OA16937A - Stabilized pharmaceutical formulations of a potent HCV inhibitor. - Google Patents
Stabilized pharmaceutical formulations of a potent HCV inhibitor. Download PDFInfo
- Publication number
- OA16937A OA16937A OA1201400281 OA16937A OA 16937 A OA16937 A OA 16937A OA 1201400281 OA1201400281 OA 1201400281 OA 16937 A OA16937 A OA 16937A
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- OA
- OAPI
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- composition
- compound
- température
- liquid pharmaceutical
- pharmaceutical composition
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- 229960004274 Stearic acid Drugs 0.000 description 1
- 229960005137 Succinic Acid Drugs 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-N Sulfamic acid Chemical compound NS(O)(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N Sulfanilic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N Tetraethylammonium Chemical class CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 229960004559 Theobromine Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N Tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
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- 229940021016 Vitamin IV solution additives Drugs 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 230000000111 anti-oxidant Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 235000006682 bigleaf mint Nutrition 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 230000002596 correlated Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 229940042397 direct acting antivirals Cyclic amines Drugs 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000003116 impacting Effects 0.000 description 1
- 238000000126 in silico method Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000009114 investigational therapy Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000006679 mint Nutrition 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000001139 pH measurement Methods 0.000 description 1
- 229920003175 pectinic acid Polymers 0.000 description 1
- 229960003424 phenylacetic acid Drugs 0.000 description 1
- 239000003279 phenylacetic acid Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
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- 229920000768 polyamine Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000003168 reconstitution method Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010517 secondary reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
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- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Abstract
Described are various methods for stabilizing pharmaceutical formulations of a specific Hepatitis C Viral (HCV) inhibitor against the formation of a particular genotoxic degradation product. Such methods include temperature control, moisture control, excipient control, capsule shell control, basification and a reconstitution approach.
Description
STABILIZED PHARMACEUTICAL FORMULATIONS OF A POTENT HCV INHIBITOR
TECHNICAL FIELD OF THE INVENTION
The présent application is directed to various methods for stabilizing pharmaceutical formulations of a spécifie Hepatitis C Viral (HCV) inhibitor against the formation of a particular genotoxic dégradation product.
BACKGROUND OF THE INVENTION
The following Compound (I):
having the chemical name: l-{[4-[8-Bromo-2-(2-isopropylcarbamoyl-thiazoI-4-yI)-7methoxy-quinolin-4-yloxy]-l-(R)-(2-cyclopentyloxycarbonyl amino-3,3-(S)-dimethyIbutyryl)-pyrrolidine-(S)-2-carbonyl]-amino)-2-(S)-vinyl-cyclopropane-(R)-carboxylic__.
v/
-I16937 acid, is known as a sélective and potent inhibitor of the HCV NS3 serine protease and useful in the treatment of HCV infection. Compound (1) fails within the scope of the acyclic peptide sériés of HCV inhibitors disclosed in U.S. Patents 6,323,180, 7,514,557 and 7,585,845. Compound (1) is disclosed specifically as Compound # 1055 in U.S. Patent 7,585,845, and as Compound # 1008 in U.S. Patent 7,514,557. Compound (1), and pharmaceutical formulations thereof, can be prepared according to the general procedures found in the above-cited references, ail of which are herein incorporated by référencé in their entirety. Preferred forrns of Compound (1) include the pharmaceutically acceptable salts thereof and crystalline forrns thereof, and in particular the crystalline sodium sait form as described in U.S. Patent Application Publication No. 2010/0093792, also incorporated herein by référencé. The sodium sait form of Compound (1) (referred to herein at ‘‘Compound (1) NA) in currently in clinical trials for the treatment of HCV infection.
