embodiments, the composition does not comprise another plant oil, e.g., tea seed oil. In one aspect, the only plant oil present in the composition is castor oil or that castor oil is at least 50% by volume of the total content of the plant oil in the vehicle, e.g., at least 60%, 70%, 80% or 90% by volume.
- The selection of a co-solvent depends on a number of factors, such as i) the amount (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in the injection vehicle, ii) the required reduction of viscosity and iii) the release properties of the injection vehicle with respect to the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate at the site of injection (diffusion rate). In some aspects, the co-solvent is at least 10 v % of the vehicle, at least 15 v %, at least 40 v %, or at least 50 v %. In some aspects, the co-solvent is in an amount ranging from about 40 to 80 v % of the vehicle, 50 to 70 v %, or 55 to 65 v % of the vehicle.
- in one embodiment, the concentration of the co-solvent in the vehicle is chosen to reduce the diffusion rate of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, for instance at the site of injection. Therefore in some aspects, the concentration of co-solvent in the vehicle is less than 90 v %, less than 85 v %, less than 80 v %, or less than 75 v %.
- In one embodiment, the volume injected intramuscularly is chosen to affect the release rate of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate from the vehicle. In one aspect, an injection volume of 5 mi. is provided for administration by one single intramuscular injection to one injection site. If an intramuscular injection of a volume greater than 5 mL is required, the injection volume can be divided into two or more separate injections to different injection sites. In one aspect, the injection volume is 4-5 mL or less, 3-4 mL or less, 2-3 mL or less, 1-2 mL or less, or 1 mL or less.
- A single dose to one injection site offers advantages in controlling the release rate of an active principle, rather than multiple injections of divided single doses. Thus, in some embodiments, an injection scheme wherein a single dose of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is divided into no more than two separate injections to one or more injection sites is provided. In one aspect, a single dose of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is injected as one single injection to one injection site. Therefore, in one aspect, the dose of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is administered as a single injection to one injection site, wherein the injected volume is from 1 to 5 mL, of 1 to 4 mL, or 1.5 to 4 mL. Suitable injection volumes for ensuring reproducible administration volumes and uniform release of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is lower than 5 mL, e.g., about 5 mL, about 4 mL, about 3 mL, about 2 mL and about 1 mL.
- In order for using single injections and low injection volumes, the concentration of the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate in the compositions can be relatively high. Thus, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is in a concentration of 50 mg to 1000 mg per mL of the vehicle. Thus, in some aspects, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is in a concentration of 100 to 750 mg per mL of the vehicle, 150 to 500 mg per mL, 175 to 400 mg per mL, or about 250 mg/mL of the vehicle.
- The composition, in some aspects, is formulated as a unit dose form such as a unit dose for injection as one single dose. In some embodiments, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is in a dose of 500 to 4000 mg, 500 mg to 3000 mg, 750 mg to 2000 mg, 750 mg to 1500 mg, or about 250 mg, about 500 mg, about 750 mg or about 1000 mg.
- The injectable compositions can further comprise another therapeutically active agent, such as a progestin and/or a further gonadotropin suppressive agent other than (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
- The compositions some embodiments (e.g., injectable) are chemically stable with respect to the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. For example, in some aspects, degradation products are not detected after long term storage (such as after 7 weeks, 10 leeks or 17 weeks or even longer) at conditions normally known to accelerate degradation processes, such as variations in temperatures, high and low temperatures and various relative humidity. For example, less than 1% by weight of degradation products of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is present after storage of the composition for at least 7 weeks, such as for 16 or 17 weeks, for 6 months, or for 9 or 12 months at 40° C. and 25% r.h. (relative humidity) in darkness. in one aspect, less than 0.5% w/w, such as less than 0.2% w/w of degradation products of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is present after storage at the above-mentioned conditions.
- The pharmaceutical compositions and dosage forms (e.g. capsule or tablet) described herein prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (as described in the embodiments above) can include a variety of pharmaceutically acceptable carriers or additives known in the art. Non-limiting examples of components that can be included as components of the pharmaceutical carrier include lipophilic surfactants, hydrophilic surfactants, triglycerides, fatty acid (C8 to C22), fatty acid glycerides (mono-, di-, tri-, or a combination thereof), or a combination thereof.
- In one embodiment, the pharmaceutical composition or dosage form comprises, or is prepared with, substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate as described herein.
- In one embodiment, the pharmaceutical composition or unit dosage form is characterized by its dissolution or release profile (e.g., at least 75% in 4 hours). In one aspect, the oral pharmaceutical composition or unit dosage form can be formulated as a tablet or capsule (e.g., hard gel or soft gel). According to this embodiment, a pharmaceutical composition or unit dosage form having a particular amount of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more).
- In one embodiment, the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate that does not change substantially as a function of storage time using a
USP type 2 apparatus in about 1000mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at 100 rpm. In one aspect, the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In one aspect, the release profile does not substantially change over a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 months. - In one embodiment, the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate using a
USP type 2 apparatus in about 1000mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0° C. (±0.5)) at 100 rpm that release at least 10, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% at 15, 20, 30, 40, 45, 50, 60, 90, 120, 180, 240, or 300 minutes. - In one embodiment, the pharmaceutical composition or unit dosage form having (or prepared from) substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has a release profile (e.g., a profile comprising 2, 3, 4, 5, or 6 or more time points each at least 5, 10, or 15 minutes apart or a single time point) of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate using a
USP type 2 apparatus in about 1000mL 8% Triton X100 solution in water at a specific temperature (e.g., 20.0, 37.0 or 40.0 ° C. (±0.5)) at 100 rpm that release less than 10, 20, 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% at 15, 20, 30, 40, 45, 50, 60, 90, 120, 180, 240, or 300 minutes. - In some embodiments, the pharmaceutically acceptable carrier of the composition (e.g., pharmaceutical composition, formulation or unit dosage form) can include a lipophilic additive. In some embodiments, the lipophilic additive can comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95 wt % of the pharmaceutically acceptable carrier. Non-limiting examples of lipophilic additives can include lipophilic surfactants, triglycerides, tocopherol, tocopherol derivatives and combinations thereof. In one embodiment, the lipophilic additive can include a fatty acid or fatty acid glyceride. In another embodiment, lipophilic additive can include the fatty acid glyceride, and the fatty acid glyceride can be a monoglyceride, a diglyceride, or mixtures thereof. In one aspect, the fatty acid is oleic acid, stearic acid or a combination thereof. In one aspect, the fatty acid glyceride is glyceryl palmitostearate. Non-limiting examples of fatty acid glycerides that can be used in the oral pharmaceutical compositions and dosage forms of the present invention include monoglycerides and/or diglycerides derived from sources such as maize oil, poppy seed oil, safflower oil, sunflower oil, borage seed oil, peppermint oil, coconut oil, palm kernel oil, castor oil, and mixtures thereof. In one embodiment, the pharmaceutical composition or dosage form thereof comprises 50%, 40%, 30%, 20%, 15%, 10%, 5% by weight or less of a triglyceride. In a specific embodiment, the pharmaceutical composition or dosage form thereof, comprises less than 50% by weight of castor oil. In another embodiment, the composition includes 10 wt % or less of triglycerides. In a further embodiment, the composition includes 5 wt % or less of triglycerides. In a still a further embodiment, the composition includes about 3 wt % or less of triglycerides. In still a further embodiment, the composition includes about 1 wt % or less of triglycerides. In another embodiment, the composition is free or substantially free of triglycerides. In another embodiment, the composition and dosage forms are free of phytosterols and phytosterol fatty acid esters.
- In another embodiment, the lipophilic additive can include a lipophilic surfactant. As used herein a surfactant is considered to be a lipophilic surfactant when it has an HLB value of 10 or less. Various lipophilic surfactants can be used including, but not limited to mono-, di- glycerides of fatty acids like glyceryl monolinoleate (e.g. Maisine® 35-1), mono- and di-glycerides of caprylic, capric acid (e.g. Capmul® MCM), glyceryl monooleate, reaction mixtures of alcohols or polyalcohols with a variety of natural and/or hydrogenated oils such as PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (e.g. Labrafil® M 2125 CS), PEG-6 almond oil (e.g. Labrafil®M 1966 CS), PEG-6 apricot kernel oil (e.g. Labrafil®M 1944 CS), PEG-6 olive oil (e.g. Labrafil®M 1980 CS), PEG-6 peanut oil (e.g. Labrafil®M 1969 CS), PEG-6 hydrogenated palm kernel oil (e.g. Labrafil®. M 2130 BS), PEG-6 palm kernel oil (e.g. Labrafil® M 2130 CS), PEG-6 triolein (e.g. Labrafil® M 2735 CS), PEG-8 corn oil (e.g. Labrafil® WL 2609 BS), PEG-20 corn glycerides (e.g. Crovol® M40), PEG-20 almond glycerides (e.g. Crovol® A40), lipophilic polyoxyethylene-polyoxypropylene block co-polymers (e.g. Pluronic® L92, L101, L121 etc.); propylene glycol fatty acid esters, such as propylene glycol monolaurate (e.g. Lauroglycol FCC), propylene glycol ricinoleate (e.g. Propymuls), propylene glycol monooleate (e.g. Myverol P-O6), propylene glycol dicaprylate/dicaprate (e.g. Captex® 200), and propylene glycol dioctanoate (e.g. Captex® 800), propylene glycol mono-caprylate (e.g. Capryol® 90); propylene glycol oleate (e.g. Lutrol OP2000); propylene glycol myristate; propylene glycol mono stearate; propylene glycol hydroxy stearate; propylene glycol ricinoleate ; propylene glycol isostearate; propylene glycol mono-oleate; propylene glycol dicaprylate/dicaprate; propylene glycol dioctanoate; propylene glycol caprylate-caprate; propylene glycol dilaurate; propylene glycol distearate; propylene glycol dicaprylate; propylene glycol dicaprate; mixtures of propylene glycol esters and glycerol esters such as mixtures composed of the oleic acid esters of propylene glycol and glycerol (e.g. Arlacel® 186); sterol and sterol derivatives such as cholesterol, sitosterol, phytosterol, phytosterol fatty acid esters, PEG-5 soya sterol, PEG-10 soya sterol, PEG-20 soya sterol, and the like; glyceryl palmitostearate, glyceryl stearate, glyceryl distearate, glyceryl monostearate, or a combination thereof; sorbitan fatty acid esters such as sorbitan monolaurate (e.g. Arlacel 20), sorbitan monopalmitate (e.g. Span-40), sorbitan monooleate (e.g. Span-80), sorbitan monostearate, and sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, sorbitan sesquistearate, and the like; fatty acids such as capric acid, caprylic acid, oleic acid, linoleic acid, myristic acid, menthol, menthol derivatives, lecithin, phosphatidyl choline, bile salts, and the like, and mixtures thereof. It is important to note that some lipophilic surfactants may also function as the solubilizer component of the compositions and oral dosage forms.
- In one embodiment, the lipophilic surfactant can be selected from the group consisting of glyceryl monolinoleate (e.g. Maisine® 35-1), mono- and di glycerides of caprylic, capric acid (e.g. Capmul® MCM), glyceryl monooleate, propylene glycol mono caprylate, propylene glycol oleate, propylene glycol monostearate, propylene glycol monolaurate, propylene glycol mono-oleate, propylene glycol dicaprylate/dicaprate, sorbitan monooleate, PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castor oil, PEG-9 hydrogenated castor oil, PEG-6 corn oil, PEG-6 almond oil, PEG-6 apricot kernel oil, PEG-6 olive oil, PEG-6 peanut oil, PEG-6 hydrogenated palm kernel oil, sorbitan monolaurate (e.g. Arlacel 20), sorbitan monopalmitate, sorbitan monooleate , sorbitan monostearate, sorbitan tristearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan trioleate, sorbitan sesquioleate, sorbitan tristearate, sorbitan monoisostearate, and combinations thereof. In some embodiments, the lipophilic surfactants can comprise at least about 10, 20, 30, 40, 50, 60, 70, 80, 90 or 95 wt % of the total pharmaceutically acceptable carrier. It should be noted that the combinations of two or more lipophilic surfactants from the same or different classes therein are also within the scope of this invention and are together can be referred to as the lipophilic surfactant, unless otherwise stated.
- In some embodiments of the present invention, the oral pharmaceutical compositions or dosage forms (e.g. capsule or tablet) can include a hydrophilic additive. In one embodiment, hydrophilic additive is a selected from the group consisting of hydrophilic surfactant, celluloses—such as hydroxypropyl celluloses low molecular weight, low viscosity types (e.g. Methocel® E5, E6, El° E15, LV100 etc. grades) and hydroxypropyl celluloses having higher molecular weight, medium to high viscosity (e.g. Methocel® K4M, Kl5M, K100M etc); polyvinylpyrrolidones (e.g. Kollidon k17, K30 etc); polyvinyl acetates and combinations thereof.