One type of pharmaceutical formulation that has been developed for formulating Compound (1) NA is a Self-Emulsifying Drug Delivery (SEDDs) formulation in the form of a 1 iquid-filled soft-gel capsule packaged in induction sealed HDPE bottles. Examples of this type of formulation can be found in U.S. Patent Application Publication No. US 2011/0160149. It has been discovered that upon storage of this formulation a potentially genotoxic dégradation product, referred to herein as “Compound X”, is formed from the parent drug molécule via the amide hydrolysis reaction shown below in Scheme I. Another type of pharmaceutical formulation that has been developed is an oral solution formulation designed for pédiatrie use, and it has been confirmed that this formulation is also prone to the formation of the Compound X dégradation product during storage. Examples of this type of formulation can be found in WO 2010/059667. While amide hydrolysis is a known mechanism of dégradation, it was not intuitive or expected that this spécifie dégradation product would form in these formulations and that this spécifie dégradation product would also be an Ames positive compound and genotoxic. In fact, Compound X was not predicted to be genotoxic based on standard in-silico prédiction software analysis. This unexpected discovery constitutes one aspect of the présent invention. *>7^
-216937
Compound X may also be depicted by the following chemical structure showing the stereochemistry at the two chiral centers in this molécule:
to
Due to the high potential toxicity of the Compound X, the increase in this impurity over the product shelf life duration was deemed unacceptable from a regulatory perspective and 15 thus there was an urgent need to solve this problem. For example, the EMEA (European
Medicines Agency) Guideline on the Limits of Genotoxic Impurities (28 June 2006) spécifiés a maximum intake value of 1.5 pg/day of a genotoxic impurity as being associated with an acceptable risk (1 in 100,000 increased cancer risk) for most marketed pharmaceuticals based on a lifetime exposure duration. For short duration treatment regimens higher levels of genotoxic impurities may be acceptable based on application of Haber’s rule (fondamental concept in toxicology) to extrapolate acceptable limits for daily intake for shorter treatment durations (Felter et al, Critical Reviews in Toxicology, 2011) without changing the associated level of cancer risk. For example, in its subséquent guidance document issued on 26 June 2008, the EMEA’s CHMP Safety Working Party indicated that the acceptable limits for daily intake of genotoxic impurities during clinical trials (1 in 1 million increased cancer risk plus an additional dose rate correction factor of 2) are 5,10,20, and 60pg/day for a duration of exposure of 6-12 months, 3-6 months, 1-3 months, and less than 1 month, respectively. Since the treatment regimen with Compound ( 1 ) NA may be as short as 12 weeks (~3 months) or 24 weeks (-6 months), maximum allowable intake values for Compound X may be as high as 20pg/day (3 month regimen) or 10pg/day (6 month regimen) when applying a 1 in 1 million increased cancer risk and a dose rate correction factor of 2. Taking into considération the benefit of an approved marketed product, the maximum allowable intake values for Compound X may be as high t5 as the calculated acceptable limit of400 pg/day (3 month regimen) or 200pg/day (6 month regimen) when applying a 1 in 100,000 increased cancer risk level. Thus, one goal of the présent invention was to develop techniques to ensure that the maximum intake value of this dégradation product would be maintained below these regulatory limits.
Prior to the discovery that Compound X was an Ames positive dégradation product, the stability of Compound (1) NA drug products was controlled by standard product packaging (HDPE bottle with induction seal) and room température storage. Such conditions were considered sufïîcient to allow for the desired commercial product shelf life. As noted above, current regulatory requirements for controlling potentially genotoxic impurities limit such impurities to levels much lower than standard impurities. The discovery that Compound X was Ames positive and genotoxic required the development of further contrôle to insure the lowest possible levels of Compound X in the drug product for patient safety and to meet requirements of regulatory authorities. —
-416937
BRIEF SUMMARY OF THE INVENTION
The présent application is directed to various methods for controlling the level of the dégradation product Compound X in liquid pharmacueutical compositions comprising Compound (1), or a pharmaceutically acceptable sait thereof, and to the resulting stabilized pharmacueutical compositions.
In a general embodiment, the présent invention is directed to a method for controlling the level of dégradation product Compound X in a liquid pharmaceutical composition comprising a Compound (1), or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, said method comprising one or more of the following:
(a) drying said composition such that it has a water content ofless than about 3.0 % w/w and storing the composition under conditions suflîcient to maintain a water content of less than about 3.0 % w/w;
(b) storing said composition at a température of between about 2 and 8 degrees Celsius;
(c) adding a basifier to said composition to achieve an internai apparent pH of greater than about 7; or (d) if the liquid pharmaceutical composition is to contain water as an excipient material, preparing a first formulation pre-mixture comprising only Compound (1), or pharmaceutically acceptable sait thereof, and non-aqueous based excipients and a second formulation pre-mixture comprising water as an excipient, and then mixing the first and second formulation pre-mixtures to préparé the final formulation just prior to patient use.