- In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. A surfactant is considered to be a hydrophilic surfactant when it has an HLB value of greater than 10. Non-limiting examples of hydrophilic surfactants include non-ionic surfactants, ionic surfactants and zwitterionic surfactants. Specifically the hydrophilic surfactants suitable for the current invention include, but not limited to alcohol-oil transesterification products; polyoxyethylene hydrogenated vegetable oils; polyoxyethylene vegetable oils; alkyl sulphate salts, dioctyl sulfosuccinate salts; polyethylene glycol fatty acids esters; polyethylene glycol fatty acids mono- and di- ester mixtures; polysorbates, polyethylene glycol derivatives of tocopherol and the like It should be noted that the combinations of two or more hydrophilic surfactants from the same or different classes are within the scope of this invention and are together can be referred to as the hydrophilic surfactant unless explicitly specified. In one embodiment, the hydrophilic additive can be a hydrophilic surfactant. Non-limiting examples of hydrophilic surfactants can include PEG-8 caprylic/capric glycerides, lauroyl macrogol-32 glyceride, stearoyl macrogol glyceride, PEG-40 hydrogenated castor oil, PEG-35 castor oil, sodium lauryl sulfate, sodium dioctyl sulfosuccinate, polyethylene glycol fatty acids mono- and di-ester mixtures,
polysorbate 80,polysorbate 20,polyethylene glycol 1000 tocopherol succinate, phytosterols, phytosterol fatty acid esters, and mixtures thereof. - In some embodiments, surfactants utilized in the pharmaceutical compositions described herein include sterols and derivatives of sterols. In various embodiments, these surfactants are hydrophilic or lipophilic. Examples of hydrophilic sterol surfactants are lanosterol PEG-24 cholesterol ether (e.g. Solulan C-24, Amerchol), PEG-30 soya sterol (e.g. Nikkol BPS-30, from Nikko), PEG-25 phyto sterol (e.g. Nikkol BPSH-25 from Nikko), PEG-30 cholestanol (e.g. Nikkol DHC, from Nikko). Examples of Lipophilic Sterol Surfactants are Cholesterol, sitosterol, Phytosterol (e.g. GENEROL series from Henkel), PEG-5 soya sterol (e.g. Nikkol BPS-S, from Nikko), PEG-10 soya sterol (e.g. Nikkol BPS-10 from Nikko), PEG-20 soya sterol (e.g. Nikkol BPS-20 from Nikko).
- In one embodiment, the oral pharmaceutical composition or the dosage form comprises or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or dosage form. In another embodiment, the compositions or the dosage form of the current invention includes substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or dosage form, and wherein the carrier includes at least 50 wt % of the composition or the dosage form and wherein the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C. In an additional more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities. In one aspect, the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel). In one aspect, the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one aspect, the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In another embodiment, the compositions or the dosage forms includes or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and wherein the carrier includes about 50 wt % to about100 wt % of lipophilic surfactant and 0 wt % to about 50 wt % of hydrophilic surfactant. In a further embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C. In an additional more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature. In one aspect, the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel). In one aspect, the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one aspect, the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In another specific embodiment, the composition or the dosage form includes or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate and a pharmaceutically acceptable carrier, wherein substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and the carrier includes about 50 wt % to about 95 wt % a lipophilic surfactant and a
hydrophilic surfactant 5 wt % to about 30 wt %. In one aspect, the lipophilic additive is a C16 to C18 fatty acid (saturated or having 1, 2, or 3 unsaturations), or a mono-, di-, or triglyceride thereof In one aspect, mono-, di-, or tri-glyceride is glyceryl palmitostearate. In one aspect, the hydrophilic component is a hydrogenated oil. In one aspect, the hydrophilic component is a polyoxylated hydrogenated oil. In a further more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C. In an additional more specific embodiment, the ester is not fully dissolved in the carrier at human body temperature. In another more specific embodiment, the composition or the dosage form can optionally contain about 10 wt % or less of ethyl alcohol. In an additional more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature. In one aspect, the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel). In one aspect, the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one aspect, the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg. In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures. - In one embodiment, the hydrophilic surfactant can comprise at least about 20% of the total pharmaceutical carrier. In another embodiment, the hydrophilic surfactant can comprise at least about 5 wt % of the carrier. In another embodiment, the hydrophilic surfactant can comprise less than 5, 4, 3, 2, or 1 wt % of the carrier.
- In another embodiment, the composition or the dosage form includes or is prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate, wherein the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate comprises about 0.5 wt % to about 50 wt %, 5 wt % to about 45 wt %, 15 wt % to about 40 wt %, 25 wt % to about 35 wt %, or 26 wt % to about 32 wt % of the composition or the dosage form, and wherein the composition includes about 50 wt % to about 100 wt % of lipophilic additive and 0 wt % to about 50 wt % of hydrophilic additive. In a specific embodiment, the lipophilic additive can be lipophilic surfactant and the hydrophilic additive can be hydrophilic surfactant. In one aspect, the lipophilic additive is a C16 to C18 fatty acid (saturated or having 1, 2, or 3 unsaturations), or a mono-, di-, or triglyceride thereof. In one aspect, mono-, di-, or tri-glyceride is glyceryl palmitostearate. In one aspect, the hydrophilic component is a hydrogenated oil. In one aspect, the hydrophilic component is a polyoxylated hydrogenated oil. In a further embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not solubilized at 30° C., or above 30° C., or at a temperature range above 30° C., including 30° C. to about 40° C. In an additional more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the lipophilic additive or the composition at human body temperature. In an additional more specific embodiment, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is not fully dissolved in the carrier at human body temperature. In one aspect, the pharmaceutical composition or unit dosage form is formulated as a tablet or capsule (e.g., soft gel or hard gel). In one aspect, the pharmaceutical composition or unit dosage form further comprises one or more additives (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one aspect, the pharmaceutical composition or unit dosage form comprises a particular amount of substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (e.g., 3 mg or more, 4 mg or more, 5 mg or more, 10 mg or more, 15 mg or more, 20 mg or more, 30 mg or more, 40 mg or more, 50 mg or more, 75 mg or more, 100 mg or more, 125 mg or more, 150 mg or more, 175 mg or more, 200 mg or more, 225 mg or more, 250 mg or more, 275 mg or more, or 300 mg or more) and typically less than 600 mg.
- In one aspect, the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially free of impurities specifically disclosed herein or in any of the Figures.
- In one embodiment, the hydrophilic surfactant can comprise at least about 20% of the composition. In another embodiment, the hydrophilic surfactant can comprise at least about 5 wt % of the composition. In another embodiment, the hydrophilic surfactant can comprise less than 5 wt % of the composition.
- In some embodiments, the oral pharmaceutical composition or the dosage form can include both a lipophilic surfactant and hydrophilic surfactant. In one embodiment, the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2:1. In another embodiment, the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2.5:1. In another embodiment, the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 3.5:1. In still another embodiment, the lipophilic surfactant and hydrophilic surfactant can be present in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is at least 6.5:1.
- Methods of Use
- Subjects that can be treated by pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities)) can be any man (e.g., male or female) in need thereof. In particular, in one embodiment, the human male is at least 14, 16, or 18 years of age. In another embodiment, the human male is at
least age 20. 21, 25 or 30. In a further embodiment, the subject is an adult male of at leastage age 60. Subjects that can be treated by pharmaceutical compositions and unit dosage forms of the present disclosure (e.g., prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities) can be any human male in need thereof. In particular, in one embodiment, the human female may be at least 14 years of age. In some embodiments, the human subject is a female. For example, in another embodiment, the human female is an adult of at least 20 or 30 years of age. In a further embodiment, the subject can be an adult female of at leastage - As discussed above, a method of treating a human subject in need of testosterone therapy is provided. The method can include the steps of administering any of the pharmaceutical compositions or dosage forms (e.g., capsule or tablet) disclosed herein. The pharmaceutical compositions and the dosage forms of the present invention can be used to treat any condition associated with testosterone deficiency, including complete absence, of endogenous testosterone in male or female subjects. Examples of conditions associated with testosterone deficiency that can be treated using the dosage forms (e.g., capsule or tablet) or compositions described herein include, but are not limited to congenital or acquired primary hypogonadism, hypogonadotropic hypogonadism, cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome, orchidectomy, Klinefelter's syndrome, post castration, eunuchoidism, hypopituitarism, endocrine impotence, infertility due to spermatogenic disorders, impotence, male sexual dysfunction (MSD) including conditions such as premature ejaculation, erectile dysfunction, decreased libido, and the like, micropenis and constitutional delay, penile enlargement, appetite stimulation, testosterone deficiency associated with chemotherapy, testosterone deficiency associated with toxic damage from alcohol, testosterone deficiency associated with toxic damage from heavy metal, osteoporosis associated with androgen deficiency, or a combination thereof
- Other conditions that can be treated by the compositions and dosage forms disclosed herein include idiopathic gonadotropin, LURE deficiency, or pituitary hypothalamic injury- from tumors, trauma, or radiation. Typically, these subjects have low serum testosterone levels but have gonadotropins in the normal or low range. In one embodiment, the composition or oral dosage form can be used to stimulate puberty in carefully selected males with clearly delayed puberty not secondary to pathological disorder, in another embodiment, the composition or oral dosage form can be used in female-to-male transsexuals in order to maintain or restore male physical and sexual characteristics including body muscle mass, muscle tone, bone density, body mass index (BMI), enhanced energy, motivation and endurance, restoring psychosexual activity etc. in some embodiments, pharmaceutical composition or unit dosage form of the present disclosure (e.g., prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities) can be useful in providing hormonal male contraception, In some embodiments, the pharmaceutical composition or unit dosage form of the present disclosure (e.g., prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities) can be used to provide treatment of one or more symptoms associated with female sexual dysfunction, anorgasmia, osteoarthritis, hormonal male contraception. Additionally, the pharmaceutical composition or unit dosage form of the present disclosure (e.g., prepared from or comprising substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities) can be used to treat and/or improve the patient related outcomes including the quality of life or wellbeing a subject suffering from deficiency of endogenous testosterone or who can otherwise benefit from the treatment, in some embodiments, the pharmaceutical composition or unit dosage form of the present disclosure (e.g., prepared from or comprising (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate substantially free of impurities) can be used to treat or improve one or more symptoms of a subject suffering from conditions such as decreased libido, diminishing memory, anemia due to marrow failure, renal failure, chronic respiratory or cardiac failure, steroid-dependent autoimmune disease, muscle wasting associated with various diseases such as AIDS, preventing attacks of hereditary angioedema or urticaria; andropause, and palliating cancer. In some situations, certain biomarkers such as for example, increased SHBG levels, can be used to diagnose a subject who may be in need of testosterone therapy. These biomarkers can be associated with conditions/disease :states such as anorexia nervosa, hyperthyroidism, hypogonadism, androgen insensitivity/ deficiency, alcoholic hepatic cirrhosis, primary biliary cirrhosis, and the like.
- Methods of Using Substantially Pure (17-β)-3-Oxoandrost-4-en-17-yl Tridecanoate and Products Derived Therefrom
- In one embodiment, a pharmaceutical composition prepared by synthesizing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate to produce substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate solid and mixing the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate with one or more pharmaceutically acceptable carriers to provide a pharmaceutical composition which is substantially free of impurities. In a related embodiment, a pharmaceutical composition is prepared by providing substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate solid and mixing the substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate with one or more pharmaceutically acceptable carriers to provide a pharmaceutical composition which is substantially free of impurities.
- The compositions and unit dosage forms can be prepared by any suitable method known to the skilled artisan or developed in view of the teachings herein.
- In one specific aspect, the carrier(s) and API are brought to or maintained at a temperature at which they are flowable (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.). In one aspect, the mixture of carrier and API is a clear solution at a specified temperature (e.g., above 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.). In one aspect, the mixture of carrier and API is a cloudy or hazy solution at a specified temperature (e.g., below 10° C., 20° C., 25° C., 30° C., 35° C., or 40° C.).
- In one example, the composition is prepared by weighing all of the components, except the API into a clean stainless steel container and mixed together at ambient temperature or at elevated temperatures e.g., at about 25° C. to about 30° C., at about 30° C. to about 35° C., at about 35° C. to about 40° C., at about 40° C. to about 45° C., at about 45° C. to about 45° C., or 50° C. to about 70° C., using a stirrer. The API is added and stirred into the mixture of other components until the API dissolves. A predetermined quantity of this “liquid fill material” is disposed into a capsule (for example, hard gelatin capsule) to get the required API dose per dosage unit. The capsules are allowed to cool at room temperature, banded (if required) and packaged in a HDPE bottle and tightly closed with an appropriate lid. It is noted that various capsule sizes (e.g., hard gel or soft gel) are available to the skilled artisan and allow for variations in the amount of loading of API in mg per unit dosage form. Typically, soft gel capsules for oral administration have fill volumes of less than 1.5 mL, 1.3 mL or 1.25 mL with numerous incremental fill volumes in these ranges. Similarly, hard gel capsules typically have fill volumes of less than 1.25 mL, 1.10 mL or 1 mL. Due to the nature of some hard gel capsules, the total fill volume may not be useable. There is a practical limit on the temperature at which capsules can be filled for example temperature above 40° C. typically melt, deform, or otherwise damage soft gel capsules typically employed in the industry. Hard gel capsules are typically less sensitive to temperature and can be filled at higher temperatures e.g., above 40° C.