Additional embodiments are directed to liquid pharmaceutical composition comprising a
Compound (I), or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, wherein the amount of dégradation product
Compound X in the composition is below a level of about 400 pg, or below a level of about 200 pg, or below a level of about 60 pg, or below a level of about 20 pg, when the composition contains a full daily dose of Compound (1 ) or pharmaceutically acceptable χ'
-516937 sait thereof in either single or multiple dosage units. And in a more spécifie embodiment, the composition has one or more of the following properties:
(a) a water content of less than about 3.0 % w/w;
(b) an internai température of between about 2 and 8 degrees Celsius; or (c) an internai apparent pH of greater than about 7.
Additional embodiments are directed to the above methods and compositions wherein the total resulting amount of dégradation product in the composition is below a level of about
1.5 pg when the composition contains a full daily dose of Compound (1), or pharmaceutically acceptable sait thereof, in either single or multiple dosage units.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the Compound X formation and stability over a 24 month period under different température conditions for a batch of 120 mg capsules of Compound (1 ) NA.
Figure 2 depicts the Compound X formation and stability over a 24 month period at room température for 120 mg capsules of Compound (i) NA having different levels of fill water content.
Figure 3 shows the combined effect of storage température and fill water content for 120 mg capsules of Compound (1) NA on Compound X formation and stability over a 12 month period.
Figure 4A is a graphie représentation of a blister packaging system incorporating a desiccant in the product packaging, and the affect on water transmission.
Figure 4B shows a more detailed depiction of a capsule in an exemplary polymer blister packaging system and the water transmission in such system —
-616937
Figure 5 depicts the changes in relative humîdity over time within the pouch and within the polymer blister cavity and the changes in moisture content within the capsule fill formulation for a packaging system comprising an aluminum pouch containing a conditioned desiccant and capsules enclosed in a polymer blister.
Figure 6 shows Compound X stability over a 24 month period under refrigerated conditions (4-5°C) for 120 mg capsules of Compound (1) NA having different levels of fill water content,
Figure 7 shows three different oral solution formulations of Compound (1 ) NA designed for employing three different dégradation product control methods ofthe présent invention.
DETAILED DESCRIPTION OF THE INVENTION t5 Définitions
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in lhe art in light of the disclosure and the context. As used throughout the présent application, however, unless specifïed to the contrary, the following 20 terms hâve the meaning îndicated:
The term “about” means within 5%, and more preferably within 1% of a given value or range. For example, “about 3.7%” means from 3.5 to 3.9%, preferably from 3.66 to 3.74%. When the term “about is associated with a range of values, e.g., “about X% to
Y%”, the term “aboul” is intended to modify both the lower (X) and upper (Y) values of the recited range. For example, “about 20% to 40%” is équivalent to “about 20% to about 40%’’.
The term pharmaceutically acceptable sait means a sait of a Compound of formula (1) which is, within the scope of Sound medical judgment, suitable for use in contact with the tissues of humans and lower animais without undue toxicity, irritation, allergie response,
-716937 and the like, commensurate with a reasonable benefit/risk ratio, generally water or oilsoluble or dispersible, and effective for their intended use.
The term includes pharmaceutically-acceptable acid addition salts and pharmaceuticallyacceptable base addition salts. Lists of suitabie salts are found in, e.g., S. M. Birge et al., J. Pharm. Sci., 1977,66, pp. 1-19.
The term pharmaceutically-acceptable acid addition sait means those salts which retain the biological efTectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethane-sulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like.
The term pharmaceutically-acceptable base addition sait means those salts which retain the biological efTectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a métal cation such as sodium, potassium, lithium, calcium, magnésium, iron, zinc, copper, manganèse, aluminum, and the like. Particularly preferred are the ammonium, potassium, sodium, calcium, and magnésium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quatemary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-8 exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, Nethylpiperidine, tétraméthylammonium compounds, tetraethylammonium compounds, pyridine, Ν,Ν-dimethylaniline, N-methyl pi péri dîne, N-methylmorpholine, dicyclohexylamine, dibenzylamine, Ν,Ν-dibenzylphenethylamine, 1-ephenamine, N,N’dibenzylethylenediamine, polyamine resins, and the like. Particularly preferred organic nontoxic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
Formation of the Compound X Dégradation Product
As noted previously, the basis for the présent invention was the discovery that a spécifie dégradation product, Compound X, is formed upon storage of a liquid formulation containing Compound (1) NA and that this spécifie dégradation product is Ames positive and genotoxic. This was unknown prior to the présent invention. As a direct resuit of this discovery, it became apparent that additional control methods would be necessary to control the level of Compound X formation in the drug product in order to meet regulatory requirent ents.