- In certain embodiments, any pharmaceutical composition described herein, e.g., a can be prepared by (i) combining and heating all ingredients until a molten mixture is obtained (e.g., 50-70° C.); and (ii) encapsulating an amount of molten mixture comprising a select dose (e.g., a therapeutically effective amount or a partial dose of a therapeutically effective amount) API to obtain an oral dosage form. In certain instances, the molten mixture is spray-congealed to obtain beads. In some instances, the molten mixture is sprayed onto inert cores (e.g., sugar spheres) to obtain coated cores. In certain embodiments, such beads, cores, or similar forms are encapsulated or otherwise formulated to provide an oral dosage form. In some instances, the molten mixture is admixed, uniformly dispersed, or granulated over a carrier and compressed into a tablet dosage form. In certain embodiments, prior to compression, the molten mixture/carrier composition is further mixed with one or more pharmaceutical aid including, by way of non-limiting example, glidants, lubricants, binders, or the like. In some embodiments, the carrier is a therapeutically inert carrier such as, by way of non-limiting example, microcrystalline cellulose, starch, lactose, or the like.
- In various embodiments, pharmaceutical compositions described herein are formulated as oral dosage forms. Oral dosage forms are prepared by any suitable process including one or more steps of, by way of non-limiting example, agglomeration, air suspension chilling, air suspension drying, balling, coacervation, comminution, compression, pelletization, cryopelletization, encapsulation, extrusion, granulation, homogenization, inclusion complexation, lyophilization, nanoencapsulation, melting, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or the like.
- In some embodiments, a pharmaceutical composition described herein is formulated with a substrate to form an oral dosage form. In various embodiments, substrates useful for formulating pharmaceutical compositions described herein as oral dosage forms include or comprise, by way of non-limiting example, a powder or a multiparticulate (e.g., one or more granule, one or more pellet, one or more bead, one or more spherule, one or more beadlet, one or more microcapsule, one or more millisphere, one or more mini capsule, one or more microcapsule, one or more nanocapsule, one or more nanosphere, one or more microsphere, one or more minitablet, one or more tablet, one or more capsule, or one or more combinations thereof). In certain instances, a powder constitutes a finely divided (milled, micronized, nanosized, precipitated) form of an active ingredient or additive molecular aggregates or a compound aggregate of multiple components or a physical mixture of aggregates of an active ingredient and/or additives.
- The following examples are provided to promote a more clear understanding of certain embodiments of the present invention, and are in no way meant as a limitation thereon.
- Preparation of Substantially Pure Pharmaceutical Ingredient, (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate
- 1) (17-β)-Hydroxy-4-Androsten-3-one (0.1 mol) is weighed into a 1000 mL 4N RB flask containing a stir bar;
- 2) Pyridine (160 mL) is added to the flask;
- 3) The flask is placed in an ice-water bath and fitted with a nitrogen inlet, addition funnel, thermocouple, and stopper. Stirring and nitrogen flow are started;
- 4) The funnel is charged with a solution of acid chloride (1.56 equiv e.g., acid chloride of tridecanoic acid) in heptane (160 mL), then fitted with an adapter connected to a bubbler;
- 5) The contents of the funnel are added dropwise over 30-40 min (Note: the internal temperature increases 5-7° C. during the addition);
- 6) When the addition is complete, the bath is removed and stirring is continued;
- 7) After 1 h, the reaction mixture is transferred to a large separatory funnel and diluted with heptane (1000 mL) (Note: Thin layer chromatography (“TLC”) can be used to monitor the reaction e.g., after one hour);
- 8) The heptane solution is washed successively with 800 mL portions of: cold water (2X), 0.05 N NaOH, saturated NaHCO3 (2X), water, brine, then dried over anhydrous Na2SO4 (−50 g). Then concentrated to dryness (rotavap/Tbath:S; 30° C.).
- A reaction mixture of Example 1 can be transferred to water, ethanol, or methanol (or any other suitable solvent) and allowed to crystallize. The crystalline mass can be filtered by suction, washed with water, dried over phosphorous pentoxide and re-crystallized from another solvent e.g., oleic acid, hexane, heptanes, etc.
- Liquid chromatography can be used to purify or analyze the purity of samples having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
- One exemplary liquid chromatographic method is as follows.
- Column: size 0.3 m, diameter 4.0 mm; stationary phase end—capped octadecylsilyl silca gel for chromatography (5 uM);
Temperature 40° C. - Mobile Phase water: acetonitrile (5:95 V/V)
- Plowrate 1.0 mL/min
- Detector 240 nm
- Dissolve sample in mobile phase e.g., 20 mg in 50 mL).
- Injection: 20 uL.
- Run time—twice the retention time of (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
- Order of retention time of purities and (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate starting with first eluting is expected as follows:
-
- (1) Tridecanoate;
- (2) (17-β)-3-Oxoandrost-4-en-3-one;
- (3) (17-β)-3-Oxoandrost-4-en-17-yl decanoate;
- (4) (17-β)-3-Oxoandrost-4-en-17-yl undecanoate;
- (5) (17-β)-3-Oxoandrost-4-en-17-yl dodecanoate;
- (6) (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate; and
- (7) (17-β)-3-Oxoandrost-4-en-17-yl tetradecanoate.
- According to this procedure, these impurities (and others) can be analyzed and identified. For example, mass spectrometry in conjunction with liquid chromatography can be used to assess or identify impurities in a sample having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.
- Differential Scanning calorimetry (DSC) of Substantially Pure (17-β)-3-Oxoandrost-4-en-17-yl Tridecanoate
- This example demonstrates that (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate is substantially pure by DSC e.g., the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate has a distinct melting point as determined using a differential scanning calorimeter. 5.9 mg of solid state substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate was placed in the chamber of a DSC instrument and was heated from 10 to 120° C. The result is shown in
FIG. 9 , which shows a peak at 72.78° C. The second heating run of this sample is show inFIG. 11 which shows a single peak at 71.77. It is expected that (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate having impurities will not have as distinct (sharp) a melting point or that it would be shifted depending on the amount and type of impurities.FIG. 10 andFIG. 12 show the first and cycle cooling cycles respectively. - Impurities in (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate or composition containing (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be separated and/or identified according to the following procedure
- Column: C18
- Mobile Phase: acetonitrile; alcohol; and deionized water.
- Detector Wavelength: about 240 nm (e.g., 242 nm)
- Flow Rate: 1.0 mL per minute
- Column Temperature: 29° C.
- The sample used in this example was derived from a (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate (89.9 mg) formulation/composition stored at 40° C. for 17 months.
FIGS. 13-15 show different portions of the HPLC trace. Placebo labeled peaks were identified from a similar formulations not having (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. RC peaks are impurities believed to be related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate.FIG. 13 shows the trace from about time zero to about 12 minutes withRC 1 identified as testosterone.FIG. 14 shows the trace from 8-105 minutes with RC 2-11 (from shortest to longest RRT) identified and the API.FIG. 15 shows trace from 8 minutes to 210 minutes with RC 2-11 shown and (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. RRT refers to the relative retention time to API. - The formulation in this Example is as follows:
-
Weight Percent of Quantity Fill Fill Pharmaceutical Material per Composition Hard Gel Capsule (±1%) (±1%) Ingredient Name % w/ w mg API 15 110 Glyceryl Monolinoleate, NF 63 463 Polyoxyl 40 Hydrogenated 15 114 Castor Oil, NF Ascorbyl Palmitate, NF 0.2 1.5 Polyethylene Glycol 6 44 8000, NF Total 100 733.3 - It is believed that formulations without a stabilizing agent e.g., antioxidant (e.g., ascorbyl palmitate) had the buildup over time of the impurities putatively identified as hydroxylated at
position 6 of the compound inFIG. 6 in the “out of the plane”, “in the plane”, or both. For example after two years storage of the composition without ascorbyl palmitate up to about 0.5% of these compounds could form. - Samples related to (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate can be analyzed by LC/MS. In one specific example, substantial pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate was exposed to elevated temperatures for 24 hours or 48 hours. The samples were dissolved in a solvent after exposure to elevated temperatures. The samples were then prepared for the LC/MS experiments by a 1:10,000 dilution into (20:80 acetonitrile:distilled/deionized water) by first dilution into the acetonitrile and then by bringing the volume up to the final volume by dilution with the distilled/deionized water.
FIG. 16 shows the result trace from the column (C18 Atlantis; injection volume). -
FIGS. 17-27 show the mass spectra corresponding to peaks from the HPLC trace. - The tables below represents the results from a stability study of the indicated compositions at the indicated times and conditions. The results were obtained from HPLC analysis of the samples.
-
Composition (A) Weight Percent Quantity Fill Quantity Fill of Fill Material per Material per Pharmaceutical Hard Gel Soft Gel Composition Capsule Capsule (±1%) (±1%) (±1%) Ingredient Name % w/w mg mg API 24 183 300 Oleic Acid, NF 41 308 513 Peppermint Oil, NF 18 136 225 Polyoxyl 40Hydrogenated 4 30 50 Castor Oil, NF Ascorbyl Palmitate, NF 0.2 1.5 2.5 Glyceryl Palmitostearate 12 90 150 (Glyceryl Distearate, NF) Total 100 750 1241 -
Composition (B) Weight Percent Quantity Fill Quantity Fill of Fill Material per Material per Pharmaceutical Hard Gel Soft Gel Composition Capsule Capsule (±1%) (±1%) (±1%) Ingredient Name % w/w mg mg API 28 183 350 Oleic Acid, NF 55 365 688 Polyoxyl 40Hydrogenated 4 26 50 Castor Oil, NF Stearic Acid, NF 4 26 50 Glyceryl Palmitostearate 8 52 100 (Glyceryl Distearate, NF; Precirol ATO 5) Ascorbyl Palmitate, 0.2 1.3 2.5 NF Total 100 654 1241 -
Composition (A) T = 1 month T = 3 months T = 0 25° C./ 40° C./ 25° C./ 40° C./ RRT Ambient 60 % RH 75 % RH 60 % RH 75% RH Assay (API) 102.7% 99.7% 99.2% 102.7% 99.4% Testosterone ND <0.05% 0.34% 0.09% 1.14% 0.39 ND ND ND ND ND 0.46 ND ND 0.07 0.06 0.09 0.88 0.06 0.06 0.05 0.06 0.05 1.36 ND 0.05 ND ND 0.05 2.52 NR NR ND ND 0.3 Total 0.06% 0.11% 0.12% 0.12% 0.49% Unspecified ND = None Detected at expected retention times above 0.05% NR = Peaks Not observed or Reported -
Composition (B) T = 1 month T = 3 months T = 0 25° C./ 40° C./ 25° C./ 40° C./ Ambient 60 % RH 75 % RH 60 % RH 75% RH Assay (API) 102.7% 99.7% 99.2% 98.8% 97.4% Known Impurity Testosterone ND <0.05% 0.34% 0.10% 0.98% Unspecified RC - RRT 0.39 ND ND ND ND ND 0.46 ND ND 0.07 ND ND 0.88 0.06 0.06 0.05 0.06 0.05 1.36 ND 0.05 ND 0.05 0.05 2.43 NR NR NR NR 0.07 2.52 NR NR NR ND 0.12 Total 0.06% 0.11% 0.12% 0.10% 0.27% Unspecified ND = None Detected at expected retention times above 0.05% NR = Peaks Not observed or Reported - RRT stands for relative retention time compared to API when analyzed by HPLC. Exemplary HPLC conditions are a C18 column (5 μm), 150×3.9 mm, 90% methanol: 10% deionized water at a flow rate of 1.0 mL/min with the column at 25° C.