It is known that the rates of many chemical reactions increase with température and moisture. For this reason, several commercial SEDDs capsule formulations eg. tipranavir soft gel capsules, are stored under réfrigération or protected from moisture using induction sealed packaging in order to provide for increased stability and/or shelf life. For the Compound (1) NA SEDDs drug product, following the discovery that Compound X.is formed and is genotoxic, the kinetics ofthe formation of this dégradation product were studied and were found to be a function of température. Investigations into the mechanism of formation suggest that Compound X is formed via acid catalyzed amide hydrolysis (see Scheme I above) and so increased levels of moisture would also be expected to drive the formation ofCompound X. This has been confirmed in studies ofCompound (I) NA
-916937 capsules manufactured with various levels offill formulation water content. Ail product stabiiity and experimental studies conducted to date hâve demonstrated that Compound X levels increased with higher températures and are significantly higher with moisture ingress. Thus, température and moisture control methods consitute aspects of the présent 5 invention. Additional control methods that hâve been discovered are discussed in detail below.
Compound X Dégradation Product Control Methods
The various control methods that hâve been developed to address the Compound X dégradation product issue, include the following methods, each of which is discussed in more detail below:
1. Température Control
2. Moisture Control
3. Excipient Control
4. Capsule Shell Control
5. Basification
6. Reconstitution Approach
1. Température Control
The initial hydrolysis formation reaction that produces Compound X from Compound (1) NA has been demonstrated to be température dépendent. As such, réfrigération can be used to reduce the rate of Compound X formation in liquid formulations by directly slowing the rate of the hydrolysis reaction. A suitable preferred température range for réfrigération of such liquid formulation is between about 2 and 8 degrees Celsius and as such constitutes a preferred embodiment of the invention. Under refrigerated conditions the rate of Compound X formation cornes into balance with the rate of Compound X dégradation (via reaction with fatty acid based excipients or other dégradation mechanisms, as discussed in detail below) within the formulation insuring a low and controlled Compound X level in the drug product. However, even formulations that do not — possess formulation excipients that react with Compound X in a sacrificiat manner may still benefit from reduced Compound X levels as a resuit of réfrigération.
With respect to température control, a refrigerated supply chain is recommended for the product throughout it’s shetf life and at least untîl the product is in the patient’s hands. The product should be stored in refrigerated warehouse facilities with température condition monitoring to insure that product is maintained at proper température. During transportation, the product should be transported under refrigerated conditions. As best practice, température monitoring devices (e.g. TempTale® from Sensitech Inc.) should be included with shipments to provide assurance that température conditions during shipment do not deviate beyond known safe product température excursion ranges. Thus, one additional embodiment of the invention is directed to a liquid pharmaceutical composition wherein the packaged dosage units of the composition are stored together with a température monitoring device to measure and record the environmental température during storage or shipment. A température monitoring device is typically attached to, or otherwîse included with, a larger shipment quantity, e.g. a pallet, of the packaged dosage units. Ail such possible température monitoring devices and attachments thereof to pharmaceutical drug product that are conventional in the industry are embraced by the présent invention.
Température control can be used independently to control the formation of dégradation product or, more preferably, together with one or more of the other control methods as described herein.
For example, the combination of réfrigération, moîsture contrat (control drying during manufacture and moîsture résistant packaging), and the presence of sacrifîcial fatty acidbased excipients (excipient control) provides for very effective control of Compound X. Under such conditions, Compound X levels hâve been demonstrated to maintain a “steady state” level of approximately 0.5-1 ppm in drug product capsules which is well below the requirements of regulatory authorities. Because the level of Compound X is at steady state, the product shetf life can be extended well beyond that possible at room température v\/” while insuring patient safety. To date, two years of stability (shelf life) for the product has been demonstrated on several représentative batches. Compound X results over the course of these stability studies show no increasing trend suggesting that considérable further extension in product shelf life is possible. See Figure 1, which depicts the Compound X formation and stability over a 24 month period under different environmental conditions for a batch of 120 mg capsules (where “Refrigerated” = 4-5 *C). The température of the refrigerated environment was set to 4-5 ’C. The results clearly demonstrate effective dégradation product control under refrigerated conditions as compared to non-refrigerated environments. In fact, the results demonstrate that the dégradation product level decreases under refrigerated storage conditions and is maintained at this lower level.