- The compositions, dosage forms described herein containing API can subjected to in vitro dissolution (release) testing using
USP type 2 apparatus in about 1000 mL aqueous medium. The composition (e.g., dosage form) is subjected to in vitro dissolution testing usingUSP type 2 apparatus in about e.g., 1000mL 8% Triton X100 solution in water at a specific temperature (e.g., 37° C.) at 100 rpm for a specific time (e.g., 1, 2, 3, 4, 5, 10, 15, 30, 45, 60, 75, 90, 120, 180, or 240 minute time point where a sample is withdrawn and analyzed for API content (e.g., via HPLC)). - The compositions, dosage forms described herein containing API can subjected to in vitro dissolution (release) testing using
USP type 2 apparatus in about 1000 mL aqueous medium as described in the above example after storage for particular amounts of time under specific conditions.FIG. 28 shows the release profile stability of composition (B) composition (e.g., unit dosage form of composition (B) described herein. The diamonds with solid line labeled 1 representstime point 0; the diamond with dotted line represents 1 month storage at 25° C. and 60% relative humidity (labeled 2); the square with long dashed line represents 1 month storage at 40° C. and 75% relative humidity (labeled 3); the square with dash dot line represents 3 month storage at 25° C. and 60% relative humidity (labeled 4); and the square with lighter solid line represents 3 month storage at 40° C. and 75% relative humidity (labeled 5). The X-axis represents time in hours with measurements made at 15 min, 30 min, 45 min, 1 hour, 2 hours and 4 hours. The Y-axis represents percent API released in 1000mL 8% Triton X-100 media at 37° C. with aUSP Type 2 Apparatus at 100 RPM. -
FIG. 29 shows the release profile stability for composition (A) at time 0 (1), 1 month stored at either 25° C. 60% RH (2) or 40° C. 75% RH (3), 2 months stored at either at either 25° C. 60% RH (4) or 40° C. 75% RH (5), and 3 months stored at either at either 25° C. 60% RH (6) or 40 ° C. 75% RH (7). RH is relative humidity. The X-axis represents time in hours with measurements made at 15 min, 30 min, 45 min, 1 hour, 2 hours and 4 hours. The Y-axis represents percent API released in 1000mL 8% Triton X-100 media at 37° C. with aUSP Type 2 Apparatus at 100 RPM. - Some of the dosage forms of compositions described herein comprising or prepared from substantially pure (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate were administered to human subjects as a single dose of the esters to subjects. Serial blood samples were drawn at predetermined time (e.g., t=0, 12, 24, etc.) and analyzed for testosterone concentration using a validated HPLC-MS/MS analytical method. The Cmax, Cavg t1-t2, Tmax and AUCt1-t2 are calculated for testosterone in the serum of the subjects. Pharmacokinetic and statistical analyses are performed on the data obtained from the subjects. The pharmacokinetic parameters are defined as follows:
- AUCt1-t2: The area under the serum concentration versus time curve, from time t1 (in hours) to time t2 (in hours) measurable concentration of the administered drug, as calculated by the linear trapezoidal method. For e.g., AUCt0-t24 refers to the area under the serum concentration versus time curve, from time 0 (zero) hours to time 24 hours post-administration of dose.
- Cmax: The maximum measured serum concentration of the administered drug.
- Cavg t1-t2: The average serum concentration of testosterone obtained by dividing the AUCt1-t2/|t2-t1|, where in t is time post-administration of dose expressed in hours.
- Tmax: The time (in hours) at which the maximum measured plasma concentration of the administered drug is achieved.
- Mean: Average value of measured parameter of all individual subjects.
- Cavg t0-t24: The average serum concentration of testosterone obtained by dividing the AUCt0-t24 value by 24. This represents the average serum testosterone level over a period starting from time 0 (zero) hours to time 24 hours post- administration of dose. It should also be noted that Cavgt0-t24 is also referred to as simply “Cavg” in this invention.
- Cavg t0-t12: The average serum concentration of testosterone obtained by dividing the AUCt0-t12 value by 12. This represents the average serum testosterone level over a period starting from time 0 (zero) hours to time 24 hours post -administration of dose.
- Cavgt12-t24: The average serum concentration of testosterone obtained by dividing the AUCt12-t24 value by 12. This represents the average serum testosterone level over the second half of the 24-hours post-administration of dose period; i.e., from a period starting from
time 12 hours to time 24 hours post-administration of dose. - Some of the pharmacokinetic results for the compositions are summarized in the Tables below.
-
TABLE 1 Starting Total mg T Equivalent % Responders Dose (±dose With Cave t0-t24 % Responders with adjustment in mg (ng/dL) Cmax (ng/dL) T equivalent)* 300-1140 ≦1500 1800-2500 >2500 (17-β)-3-Oxoandrost- 300 (±50) QD 100 100 0-5 0-1 4-en-17-yl tridecanoate 350 (±100) BID 100 100 0-5 0-1 (12-20% EAPI, 55-70% 1000 (±200) QD or BID 100 0 20-30 60-80 lipophilic additive (e.g., 100 (±50) QD or BID 50-65 100 0-5 0-1 lipophilic surfactant) Hydrophilic additive 12-20% (e.g. Hydrophilic surfactant)) -
TABLE 2 Composition (weight %) Composition No. 12 13 14 Components (17-β)-3-Oxoandrost-4-en-17-yl 10-30 10-30 10-30 tridecanoate Lipophilic additive [e.g. surfactant 55-80 55-80 55-80 of HLB <10 such as mono- or di- or tri- glyceride of fatty acid or fatty acid] Hydrophilic additive (e.g. Surfactant 0-20 0-20 0-20 with HLB >10 such as Cremophor RH40) Adjuvant q.s. q.s q.s. Serum T pharmacokinetic results PK parameter Daily dose as mg T Equivalent 250-400 250-500 250-400 % of T-ester not dissolved in 0 >12 >40 lipophilic additive at body temperature % of T-ester not dissolved in 0 >15 >50 lipophilic additive at 20° C. No. of capsules/daily T dose 4-5 3-7 1-3 Mean serum T Cavg t0-t24/mg T 1.65 1-2-2.2 1.86 equivalent [ng/dL/mg] - It is also notable that Compositions 12-14 can be formulated as a capsule or tablet dosage form. Further, each of the capsule dosage forms can be formulated to contain from about 50 mg to about 450 mg of the ester (or more or less). For instance, the Compositions 12-14 can be formulated as a capsule or tablet dosage form.
- Total daily ester dose administered is 300 to 1500 mg for Compositions 12-14. Specifically, for Compositions 12-14 the total daily (17-β)-3-Oxoandrost-4-en-17-yl dose administered is from about 3000 mg to about 1500. However, it is notable that unlike
Composition 12 that has no “not dissolved” ester,Compositions - Table 2 shows that the higher the fraction of the lipobalanced ester not dissolved or not solubilized, the fewer the number of daily dosage form units (e.g., capsules) that need to be administered to achieve the desirable serum testosterone levels when treating hypogonadism in a male with (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate. It should be noted that to provide the total daily dose of about 420 mg 850 mg of the (17-β)-3-Oxoandrost-4-en-17-yl tridecanoate for a hypogonadal subject, no more than four oral dosage form units are required; even more preferred is that no more than two oral dosage form units per day are required for administration.
- Compositions 12-14 can be prepared with the lipophilic surfactant and hydrophilic surfactant in amounts such that the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant is greater than 2:1. Specifically, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 2.5:1. Further, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 3.5:1. Even further, the ratio of amount (wt %) of lipophilic surfactant to amount (wt %) of hydrophilic surfactant can be greater than 6.5:1.
- Compositions 12-14 can be prepared with hydrophilic surfactant present at 20 wt % or more of the total carrier. Compositions 12-14 can be prepared with hydrophilic surfactant present at 5 wt % or less of the total carrier. The lipophilic additives, the hydrophilic additives, and the adjuvant for the representative inventive compositions shown in Table 7 can be similar to those described for compositions in Table 2. The pharmacokinetic (PK) evaluation procedure is given under Example 2. The PK results for the
Compositions -
TABLE 3A Serum T pharmacokinetics for Compositions 13 and 14 following single administration PK parameter Results Range of mean Cmax/mg of T equivalent dose, [ng/dL/mg] 1.4-4.5 Range of mean Cavg t0-t24/mg of T equivalent dose, [ng/dL/mg] 1.2-2.2 Range of the Cavg t12-t24 as % of the Cavg t0-t24 35-70 Duration of post-dosing time with serum T at >300 ng/ dL 12 to 24 hours -
TABLE 3B Serum T pharmacokinetics for Compositions 14 following two consecutive dose administration PK parameter Results Time of T concentration below 300 ng/dL following two 2 to 7 consecutive administrations 24 hours apart (once daily) within hours 48 hour time period Time of T concentration below 300 ng/dL following two 0.5 to 3.5 consecutive administrations about 12 hours apart (twice daily) hours within 24 hours -
TABLE 3C Steady state serum T pharmacokinetics for Compositions 13 and 14 following at least 7 days continuous administration to a group of at least 12 subjects PK parameter Results Time of T concentration below 300 ng/dL following once 3.5-6.5 daily administration hours % of patients with serum T <300 ng/dL for more than 7 <50% hours following once daily administration Time of T concentration below 300 ng/dL following twice 0.3 to 3.5 daily administration hours % of patients with serum T <300 ng/dL for more than 7 <20% hours following twice daily administration - It is noteworthy that unlike
Composition 12,Compositions Compositions Compositions - It is understood that the above-described various types of compositions, dosage forms and/or modes of applications are only illustrative of preferred embodiments of the present invention.
- Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention and the appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity and detail in connection with what is presently deemed to be the most practical and preferred embodiments of the invention, it will be apparent to those of ordinary skill in the art that variations including, but not limited to, variations in size, materials, shape, form, function and manner of operation, assembly and use may be made without departing from the principles and concepts set forth herein.