Achieving a low steady state level of Compound X in Compound (1) NA capsules throughout shelf life by this invention, allows for greater opportunity for room température use and storage of the product with the patient for a limited period of time during patient use of the product. This accommodation for greater flexibility in patient handling of the product provides greater ease of patient use and potentially greater patient dosing compliance. It thus provides a significant advantage versus requiring the patient to store the product in a refrigerator. Preliminary studies under conditions of simulated patient use hâve shown that Compound X does not exceed commercial regulatory limits even after 60 days of storage at 25°C/70% RH or 30°C/75% RH. See Table 1 below:
Table 1. Compound X in Compound (I) NA Capsules (120 mg) During Simulated Patient
Use:
| Timepolnt | TlmeO | 30 Days | 60 Days | ||||
| Condition | NA | 5°C | 25 °C/ 60% RH | 30 °C/ 75% RH | 5 °C | 25 °C/ 60% RH | 30 °C/ 75% RH |
| Compound X (ppm) | 1.3 | 0.8 | 0.8 | i.O | 1.3 | 1.4 | 2.4 |
Implémentation of température control methods does not negatively impact other qualîty aspects ofthe product. As drug solubility in the formulation increases upon lowering température, this product can be stored under réfrigération without impacting assay.
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Furthermore, the capsules maintain their physical properties such as hardness and show an improved overall product dégradation profile.
2. Moisture Control
Compound X is formed via hydrolysis and, as such, the concentration of water présent in the solution/fill formulation has a direct impact on the rate of Compound X formation. As the rate of hydrolytic Compound X formation from Compound (1) NA is dépendent on the presence of water to drive the reaction, ultra dry formulations can minimize Compound X 10 formation. This has been demonstrated, for example, by the development of the
Compound (1) NA oral solution drug product formulation that consists of two solutions designed to be mixed at time of patient use: Compound (1) NA dissolved in a dry solvent (e.g. PEG400 and propylene glycol) and an excipient vehicle containing water. This is the so-called “Reconstitution Approach” method described hereinbelow as an alternative 15 technique to minimize the effect of water in the formulation.
Investigation of Compound (1) NA capsules manufactured with different levels for water content has demonstrated that at very low levels of water, Compound X growth can be efTectively controlled even at room température storage. See Figure 2, which depicts the 20 Compound X formation and stability over a 24 month period at room température storage for 120 mg capsules having different levels of water content in the fit! formulation. When such data are also evaluated with the considération of température, the results indicate that for capsules with the lowest water content, Compound X growth shows relatively little température dependency (see Figure 3), and can therefore be maintained below regulatory 25 limits even at room température storage. As such, tow water content formulations might be suitably stable to Compound X formation and not require réfrigération or other température controls.
Unfortunateiy, at such low water levels, current soft gelatin capsule shell material becomes 30 highly brittle and lacks sufficient robustness to avoid cracking when packaged and shipped in bottles. tt may be possible to develop alternative capsule formulations that are jv'' sufïîcîently elastîc and robust even when filled with low water content formulations to produce Compound (1) NA capsules with commercially acceptable physical robustness to be packaged and distributed in bottles.
In a preferred embodiment, SEDDSs capsules are dried to less than about 3.0% water content during manufacturing and then stored under conditions suitable to maintain such water content level. At this water content, réfrigération efîectively controls Compound X formation in the formulation while insuring that the capsule shell possesses sufïïcient elasticity to be robust for product packaging and distribution. Addîtional embodiments include drying the capsules to less than about 2.5% water content, or less than about 2.0% water content, and then storing the capsules under conditions suitable to maintain such water content level. Drying methods that may be used include any ofthe conventional drying methods known in the art, including but not limited to adsorption drying or condensation heat drying. For capsules, a typical drying method is in drying tunnels at 2025 °C/10-15%RH.