Claims (32)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US15/507,754 US20170246187A1 (en) | 2014-08-28 | 2015-08-28 | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462043343P | 2014-08-28 | 2014-08-28 | |
PCT/US2015/047579 WO2016033549A2 (en) | 2014-08-28 | 2015-08-28 | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
US15/507,754 US20170246187A1 (en) | 2014-08-28 | 2015-08-28 | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2015/047579 A-371-Of-International WO2016033549A2 (en) | 2014-08-28 | 2015-08-28 | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/367,091 Continuation US11707467B2 (en) | 2014-08-28 | 2019-03-27 | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use |
Publications (1)
Publication Number | Publication Date |
---|---|
US20170246187A1 true US20170246187A1 (en) | 2017-08-31 |
Family
ID=55400833
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/507,754 Abandoned US20170246187A1 (en) | 2014-08-28 | 2015-08-28 | (17-ß)-3-OXOANDROST-4-EN-17-YL TRIDECANOATE COMPOSITIONS AND METHODS OF THEIR PREPARATION AND USE |
US16/367,091 Active US11707467B2 (en) | 2014-08-28 | 2019-03-27 | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/367,091 Active US11707467B2 (en) | 2014-08-28 | 2019-03-27 | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use |
Country Status (2)
Country | Link |
---|---|
US (2) | US20170246187A1 (en) |
WO (1) | WO2016033549A2 (en) |
Family Cites Families (319)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2680749A (en) | 1951-12-01 | 1954-06-08 | Eastman Kodak Co | Water-soluble tocopherol derivatives |
US2742487A (en) | 1952-05-02 | 1956-04-17 | Coconut Processes Inc | Method of extracting oil from mature, fresh coconut meats |
US3097139A (en) | 1960-03-10 | 1963-07-09 | Ici Ltd | Hypocholesterolaemia compositions |
US3097144A (en) | 1960-10-14 | 1963-07-09 | Upjohn Co | Heat-cured, polymeric, medicinal dosage film coatings containing a polyvinylpyrrolidone copolymer, polyethenoid acid, and polyethylene glycol |
CH399447A (en) | 1961-04-14 | 1965-09-30 | Ciba Geigy | Process for the production of a new steroid hormone ester |
US3164520A (en) | 1962-10-29 | 1965-01-05 | Olin Mathieson | Injectable steroid compositions containing at least 75% benzyl benzoate |
US3510561A (en) | 1965-05-20 | 1970-05-05 | Canada Packers Ltd | Sulfone-enhanced heparin absorption through mucous membranes |
FR1578974A (en) | 1968-05-16 | 1969-08-22 | ||
US4098802A (en) | 1975-02-18 | 1978-07-04 | Akzona Incorporated | Oral pharmaceutical preparation having androgenic activity |
US4147783A (en) * | 1974-02-28 | 1979-04-03 | Akzona Incorporated | Oral pharmaceutical preparation |
NL189235C (en) | 1974-02-28 | 1993-02-16 | Akzo Nv | METHOD FOR THE PREPARATION OF AN ORAL PHARMACEUTICAL PREPARATION WITH ANDROGENIC ACTION |
JPS5266616A (en) | 1975-11-29 | 1977-06-02 | Sawai Seiyaku Kk | Manufacturing of solidified oily liquid substance |
FR2374910A1 (en) | 1976-10-23 | 1978-07-21 | Choay Sa | PREPARATION BASED ON HEPARIN, INCLUDING LIPOSOMES, PROCESS FOR OBTAINING IT AND MEDICINAL PRODUCTS CONTAINING SUCH PREPARATIONS |
FR2408345A1 (en) | 1976-11-30 | 1979-06-08 | Besins Jean Louis | NEW COMPOSITION WITH ANTI-CONCEPTIONAL ACTION |
DK25877A (en) | 1977-01-21 | 1978-08-15 | Nordisk Insulinlab | PROCEDURE FOR EXTRACTING PURE ALBUMIN FROM BLOOD PLASMA |
JPS53107408A (en) | 1977-02-28 | 1978-09-19 | Yamanouchi Pharmaceut Co Ltd | Micellar preparation for rectal infusion |
DE2907460A1 (en) | 1978-03-07 | 1979-09-13 | Sandoz Ag | NEW RESORBABLE GALENIC COMPOSITIONS |
NZ196349A (en) | 1980-03-07 | 1984-08-24 | Interx Research Corp | Enhancement of absorption rate of orally administered polar bioactive agents |
JPS5770824A (en) | 1980-10-20 | 1982-05-01 | Nippon Saafuakutanto Kogyo Kk | Vehicle for medicine |
FR2494112B1 (en) | 1980-11-19 | 1986-01-10 | Laruelle Claude | |
FR2502951B1 (en) | 1981-04-06 | 1985-12-06 | Sandoz Sa | TOPICAL PHARMACEUTICAL COMPOSITIONS IN THE FORM OF A MICRO-EMULSION |
US4439432A (en) | 1982-03-22 | 1984-03-27 | Peat Raymond F | Treatment of progesterone deficiency and related conditions with a stable composition of progesterone and tocopherols |
US4654327A (en) | 1982-04-21 | 1987-03-31 | Research Corp. | Quaternary ammonium complexes of heparin |
DE3237814A1 (en) | 1982-10-12 | 1984-04-12 | Warner-Lambert Co., 07950 Morris Plains, N.J. | WATER-FREE EMULSIONS AND USE THEREOF |
SE8206744D0 (en) | 1982-11-26 | 1982-11-26 | Fluidcarbon International Ab | PREPARATION FOR CONTROLLED RELEASE OF SUBSTANCES |
IL68769A (en) | 1983-05-23 | 1986-02-28 | Hadassah Med Org | Pharmaceutical compositions containing insulin for oral administration |
US4731384A (en) | 1983-07-01 | 1988-03-15 | Troponwerke Gmbh & Co, Kg | Etofenamate formulation |
US4832952A (en) | 1983-07-07 | 1989-05-23 | American Home Products Corporation | Pharmaceutical composition containing a liquid lubricant |
DE3331009A1 (en) | 1983-08-27 | 1985-03-14 | Basf Ag, 6700 Ludwigshafen | METHOD FOR INCREASING THE ENTERAL RESORBABILITY OF HEPARIN OR. HEPARINOIDS AND THE SO AVAILABLE HEPARIN OR HEPARINOID PREPARATION |
DE3406497A1 (en) | 1984-02-23 | 1985-09-05 | Mueller Bernhard Willi Werner | HIGHLY DISPERSAL PHARMACEUTICAL MULTI-COMPONENT SYSTEMS AND METHOD FOR THEIR PRODUCTION |
US4713246A (en) | 1984-03-19 | 1987-12-15 | Bristol-Myers Company | Etoposide oral dosage form |
US4795327A (en) | 1984-03-26 | 1989-01-03 | Forest Laboratories, Inc. | Controlled release solid drug dosage forms based on mixtures of water soluble nonionic cellulose ethers and anionic surfactants |
JPS60226062A (en) | 1984-04-23 | 1985-11-11 | Seiko Seiki Co Ltd | Clutch device of magnetic disc in cartridge type magnetic disc device |
US4572915A (en) | 1984-05-01 | 1986-02-25 | Bioglan Laboratories | Clear micellized solutions of fat soluble essential nutrients |
US4703042A (en) | 1984-05-21 | 1987-10-27 | Bodor Nicholas S | Orally active heparin salts containing multivalent cationic units |
GB8414221D0 (en) | 1984-06-04 | 1984-07-11 | Sterwin Ag | Unit dosage form |
DE3421468A1 (en) | 1984-06-08 | 1985-12-19 | Dr. Rentschler Arzneimittel Gmbh & Co, 7958 Laupheim | LIPID NANOPELLETS AS A CARRIER SYSTEM FOR MEDICINAL PRODUCTS FOR PERORAL USE |
US5639724A (en) | 1984-07-24 | 1997-06-17 | Sandoz Ltd. | Cyclosporin galenic forms |
GB8903804D0 (en) | 1989-02-20 | 1989-04-05 | Sandoz Ltd | Improvements in or relating to organic compounds |
JPS6150978A (en) | 1984-08-16 | 1986-03-13 | Takeda Chem Ind Ltd | Pyridine derivative and preparation thereof |
US4897269A (en) | 1984-09-24 | 1990-01-30 | Mezei Associates Limited | Administration of drugs with multiphase liposomal delivery system |
US4867984A (en) | 1984-11-06 | 1989-09-19 | Nagin K. Patel | Drug in bead form and process for preparing same |
CA1282326C (en) | 1984-12-14 | 1991-04-02 | Paul J. Jarosz | Pharmaceutical composition containing 13-cis vitamin a acid as the active ingredient |
DE3500103A1 (en) | 1985-01-04 | 1986-07-10 | R.P. Scherer GmbH, 6930 Eberbach | PHARMACEUTICAL PREPARATION WITH AN INTENSIVE SOLUTION IN WATER AND DIGESTIVE JUICES |
US4874795A (en) | 1985-04-02 | 1989-10-17 | Yesair David W | Composition for delivery of orally administered drugs and other substances |
US4628052A (en) | 1985-05-28 | 1986-12-09 | Peat Raymond F | Pharmaceutical compositions containing dehydroepiandrosterone and other anesthetic steroids in the treatment of arthritis and other joint disabilities |
FR2585246A1 (en) | 1985-07-26 | 1987-01-30 | Cortial | PROCESS FOR OBTAINING SOLID PHARMACEUTICAL FORMS WITH PROLONGED RELEASE |
US4717596A (en) | 1985-10-30 | 1988-01-05 | International Business Machines Corporation | Method for vacuum vapor deposition with improved mass flow control |
US5023108A (en) | 1986-01-13 | 1991-06-11 | Research Corporation | Aqueous dispersions of waxes and lipids for pharmaceutical coating |
CA1327010C (en) | 1986-02-13 | 1994-02-15 | Tadashi Makino | Stabilized solid pharmaceutical composition containing antiulcer benzimidazole compound and its production |
US5433959A (en) | 1986-02-13 | 1995-07-18 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US4849227A (en) | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
US5140021A (en) | 1986-04-16 | 1992-08-18 | Genesis Systems Corporation | Method and dosage form for treatment of premenstrual syndrome |
US4963540A (en) | 1986-04-16 | 1990-10-16 | Maxson Wayne S | Method for treatment of premenstrual syndrome |
SE457693B (en) | 1986-07-01 | 1989-01-23 | Drilletten Ab | COMPOSITION WITH REGULATED RELEASE WAS A BIOLOGICAL MATERIAL LOST OR DISPERSED IN AN L2 PHASE |
FR2602423B1 (en) | 1986-08-08 | 1989-05-05 | Ethypharm Sa | PROCESS FOR THE PREPARATION OF A FENOFIBRATE-BASED MEDICINAL PRODUCT, OBTAINED BY THIS PROCESS |
NZ221411A (en) | 1986-08-11 | 1989-10-27 | Innovata Biomed Ltd | Pharmaceutical compositions containing microcapsules and a surfactant |
US5071643A (en) | 1986-10-17 | 1991-12-10 | R. P. Scherer Corporation | Solvent system enhancing the solubility of pharmaceuticals for encapsulation |
GB8630273D0 (en) | 1986-12-18 | 1987-01-28 | Til Medical Ltd | Pharmaceutical delivery systems |
HU205861B (en) | 1986-12-19 | 1992-07-28 | Sandoz Ag | Process for producing hydrosole of pharmaceutically effective material |
JPH0662402B2 (en) | 1987-01-14 | 1994-08-17 | アライアンス ファーマシューチカル コーポレイション | Brominated perfluorocarbon emulsion and method for producing the same |
US5026560A (en) | 1987-01-29 | 1991-06-25 | Takeda Chemical Industries, Ltd. | Spherical granules having core and their production |
US4900734A (en) | 1987-08-27 | 1990-02-13 | Maxson Wayne S | Novel pharmaceutical composition containing estradiol and progesterone for oral administration |
US5756450A (en) | 1987-09-15 | 1998-05-26 | Novartis Corporation | Water soluble monoesters as solubilisers for pharmacologically active compounds and pharmaceutical excipients and novel cyclosporin galenic forms |
US5035891A (en) | 1987-10-05 | 1991-07-30 | Syntex (U.S.A.) Inc. | Controlled release subcutaneous implant |
US5244925A (en) | 1987-12-18 | 1993-09-14 | Kabi Pharmacia Aktiebolag | Emulsion for parenteral administration |
GB8730011D0 (en) | 1987-12-23 | 1988-02-03 | Smithkline Dauelsberg | Pharmaceutical compositions |
FR2627696B1 (en) | 1988-02-26 | 1991-09-13 | Fournier Innovation Synergie | NEW GALENIC FORM OF FENOFIBRATE |
DE3807895A1 (en) | 1988-03-10 | 1989-09-21 | Knoll Ag | PRODUCTS CONTAINING A CALCIUM ANTAGONIST AND A LIPID DOWNER |
US5350741A (en) | 1988-07-30 | 1994-09-27 | Kanji Takada | Enteric formulations of physiologically active peptides and proteins |
US6007840A (en) | 1988-09-16 | 1999-12-28 | Novartis Ag | Pharmaceutical compositions comprising cyclosporins |
US5342625A (en) | 1988-09-16 | 1994-08-30 | Sandoz Ltd. | Pharmaceutical compositions comprising cyclosporins |
GB2222770B (en) | 1988-09-16 | 1992-07-29 | Sandoz Ltd | Pharmaceutical compositions containing cyclosporins |
GB8822857D0 (en) | 1988-09-29 | 1988-11-02 | Patralan Ltd | Pharmaceutical formulations |
DE3838094A1 (en) | 1988-11-10 | 1990-05-17 | Nordmark Arzneimittel Gmbh | SOLID PHARMACEUTICAL RETARD FORM |
US4994439A (en) | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
US5364632A (en) | 1989-04-05 | 1994-11-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Medicinal emulsions |
FR2647346B1 (en) | 1989-05-29 | 1991-09-06 | Besins Iscovesco Laboratoires | STABILIZED PROGESTERONE COMPOUND, PROCESS FOR PREPARING THE SAME, AND USE OF THE COMPOUND FOR OBTAINING A MEDICAMENT |