It is also preferred to use drug product packaging with high résistance to moîsture ingress, such that the water content of Compound (1) NA capsules is maintained essentially constant during refrigerated storage. This allows the rate of Compound X formation to stay essentially constant and in balance with the rate of Compound X dégradation, thereby maintaining the low steady state level ofthis impurity. One example ofsuch packaging is a blister system incorporating desiccant material to further dry capsules during storage. The use of a pervious polymer blister enclosed in Alu foil with desiccant provides for an économie solution for moisture control and protection in a blister-packed product. Figure 4A depicts a graphie représentation of such blister system incorporating a desiccant in the product packaging and the affect on water transmission and Figure 4B shows a more detailed depiction ofthe capsule in an exemplary polymer blister packaging system and the water transmission in such System. In one example, the use of a polymer blister system with desiccant quickly reduced the water content to approximately 1.5% in the capsule fill formulation and allowed the maintenance of this low water content during storage. See Figure 5 depicting the changes in relative humidity over time within the pouch and within the capsule blister cavity and the changes in moisture content within the capsule fill formulation over the same storage period. In this example, the packaging used comprised an aluminum pouch containing a conditioned desiccant and Compound (1) NA capsules packed in a low moisture barrier thermo formable polymer film (e.g. poly vinyl ch lo ri de film) blister system)
Thus, in one general embodiment, the composition is stored in a moisture résistant packaging, optionaliy including a desiccant material. In addition to the polymer blister enclosed in Alu foil mentioned above, other commercially available moisture résistant packaging materials may be used, optionaliy along with conventional desiccant materials, for the purpose ofmaintaining reduced water content levels. Additional examples of packaging materials that may be used include thermo formable polychloride trifluoric ethylene (PCTFE) polymer films and alternative materials that show water vapor transmission rates below 0.1 g/m1 d, including, e.g.. ACLAR® 300 blisters and HPDE bottles.
One preferred embodiment of the invention combines the moisture control and température control methods to achieve dégradation product control. For SEDDs capsules, the product should be dried during manufacture to less than about 3.0% water content, and once 20 manufactured it is preferred to implement refrigerated storage for the bulk capsules (as outlined above) and to package them in moisture résistant packaging as early after manufacture as economically feasible. Doing so insures the lowest possible levels of Compound X in the drug product.
It has even been discovered that in formulations with even higher water content than 3%, the level of Compound X can be maintained below the limit from regulatory authorities by use of réfrigération in a moisture protective package. See Figure 6 showing Compound X stability over a 24 month period under refrigerated conditions (4-5°C) for 120 mg capsules of Compound (1) NA having different levels of fill water content, clearly demonstrating effective control even at higher water content levels under refrigerated conditions, w—
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3. Excipient Control
It has been further discovered that Compound X is unstable and further dégradés in the formulation and also reacts with fatty acid-based excipient materials, such as capmul and cremophor, to produce products that are not genotoxic as shown below:
Dégradation Products
β-Angelica Lactono
Excipient Interaction Products
ΗΛ.ΧΟ,Η '’ps (S)lç
Compound X
These subséquent dégradation reactions resuit in the removal of Compound X and counterbalance the rate of Compound X formation. At refrigerated températures and under conditions of controlled moisture, the rates of formation and élimination of Compound X hâve been demonstrated to balance resulting in a steady state level of Compound X of approximately 0.5-1 ppm in drug product capsules. The above secondary reactions with fatty acid excipients has also been studied to be directly correlated with température. This provides an advantage under room température storage during patient use by maintaining Compound X levels well below allowable safety thresholds.
In view of the ability of fatty acids to contribute to the dégradation of Compound X, the use of a fatty-acid based excipient material in the formulation constitutes an additional preferred embodiment of the présent invention and an additional method for controlling the level of Compound X dégradation product. Spécifie examples of fatty acids that may be used include capric acid, caprylic acid and ricinoleyl acid, although other fatty acids may also be suitable.
Experimental evidence for the reaction of Compound X with fatty acid-based excipient materials to form further dégradation products as described above has also been obtained via spiking experiments.
4. Capsule Shell Control
It has been further discovered that for liquid formulations, e.g. SEDDS, contained within a soft gelatin capsule, the level of citric acid excipient contained within the gelatin capsule shell material has an affect on the level of Compound X.formation within the fiil formulation upon storage. This effect was demonstrated via a spiking experiment comparing Compound X formation in a liquid fiil formulation stored in the presence of gelatin capsule shell material, the formulation being spiked with citric acid vs. without citric acid spiking. See the results in the table below (the capsule fiil formulation used corresponds to that described in Example 1 of U.S. Patent Application Publication 2011/0160149):
| Sample Description | Determined amount of Compound X | |
| Orne Zéro | 1 Month storage at 30 •c | |
| Capsule shell material suspended In active capsule fiil formulation | < lppm | < 1 ppm |
| Capsule shell material suspended in active capsule fil! formulation spiked with approximately 1% citric acid | < 1 ppm | 3 ppm |
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As shown above, in the absence of citric acid there is stability upon 1 month storage of the formulation, whereas in the presence of only 1% citric acid there was an increase in the level of Compound X from less than 1 ppm to 3 ppm over the same storage period.
Although the spécifie mechanism by which citric acid contributes to Compound X formation is yet to be fully elucidated, a preferred embodiment is therefore to use a capsule shell that is substantially free of citric acid in order to minimize the formation of this dégradation product. In this context, the term “substantially free” means less than about 1% of citric acid présent in the capsule shell material.
5. Basification
Mechanistic studies hâve demonstrated that Compound X formation occurs via an acid catalyzed hydrolysis reaction. Formation of Compound X has not been observed under basic conditions. Modulation of formulation pH is therefore a potential means to reduce or 15 eliminate formation of Compound X in liquid drug product formulations. The concept has been demonstrated in oral liquid formulations in which Tris has been included as abasifier.
Thus, an additional embodiment ofthe invention is a method for controlling the level of dégradation product Compound X in a liquid pharmaceutical composition comprising a 20 Compound (1), or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, said method comprising adding abasifier to said composition to achieve an internai apparent pH of greater than about 7. In another embodiment, basifier is added to said composition to achieve an internai apparent pH of greater than about 8.
Basifiers that may be used include, for example, Tris (Tromethamine), Meglumine, Carbonate buffer and Arginine. Basifiers can be added to the formulation, dissolved in Water or in some of the co-solvents such as Polyethylene Glycol 400 or Propylene Glycol
The term “apparent pH” is in reference to the pH measurement obtained when using a standard pH electrode/meter to measure the pH of a non-aqueous solution, and is well —
-1816937 understood in the art. See, e.g., USP Chapter <791>pH. Where a pH meter is standardîzed by use of an aqueous buffer and then used to measure the “pH” of a nonaqueous solution or suspension, the ionization constant ofthe acid or base, the dielectric constant ofthe medium, the liquid-junctîon potential (which may give rise to errors of approximately 1 pH 5 unit), and the hydrogen-ion response of the glass electrode are ail changed. For these reasons, the values so obtained with solutions that are only partiatly aqueous in character can be regarded only as apparent pH values. The term “apparent pH is used herein, therefore, when referring to the pH value of a non-aqueous or only partially aqueous solution. An example of this type of formulation would be the oral solution formulation 10 designed for pédiatrie use disclosed in WO 2010/059667. Thus, in a spécifie embodiment, the basifier is added to a water-containing solution designed for oral administration in order to achieve an internai apparent pH of greater than about 7. By using this technique, a level of dégradation product in the oral solution is controlled.
To demonstrate this effect, the below table provides the storage stability results (level of Compound X) under various storage conditions for two oral solution formulations, one having no basifier added (F248) and the other having an added basifier (F383; containing Tris). The results demonstrate that the addition of a basifier results in a reduced level of dégradation product being formed upon 12 months of storage.
| Balches | Description | 6m 40°C /75%RH | 12m 25°C /60%RH | 12m30°C /75%R1I |
| F 248 | Formula without basifier | < 2ppm | 3.3 ppm | 3.3 ppm |
| F 383 | Formula with basifier | 2,1 ppm | 0,9 ppm | 2,0 ppm |
| Below are the formulas for the two tested oral so | ution formulations: |
Formula 248:
| INGREDIENT | g/lOOg |
| Compound (1) Na | 4.4 |
| PEG 400 | 40.1 |
| Propylene Glycol | 5.7 |
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| Vitamin ETPGS | 28.6 |
| Capmul MCM | 2.9 |
| Water | 14.4 |
| Sucra lose | 1.9 |
| Butter mint | 1.0 |
| Butter toffee | 1.0 |
| Total | 100.0 |
Formula 383:
| INGREDIENT | g/lOOg |
| Compound (1) Na | 4.6 |
| PEG 400 | 54.6 |
| Propylene Glycol | 5.4 |
| Vitamin ETPGS | 13.4 |
| Water