DE3919982A1 (en) | 1989-06-19 | 1990-12-20 | Liedtke Pharmed Gmbh | ORAL LIPID MEDICINE FORM |
US5532002A (en) | 1989-08-17 | 1996-07-02 | Cortecs Limited | Gelatin pharmaceutical formulations |
US5014656A (en) | 1990-04-25 | 1991-05-14 | General Motors Corporation | Internal combustion engine having a permanent ground electrode and replaceable center electrode element |
US5091187A (en) | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5091188A (en) | 1990-04-26 | 1992-02-25 | Haynes Duncan H | Phospholipid-coated microcrystals: injectable formulations of water-insoluble drugs |
US5298497A (en) | 1990-05-15 | 1994-03-29 | E. R. Squibb & Sons, Inc. | Method for preventing onset of hypertension employing a cholesterol lowering drug |
WO1992003121A1 (en) | 1990-08-13 | 1992-03-05 | Yesair David W | Mixed lipid-bicarbonate colloidal particles for delivering drugs or calories |
US5270005A (en) | 1990-09-07 | 1993-12-14 | Baxter International Inc. | Extracorporeal blood oxygenation system incorporating integrated reservoir-membrane oxygenerator-heat exchanger and pump assembly |
US5665379A (en) | 1990-09-28 | 1997-09-09 | Pharmacia & Upjohn Aktiebolag | Lipid particle forming matrix, preparation and use thereof |
CZ280909B6 (en) | 1990-11-02 | 1996-05-15 | Novartis Ag | Cyclosporins, their use when preparing a medicament for treating and prevention of aids, process of their preparation and mould strains usable in the process |
US5152997A (en) | 1990-12-11 | 1992-10-06 | Theratech, Inc. | Method and device for transdermally administering testosterone across nonscrotal skin at therapeutically effective levels |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
IT1245761B (en) | 1991-01-30 | 1994-10-14 | Alfa Wassermann Spa | PHARMACEUTICAL FORMULATIONS CONTAINING GLYCOSAMINOGLICANS ABSORBABLE ORALLY. |
US5300529A (en) | 1991-02-12 | 1994-04-05 | Isp Investments Inc. | Stable, clear, efficacious aqueous microemulsion compositions containing a high loading of a water-insoluble, agriculturally active chemical |
US5403593A (en) | 1991-03-04 | 1995-04-04 | Sandoz Ltd. | Melt granulated compositions for preparing sustained release dosage forms |
TW212139B (en) | 1991-04-15 | 1993-09-01 | Yamanouchi Pharma Co Ltd | |
US5688761A (en) | 1991-04-19 | 1997-11-18 | Lds Technologies, Inc. | Convertible microemulsion formulations |
WO1992018147A1 (en) | 1991-04-19 | 1992-10-29 | Affinity Biotech, Inc. | Convertible microemulsion formulations |
US5223268A (en) | 1991-05-16 | 1993-06-29 | Sterling Drug, Inc. | Low solubility drug-coated bead compositions |
US5380535A (en) | 1991-05-28 | 1995-01-10 | Geyer; Robert P. | Chewable drug-delivery compositions and methods for preparing the same |
US5698155A (en) | 1991-05-31 | 1997-12-16 | Gs Technologies, Inc. | Method for the manufacture of pharmaceutical cellulose capsules |
ZA925581B (en) | 1991-07-26 | 1993-05-14 | Smithkline Beecham Corp | Pharmaceutical microemulsions. |
WO1993006921A1 (en) | 1991-10-04 | 1993-04-15 | Gs Biochem Ab | Particles, method of preparing said particles and uses thereof |
JPH0597672A (en) | 1991-10-08 | 1993-04-20 | Terumo Corp | Amide derivative-containing solid preparation and its production |
SK279589B6 (en) | 1991-11-22 | 1999-01-11 | Procter And Gamble Pharmaceuticals | Delayed-release pharmaceutical composition for oral administration useful for the treatment of calcium and phosphate metabolism |
US5206219A (en) | 1991-11-25 | 1993-04-27 | Applied Analytical Industries, Inc. | Oral compositions of proteinaceous medicaments |
HUT63579A (en) | 1991-12-20 | 1993-09-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing double-phase pharmaceutical compositions suitable for treating diseases occurring during neurodegenerative processes |
GB9201857D0 (en) | 1992-01-29 | 1992-03-18 | Smithkline Beecham Plc | Novel compound |
US5571533A (en) | 1992-02-07 | 1996-11-05 | Recordati, S.A., Chemical And Pharmaceutical Company | Controlled-release mucoadhesive pharmaceutical composition for the oral administration of furosemide |
SE9200951D0 (en) | 1992-03-27 | 1992-03-27 | Kabi Pharmacia Ab | PHARMACEUTICAL COMPOSITION CONTAINING A DEFINED LIPID SYSTEM |
GB9212511D0 (en) | 1992-06-12 | 1992-07-22 | Cortecs Ltd | Pharmaceutical compositions |
IT1255449B (en) | 1992-06-30 | 1995-10-31 | Fabio Berlati | USE OF NOR- AND HOMO-DERIVATIVES OF BILE ACIDS AS DRUGS ABSORPTION PROMOTERS. |
PH30929A (en) | 1992-09-03 | 1997-12-23 | Janssen Pharmaceutica Nv | Beads having a core coated with an antifungal and a polymer. |
WO1994008610A1 (en) | 1992-10-16 | 1994-04-28 | Smithkline Beecham Corporation | Pharmaceutical emulsion compositions |
US5376688A (en) | 1992-12-18 | 1994-12-27 | R. P. Scherer Corporation | Enhanced solubility pharmaceutical solutions |
GB9300875D0 (en) | 1993-01-18 | 1993-03-10 | Ucb Sa | Nanocapsule containing pharmaceutical compositions |
US5686105A (en) | 1993-10-19 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
DE4312034A1 (en) | 1993-04-13 | 1994-10-20 | Hesch Rolf Dieter Prof Dr Med | Novel androgens and anabolic steroids |
TW438603B (en) | 1993-04-19 | 2001-06-07 | Advanced Skin Res Kenkyusho Kk | Microemulsion preparation containing peptide pharmaceuticals |
BE1006990A5 (en) | 1993-04-22 | 1995-02-07 | Univ Gent | METHOD AND COMPOSITION TO MAKE AN ACTIVE INGREDIENT IN A solid dosage form. |
DE69425453T2 (en) | 1993-04-23 | 2001-04-12 | Novartis Ag | Drug delivery device with controlled release |
NZ247516A (en) | 1993-04-28 | 1995-02-24 | Bernard Charles Sherman | Water dispersible pharmaceutical compositions comprising drug dissolved in solvent system comprising at least one alcohol and at least one surfactant |
US5639474A (en) | 1993-07-01 | 1997-06-17 | Hanmi Pharm. Ind., Ltd. | Cyclosporin soft capsule composition |
DE4322826A1 (en) | 1993-07-08 | 1995-01-12 | Galenik Labor Freiburg Gmbh | Pharmaceutical preparation |
ES2068762B1 (en) | 1993-07-21 | 1995-12-01 | Lipotec Sa | A NEW PHARMACEUTICAL PREPARATION TO IMPROVE THE BIOAVAILABILITY OF DRUGS OF DIFFICULT ABSORPTION AND PROCEDURE FOR THEIR OBTAINING. |
JPH0741422A (en) | 1993-07-30 | 1995-02-10 | Nissui Pharm Co Ltd | Method for solubilizing gamma-oryzanol in water |
TW359614B (en) | 1993-08-31 | 1999-06-01 | Takeda Chemical Industries Ltd | Composition containing benzimidazole compounds for rectal administration |
EP0995447A1 (en) | 1993-09-09 | 2000-04-26 | Takeda Chemical Industries, Ltd. | Formulation comprising antibacterial substance and antiulcer substance |
US6022852A (en) | 1993-10-22 | 2000-02-08 | Hexal Ag | Pharmaceutical composition containing cyclosporin A |
CA2176927C (en) | 1993-11-17 | 2010-03-23 | Seang H. Yiv | Transparent liquid for encapsulated drug delivery |
DE4340781C3 (en) | 1993-11-30 | 2000-01-27 | Novartis Ag | Liquid preparations containing cyclosporin and process for their preparation |
US5374446A (en) | 1993-12-10 | 1994-12-20 | Arco Chemical Technology, L.P. | Linked esterified alkoxylated polyols useful as reduced calorie fat substitutes |
KR0146671B1 (en) | 1994-02-25 | 1998-08-17 | 김충환 | Cyclosporin-containing powder composition |
US5811120A (en) | 1994-03-02 | 1998-09-22 | Eli Lilly And Company | Solid orally administerable raloxifene hydrochloride pharmaceutical formulation |
GB9405304D0 (en) | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
US5731355A (en) | 1994-03-22 | 1998-03-24 | Zeneca Limited | Pharmaceutical compositions of propofol and edetate |
GB9409778D0 (en) | 1994-05-16 | 1994-07-06 | Dumex Ltd As | Compositions |
US6692766B1 (en) | 1994-06-15 | 2004-02-17 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Controlled release oral drug delivery system |
SE518578C2 (en) | 1994-06-15 | 2002-10-29 | Gs Dev Ab | Lipid-based composition |
US5817320A (en) | 1994-06-20 | 1998-10-06 | The United States Of America As Represented By The Secretary Of The Agriculture | In ovo immunization of avian embryos with oil-emulsion vaccines |
US5616330A (en) | 1994-07-19 | 1997-04-01 | Hemagen/Pfc | Stable oil-in-water emulsions incorporating a taxine (taxol) and method of making same |
FR2722984B1 (en) | 1994-07-26 | 1996-10-18 | Effik Lab | PROCESS FOR THE PREPARATION OF DRY PHARMACEUTICAL FORMS AND THE PHARMACEUTICAL COMPOSITIONS THUS PRODUCED |
GB9417524D0 (en) | 1994-08-31 | 1994-10-19 | Cortecs Ltd | Pharmaceutical compositions |
SE518619C2 (en) | 1994-12-09 | 2002-10-29 | Gs Dev Ab | Controlled release composition containing monocaproin |
US5858398A (en) | 1994-11-03 | 1999-01-12 | Isomed Inc. | Microparticular pharmaceutical compositions |
US5965161A (en) | 1994-11-04 | 1999-10-12 | Euro-Celtique, S.A. | Extruded multi-particulates |
KR0167613B1 (en) | 1994-12-28 | 1999-01-15 | 한스 루돌프 하우스, 니콜 케르커 | Cyclosporin-containing soft capsule compositions |
US5545628A (en) | 1995-01-10 | 1996-08-13 | Galephar P.R. Inc. | Pharmaceutical composition containing fenofibrate |
US5629021A (en) | 1995-01-31 | 1997-05-13 | Novavax, Inc. | Micellar nanoparticles |
FR2730231B1 (en) | 1995-02-02 | 1997-04-04 | Fournier Sca Lab | COMBINATION OF FENOFIBRATE AND VITAMIN E, USE IN THERAPEUTICS |
US5560931A (en) | 1995-02-14 | 1996-10-01 | Nawosystems L.L.C. | Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids |
US5571536A (en) | 1995-02-06 | 1996-11-05 | Nano Systems L.L.C. | Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids |
US5573783A (en) | 1995-02-13 | 1996-11-12 | Nano Systems L.L.C. | Redispersible nanoparticulate film matrices with protective overcoats |
JP2740153B2 (en) | 1995-03-07 | 1998-04-15 | エフ・ホフマン−ラ ロシユ アーゲー | Mixed micelle |
US5653987A (en) | 1995-05-16 | 1997-08-05 | Modi; Pankaj | Liquid formulations for proteinic pharmaceuticals |
SI9500173B (en) | 1995-05-19 | 2002-02-28 | Lek, | Three-phase pharmaceutical form with constant and controlled release of amorphous active ingredient for single daily application |
US5698217A (en) * | 1995-05-31 | 1997-12-16 | Minnesota Mining And Manufacturing Company | Transdermal drug delivery device containing a desiccant |
US5726181A (en) | 1995-06-05 | 1998-03-10 | Bionumerik Pharmaceuticals, Inc. | Formulations and compositions of poorly water soluble camptothecin derivatives |
FR2737121B1 (en) | 1995-07-27 | 1997-10-03 | Cl Pharma | NEW GALENIC FORMULATIONS OF FENOFIBRATE AND THEIR APPLICATIONS |
DE19527661C2 (en) | 1995-07-28 | 1998-02-19 | Optrex Europ Gmbh | Carrier comprising electrical conductors with an electronic component and method for contacting conductors of a substrate with contact warts of an electronic component |
US5766629A (en) | 1995-08-25 | 1998-06-16 | Sangstat Medical Corporation | Oral cyclosporin formulations |
WO1998056357A1 (en) | 1995-12-19 | 1998-12-17 | Abbott Laboratories | A controlled release formulation for poorly soluble basic drugs |
US6645988B2 (en) | 1996-01-04 | 2003-11-11 | Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
US5858401A (en) | 1996-01-22 | 1999-01-12 | Sidmak Laboratories, Inc. | Pharmaceutical composition for cyclosporines |
JPH09241152A (en) | 1996-03-01 | 1997-09-16 | Sunstar Inc | Oil-in-water emulsion |
IL117773A (en) | 1996-04-02 | 2000-10-31 | Pharmos Ltd | Solid lipid compositions of coenzyme Q10 for enhanced oral bioavailability |
GB9608719D0 (en) | 1996-04-26 | 1996-07-03 | Scherer Ltd R P | Pharmaceutical compositions |
DE19619045C1 (en) | 1996-05-02 | 1997-11-13 | Jenapharm Gmbh | Use of combination products for the treatment of hypogonadal men and men with pituitary disorders |
US6057339A (en) | 1996-05-09 | 2000-05-02 | Bristol-Myers Squibb Company | Method of inhibiting or treating phytosterolemia with an MTP inhibitor |
AU2976897A (en) | 1996-06-18 | 1998-01-07 | Otsuka Pharmaceutical Co., Ltd. | Multiple-unit type prolonged action drug preparation |
US5846971A (en) | 1996-06-28 | 1998-12-08 | Schering Corporation | Oral antifungal composition |
PL330864A1 (en) | 1996-06-28 | 1999-06-07 | Schering Corp | Orally administered composition containing antimycotic compounds of triazole |
US5883109A (en) | 1996-07-24 | 1999-03-16 | Bristol-Myers Squibb Company | Method for lowering serum lipid levels employing an MTP inhibitor in combination with another cholesterol lowering drug |
ES2270948T3 (en) | 1996-07-30 | 2007-04-16 | Novartis Ag | PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF REPLACEMENT OF TRANSPLANTS, AS WELL AS THE AUTOIMMUNE OR INFLAMMATORY CONDITIONS. |
US6465016B2 (en) | 1996-08-22 | 2002-10-15 | Research Triangle Pharmaceuticals | Cyclosporiine particles |
CZ299790B6 (en) | 1996-08-22 | 2008-11-26 | Skyepharma Canada Inc. | Composition of microparticles of water-insoluble substance, pharmaceutical composition, process for preparing stable particles, microparticles of water-insoluble or poorly soluble substance per se, composition containing such microparticles and proce |
SE9603077D0 (en) | 1996-08-29 | 1996-08-29 | Tetra Laval Holdings & Finance | An apparatus for and method of performing an animal-related action regarding at least a portion of the body of an animal |
US5891469A (en) | 1997-04-02 | 1999-04-06 | Pharmos Corporation | Solid Coprecipitates for enhanced bioavailability of lipophilic substances |
US5798333A (en) | 1996-09-17 | 1998-08-25 | Sherman; Bernard C. | Water-soluble concentrates containing cyclosporins |
US6361796B1 (en) | 1996-10-25 | 2002-03-26 | Shire Laboratories, Inc. | Soluble form osmotic dose delivery system |
JP2001507700A (en) | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティック・システムズ | Hydrophobic aerosol drug |
US6458373B1 (en) | 1997-01-07 | 2002-10-01 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
US6066653A (en) | 1997-01-17 | 2000-05-23 | Bristol-Myers Squibb Co. | Method of treating acid lipase deficiency diseases with an MTP inhibitor and cholesterol lowering drugs |
GB9700878D0 (en) | 1997-01-17 | 1997-03-05 | Scherer Ltd R P | Dosage forms and method for ameliorating male erectile dysfunction |
FR2758459B1 (en) | 1997-01-17 | 1999-05-07 | Pharma Pass | FENOFIBRATE PHARMACEUTICAL COMPOSITION HAVING HIGH BIODAVAILABILITY AND PROCESS FOR PREPARING THE SAME |
RU2211047C2 (en) | 1997-01-30 | 2003-08-27 | Новартис Аг | Gelatin capsule with solid film including oil-free pharmaceutically compositions |
JP4713698B2 (en) | 1997-03-05 | 2011-06-29 | スージェン, インク. | Formulation of hydrophobic drugs |
IL131609A0 (en) | 1997-03-12 | 2001-01-28 | Abbott Lab | Hydrophilic binary systems for the administration of cyclosporine |
JPH1149664A (en) | 1997-04-18 | 1999-02-23 | Taisho Pharmaceut Co Ltd | Microemulsion |
CN1252711A (en) | 1997-04-18 | 2000-05-10 | 大正制药株式会社 | Microemulsion |
US5874418A (en) | 1997-05-05 | 1999-02-23 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use |
US6046177A (en) | 1997-05-05 | 2000-04-04 | Cydex, Inc. | Sulfoalkyl ether cyclodextrin based controlled release solid pharmaceutical formulations |
US5981586A (en) | 1997-05-23 | 1999-11-09 | Pershadsingh; Harrihar A. | Methods for treating proliferative and inflammatory skin diseases |
TW580397B (en) | 1997-05-27 | 2004-03-21 | Takeda Chemical Industries Ltd | Solid preparation |
IL133478A0 (en) | 1997-06-27 | 2001-04-30 | Astra Ab | Proliposome powders for inhalation stabilised by tocopherol |
BR9810866B1 (en) | 1997-07-29 | 2010-07-13 | pharmaceutical composition in a self-emulsifying formulation form for lipophilic compounds. | |
IT1294760B1 (en) | 1997-09-03 | 1999-04-12 | Jagotec Ag | PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL TABLETS ABLE TO RELEASE, ACCORDING TO PREDETERMINABLE SCHEMES, LITTLE ACTIVE INGREDIENTS |
KR100222918B1 (en) | 1997-09-04 | 1999-10-01 | 윤덕용 | Absorbent comprising of alkali salt and copper oxide deposited ñ-alumina |
CA2214895C (en) | 1997-09-19 | 1999-04-20 | Bernard Charles Sherman | Improved pharmaceutical composition comprising fenofibrate |
US6296876B1 (en) | 1997-10-06 | 2001-10-02 | Isa Odidi | Pharmaceutical formulations for acid labile substances |
US20050070516A1 (en) | 1997-10-28 | 2005-03-31 | Vivus Inc. | As-needed administration of an androgenic agent to enhance female desire and responsiveness |
US20020013304A1 (en) | 1997-10-28 | 2002-01-31 | Wilson Leland F. | As-needed administration of an androgenic agent to enhance female sexual desire and responsiveness |
US6027747A (en) | 1997-11-11 | 2000-02-22 | Terracol; Didier | Process for the production of dry pharmaceutical forms and the thus obtained pharmaceutical compositions |
US5891845A (en) | 1997-11-21 | 1999-04-06 | Fuisz Technologies Ltd. | Drug delivery systems utilizing liquid crystal structures |
JP4546643B2 (en) | 1997-12-08 | 2010-09-15 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | Novel suppository form containing an acid labile active compound |
WO1999029300A1 (en) | 1997-12-10 | 1999-06-17 | Rtp Pharma Inc. | Self-emulsifying fenofibrate formulations |
US6013665A (en) | 1997-12-16 | 2000-01-11 | Abbott Laboratories | Method for enhancing the absorption and transport of lipid soluble compounds using structured glycerides |
EP1049459B1 (en) | 1998-01-20 | 2009-04-22 | Applied Analytical Industries, Inc. | Oral liquid compositions |
US6086376A (en) | 1998-01-30 | 2000-07-11 | Rtp Pharma Inc. | Dry aerosol suspension of phospholipid-stabilized drug microparticles in a hydrofluoroalkane propellant |
FR2774591B1 (en) | 1998-02-12 | 2000-05-05 | Lipha | PHARMACEUTICAL COMPOSITION COMPRISING THE ASSOCIATION OF METFORMIN AND FIBRATE AND THE USE THEREOF FOR THE PREPARATION OF MEDICINES FOR REDUCING HYPERGLYCEMIA |
ID25908A (en) | 1998-03-06 | 2000-11-09 | Novartis Ag | EMULSION PRACTONCENTRATES CONTAINING CYCLOSPORINE OR MACROLIDES |
DK173431B1 (en) | 1998-03-20 | 2000-10-23 | Gea Farmaceutisk Fabrik As | Pharmaceutical formulation comprising a 2 - [[(2-pyridinyl) methyl] sulfinyl] benzimidazole with anti-ulcer activity and progress |
CA2268211A1 (en) | 1998-04-13 | 1999-10-13 | Medical College Of Hampton Roads | Control of selective estrogen receptor modulators |
AU3731699A (en) | 1998-05-18 | 1999-12-06 | Takeda Chemical Industries Ltd. | Orally disintegrable tablets |
EP1015046A2 (en) | 1998-07-14 | 2000-07-05 | Em Industries, Inc. | Microdisperse drug delivery systems |
ES2157731B1 (en) | 1998-07-21 | 2002-05-01 | Liconsa Liberacion Controlada | ORAL PHARMACEUTICAL PREPARATION OF AN ANTIFUNGIC ACTIVITY COMPOUND AND PROCEDURE FOR PREPARATION. |
US6174547B1 (en) | 1999-07-14 | 2001-01-16 | Alza Corporation | Dosage form comprising liquid formulation |
FR2783421B1 (en) | 1998-09-17 | 2000-11-24 | Cll Pharma | PROCESS FOR THE PREPARATION OF NOVEL GALENIC FORMULATIONS OF FENOFIBRATE, GALENIC FORMULATIONS OBTAINED BY SAID PROCESS AND THEIR APPLICATIONS |
US5993880A (en) | 1998-10-01 | 1999-11-30 | Kraft Foods Inc. | Non-staining, acid-stable, cold-water-soluble, edible green color and compositions for preparing acidic foods and beverages |
US6977083B1 (en) | 1998-10-02 | 2005-12-20 | Jenapharm Gmbh & Co. Kg | Bioadhesive tablet containing testosterone/testosterone ester mixtures and method for producing a predetermined testosterone time-release profile with same |
PE20001227A1 (en) | 1998-10-30 | 2000-11-06 | Hoffmann La Roche | PROCESSES TO PRODUCE AN ISOTRETINOIN COMPOSITION |
EP1140036A2 (en) | 1998-12-18 | 2001-10-10 | Abbott Laboratories | Novel formulations comprising lipid-regulating agents |
US6180138B1 (en) | 1999-01-29 | 2001-01-30 | Abbott Laboratories | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption |
US6383517B1 (en) | 1999-01-29 | 2002-05-07 | Abbott Laboratories | Process for preparing solid formulations of lipid-regulating agents with enhanced dissolution and absorption |
US6447806B1 (en) | 1999-02-25 | 2002-09-10 | Novartis Ag | Pharmaceutical compositions comprised of stabilized peptide particles |
US20030104048A1 (en) | 1999-02-26 | 2003-06-05 | Lipocine, Inc. | Pharmaceutical dosage forms for highly hydrophilic materials |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US6267985B1 (en) | 1999-06-30 | 2001-07-31 | Lipocine Inc. | Clear oil-containing pharmaceutical compositions |
US6294192B1 (en) | 1999-02-26 | 2001-09-25 | Lipocine, Inc. | Triglyceride-free compositions and methods for improved delivery of hydrophobic therapeutic agents |
US6761903B2 (en) | 1999-06-30 | 2004-07-13 | Lipocine, Inc. | Clear oil-containing pharmaceutical compositions containing a therapeutic agent |
US7374779B2 (en) | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
WO2000057918A2 (en) | 1999-03-31 | 2000-10-05 | Abbott Laboratories | Novel formulations comprising lipid-regulating agents |
MXPA01009840A (en) | 1999-03-31 | 2002-06-21 | Abbott Lab | Novel formulations comprising lipid-regulating agents. |
GB9907715D0 (en) | 1999-04-01 | 1999-05-26 | Scherer Corp R P | Pharmaceutical compositions |
US6652880B1 (en) | 1999-04-01 | 2003-11-25 | R.P. Scherer Technologies, Inc. | Oral pharmaceutical compositions containing long-chain triglycerides and liphophilic surfactants |
WO2000059512A1 (en) | 1999-04-01 | 2000-10-12 | Akzo Nobel N.V. | Formulation comprising testosteron undecanoate and castor oil |
US6383471B1 (en) | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
EP1185301A1 (en) | 1999-05-24 | 2002-03-13 | Sonus Pharmaceuticals, Inc. | Emulsion vehicle for poorly soluble drugs |
GB9912476D0 (en) | 1999-05-28 | 1999-07-28 | Novartis Ag | Organic compounds |
US6465011B2 (en) | 1999-05-29 | 2002-10-15 | Abbott Laboratories | Formulations comprising lipid-regulating agents |
US6372251B2 (en) | 1999-06-11 | 2002-04-16 | Abbott Laboratories | Formulations comprising lipid-regulating agents |
US6458383B2 (en) | 1999-08-17 | 2002-10-01 | Lipocine, Inc. | Pharmaceutical dosage form for oral administration of hydrophilic drugs, particularly low molecular weight heparin |
US20030236236A1 (en) | 1999-06-30 | 2003-12-25 | Feng-Jing Chen | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US6309663B1 (en) | 1999-08-17 | 2001-10-30 | Lipocine Inc. | Triglyceride-free compositions and methods for enhanced absorption of hydrophilic therapeutic agents |
US6982281B1 (en) | 2000-11-17 | 2006-01-03 | Lipocine Inc | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
US20030235595A1 (en) | 1999-06-30 | 2003-12-25 | Feng-Jing Chen | Oil-containing, orally administrable pharmaceutical composition for improved delivery of a therapeutic agent |
AR024462A1 (en) | 1999-07-01 | 2002-10-02 | Merck & Co Inc | PHARMACEUTICAL TABLETS |
WO2001021154A2 (en) | 1999-09-21 | 2001-03-29 | Rtp Pharma Inc. | Surface modified particulate compositions of biologically active substances |
US6228400B1 (en) | 1999-09-28 | 2001-05-08 | Carlsbad Technology, Inc. | Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same |
US6720001B2 (en) | 1999-10-18 | 2004-04-13 | Lipocine, Inc. | Emulsion compositions for polyfunctional active ingredients |
US20030180352A1 (en) | 1999-11-23 | 2003-09-25 | Patel Mahesh V. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US20060034937A1 (en) | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
EP1108425B1 (en) | 1999-12-16 | 2005-06-08 | Laboratorio Medinfar-Produtos Farmaceuticos, S.A. | New stable multi-unitary pharmaceutical preparations containing substituted benzimidazoles |
PT1239831E (en) | 1999-12-23 | 2013-01-23 | Mayne Pharma International Pty Ltd | Improved pharmaceutical compositions for poorly soluble drugs |
WO2001047495A1 (en) | 1999-12-23 | 2001-07-05 | Pfizer Products Inc. | Pharmaceutical compositions providing enhanced drug concentrations |
US6340471B1 (en) | 1999-12-30 | 2002-01-22 | Alvin Kershman | Method for preparing solid delivery system for encapsulated and non-encapsulated pharmaceuticals |
FR2803203B1 (en) | 1999-12-31 | 2002-05-10 | Fournier Ind & Sante | NEW GALENIC FORMULATIONS OF FENOFIBRATE |
US20020102301A1 (en) | 2000-01-13 | 2002-08-01 | Joseph Schwarz | Pharmaceutical solid self-emulsifying composition for sustained delivery of biologically active compounds and the process for preparation thereof |
US7025979B2 (en) | 2000-02-15 | 2006-04-11 | Schering Ag | Male contraceptive formulation comprising norethisterone |
US6468559B1 (en) | 2000-04-28 | 2002-10-22 | Lipocine, Inc. | Enteric coated formulation of bishosphonic acid compounds and associated therapeutic methods |
WO2002000261A2 (en) | 2000-06-26 | 2002-01-03 | Monsanto Technology Llc | Surfactant-containing formulations for extended release of somatotropin |
BR0106942A (en) | 2000-07-07 | 2002-06-11 | Baxter Int | Medical system, method and apparatus using mems |
EP1313511B1 (en) | 2000-08-23 | 2005-11-30 | Akzo Nobel N.V. | Testosterone ester formulation for human use |
US20040002482A1 (en) | 2000-08-30 | 2004-01-01 | Dudley Robert E. | Androgen pharmaceutical composition and method for treating depression |
US6503894B1 (en) | 2000-08-30 | 2003-01-07 | Unimed Pharmaceuticals, Inc. | Pharmaceutical composition and method for treating hypogonadism |
JP4637338B2 (en) | 2000-09-22 | 2011-02-23 | 大塚製薬株式会社 | Cilostazol dry coated tablets |
US6887493B2 (en) | 2000-10-25 | 2005-05-03 | Adi Shefer | Multi component controlled release system for oral care, food products, nutraceutical, and beverages |
US6589562B1 (en) | 2000-10-25 | 2003-07-08 | Salvona L.L.C. | Multicomponent biodegradable bioadhesive controlled release system for oral care products |
US20020103139A1 (en) | 2000-12-01 | 2002-08-01 | M. Weisspapir | Solid self-emulsifying controlled release drug delivery system composition for enhanced delivery of water insoluble phytosterols and other hydrophobic natural compounds for body weight and cholestrol level control |
US20060142257A1 (en) | 2001-01-19 | 2006-06-29 | Eberhard Nieschlag | Male contraceptive formulation comprising norethisterone |
DE10164844B4 (en) | 2001-02-22 | 2005-05-25 | Aquanova German Solubilisate Technologies (Agt) Gmbh | Tocopherol concentrate |
AUPR573001A0 (en) | 2001-06-15 | 2001-07-12 | Glaxo Wellcome Australia Ltd | Lymphatic drug delivery system |
US20030022875A1 (en) | 2001-07-27 | 2003-01-30 | Wilson Leland F. | As-needed administration of orally active androgenic agents to enhance female sexual desire and responsiveness |
US6665880B2 (en) | 2001-11-01 | 2003-12-23 | Kimberly-Clark Worldwide, Inc. | Protective garments with glove flaps |
US6630134B1 (en) | 2002-01-08 | 2003-10-07 | Zenitech Llc | Guerbet wax esters in personal care applications |
ATE395044T1 (en) | 2002-02-01 | 2008-05-15 | Pfizer Prod Inc | PHARMACEUTICAL COMPOSITIONS OF AMORPHIC DISPERSIONS OF ACTIVE INGREDIENTS AND LIPOPHILIC MICROPHASE-FORMING MATERIALS |
US20030186892A1 (en) | 2002-03-28 | 2003-10-02 | Rajneesh Taneja | Enhancement of endogenous gonadotropin production |
US20040002445A1 (en) | 2002-03-28 | 2004-01-01 | Rajneesh Taneja | Enhancement of endogenous gonadotropin production |
US20050287203A1 (en) | 2002-05-08 | 2005-12-29 | Nijs De H | Formulation comprising testosteron undecanoate and castor oil |
US20040127476A1 (en) | 2002-11-14 | 2004-07-01 | Alvin Kershman | Oral testosterone delivery system with improved sustained release |
US20040115287A1 (en) | 2002-12-17 | 2004-06-17 | Lipocine, Inc. | Hydrophobic active agent compositions and methods |
US20050100608A1 (en) | 2003-02-21 | 2005-05-12 | Watson Pharmaceuticals, Inc. | Testosterone oral dosage formulations and associated methods |
JO2505B1 (en) * | 2003-03-14 | 2009-10-05 | باير شيرنغ فارما اكتنجيسيلشافت | method and pharmaceutical compositions for reliable achievements of acceptable serum testosterone levels |
US6913244B1 (en) | 2003-05-02 | 2005-07-05 | Gordon Edgar Atkinson | Urinary slide valve |
DE602004017198D1 (en) | 2003-08-04 | 2008-11-27 | Camurus Ab | METHOD FOR LOADING AMPHIPHILIC PARTICLES WITH ACTIVE SUBSTANCES |
ATE540671T1 (en) | 2003-08-04 | 2012-01-15 | Bend Res Inc | PHARMACEUTICAL COMPOSITIONS OF AMORPHOUS DRUG ADSORBATES AND LIPOPHILIC MICROPHASE-FORMING MATERIALS |
US20050080075A1 (en) | 2003-08-25 | 2005-04-14 | Nichols M. James | Formulations, conjugates, and combinations of drugs for the treatment of neoplasms |
US7658944B2 (en) | 2003-10-10 | 2010-02-09 | Lifecycle Pharma A/S | Solid dosage form comprising a fibrate |
US20050096365A1 (en) | 2003-11-03 | 2005-05-05 | David Fikstad | Pharmaceutical compositions with synchronized solubilizer release |
US20060003002A1 (en) | 2003-11-03 | 2006-01-05 | Lipocine, Inc. | Pharmaceutical compositions with synchronized solubilizer release |
US7138389B2 (en) | 2004-02-09 | 2006-11-21 | University Of Washington | Oral androgen therapy using modulators of testosterone bioavailability |
US20050220825A1 (en) | 2004-03-10 | 2005-10-06 | Adrian Funke | Molecular dispersions of drospirenone |
EP1761265A2 (en) | 2004-06-28 | 2007-03-14 | ALZA Corporation | A drug/polymer complex, preferably ciprofloxacin/hpmc, its method of manufacturing using lyophilization and its use in an osmotic device |
US20060051406A1 (en) | 2004-07-23 | 2006-03-09 | Manjeet Parmar | Formulation of insoluble small molecule therapeutics in lipid-based carriers |
US8541400B2 (en) | 2004-08-04 | 2013-09-24 | Camurus Ab | Compositions forming non-lamellar dispersions |
US20060106004A1 (en) | 2004-11-12 | 2006-05-18 | Brody Steven A | Unique methods and formulations of bio-identical sex steroids for the treatment of pathophysiologic aberrations of menopause |
US20060134210A1 (en) | 2004-12-22 | 2006-06-22 | Astrazeneca Ab | Solid dosage form comprising proton pump inhibitor and suspension made thereof |
WO2006105615A1 (en) | 2005-04-08 | 2006-10-12 | Ozpharma Pty Ltd | Buccal delivery system |
US20070154533A1 (en) | 2005-04-13 | 2007-07-05 | Dudley Robert E | Method of increasing testosterone and related steriod concentrations in women |
US8492369B2 (en) | 2010-04-12 | 2013-07-23 | Clarus Therapeutics Inc | Oral testosterone ester formulations and methods of treating testosterone deficiency comprising same |
KR20080009201A (en) * | 2005-04-15 | 2008-01-25 | 클라루스 쎄러퓨틱스, 아이엔씨. | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
CN101217963A (en) | 2005-04-15 | 2008-07-09 | 克劳拉斯医疗有限公司 | Pharmaceutical delivery systems for hydrophobic drugs and compositions comprising same |
US20100148675A1 (en) | 2005-06-30 | 2010-06-17 | Koninklijke Philips Electronics, N.V. | Method and system for controlling the output of a luminaire |
US7400031B2 (en) | 2005-09-19 | 2008-07-15 | International Business Machines Corporation | Asymmetrically stressed CMOS FinFET |
FR2895679B1 (en) * | 2005-12-29 | 2012-06-08 | Pf Medicament | STABILIZATION OF TESTOSTERONE IN TRANSDERMAL DEVICES |
WO2007100614A2 (en) | 2006-02-24 | 2007-09-07 | Scidose, Llc | STABLE NON-CRYSTALLINE FORMULATION COMPRISING HMG-CoA REDUCTASE INHIBITOR |
JP5194209B2 (en) | 2007-10-18 | 2013-05-08 | 日本フェンオール株式会社 | Semiconductor processing unit and semiconductor manufacturing apparatus |
WO2009088673A2 (en) | 2007-12-17 | 2009-07-16 | Alpharma Pharmaceuticals, Llc | Pharmaceutical composition |
GB0807605D0 (en) | 2008-04-28 | 2008-06-04 | Diurnal Ltd | Lipid composition |
US20130225544A1 (en) * | 2009-01-08 | 2013-08-29 | Lipocine Inc. | Lipobalanced long chain testosterone esters for oral delivery |
US20140288039A1 (en) * | 2009-01-08 | 2014-09-25 | Lipocine Inc. | Lipobalanced long chain testosterone prodrugs for oral delivery |
US11304960B2 (en) | 2009-01-08 | 2022-04-19 | Chandrashekar Giliyar | Steroidal compositions |
EP2229936B1 (en) | 2009-03-09 | 2015-05-06 | PharmaSol GmbH | Nanonized testosterone formulations for improved bioavailability |
EP2682111A1 (en) | 2009-12-31 | 2014-01-08 | Differential Drug Development Associates LLC | Modulation of solubility, stability, absorption, metabolism, and pharmacokinetic profile of lipophilic drugs by sterols |
US20110263552A1 (en) | 2009-12-31 | 2011-10-27 | Sov Therapeutics | Modulation of side effect profile of 5-alpha reductase inhibitor therapy |
RU2012142997A (en) | 2010-04-12 | 2014-06-20 | Кларус Терапеутикс, Инк. | ORAL PHARMACEUTICAL COMPOSITIONS OF TESTOSTERONE ETHERS AND METHODS FOR TREATING A TESTOSTERONE DEFICIENCY WITH THEIR USE |
US9358241B2 (en) | 2010-11-30 | 2016-06-07 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US9034858B2 (en) | 2010-11-30 | 2015-05-19 | Lipocine Inc. | High-strength testosterone undecanoate compositions |
US20120135074A1 (en) | 2010-11-30 | 2012-05-31 | Chandrashekar Giliyar | High-Strength Testosterone Undecanoate Compositions |
US20120148675A1 (en) | 2010-12-10 | 2012-06-14 | Basawaraj Chickmath | Testosterone undecanoate compositions |
WO2016033556A1 (en) * | 2014-08-28 | 2016-03-03 | Lipocine Inc. | BIOAVAILABLE SOLID STATE (17-β)-HYDROXY-4-ANDROSTEN-3-ONE ESTERS |
-
2015
- 2015-08-28 US US15/507,754 patent/US20170246187A1/en not_active Abandoned
- 2015-08-28 WO PCT/US2015/047579 patent/WO2016033549A2/en active Application Filing
-
2019
- 2019-03-27 US US16/367,091 patent/US11707467B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
US20190350943A1 (en) | 2019-11-21 |
WO2016033549A3 (en) | 2016-05-26 |
US11707467B2 (en) | 2023-07-25 |
WO2016033549A2 (en) | 2016-03-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11298365B2 (en) | Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters | |
US20190388434A1 (en) | (17-ß)-3-Oxoandrost-4-En-17-Yl Undecanoate Compositions and Methods of Their Preparation and Use | |
US20190175615A1 (en) | Lipobalanced long chain testosterone esters for oral delivery | |
CN114026106A (en) | Abiraterone prodrugs | |
US20190240235A1 (en) | Lipobalanced long chain testosterone esters for oral delivery | |
US20220332753A1 (en) | (17-)-3-Oxoandrost-4-EN-17-YL Dodecanoate Compositions and Methods of Preparation and Use | |
AU2019200097B2 (en) | Lipobalanced long chain testosterone esters for oral delivery | |
KR20200052280A (en) | Pharmaceutical composition | |
CA3189989A1 (en) | Abiraterone prodrugs | |
US11707467B2 (en) | (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use | |
CN114555056A (en) | Micromolecular PI4KIII alpha inhibitor composition, preparation method and application thereof | |
WO2024005770A1 (en) | (17-)-3-oxoandrost-4-en-17-yl dodecanoate compositions and methods of preparation and use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: LIPOCINE INC., UTAH Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PATEL, MAHESH V.;CHIDAMBARAM, NACHIAPPAN;NACHAEGARI, SATISH KUMAR;AND OTHERS;SIGNING DATES FROM 20161219 TO 20161228;REEL/FRAME:041688/0039 Owner name: LIPOCINE INC., UTAH Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:PATEL, MAHESH V.;CHIDAMBARAM, NACHIAPPAN;NACHAEGARI, SATISH KUMAR;AND OTHERS;REEL/FRAME:041688/0153 Effective date: 20161228 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |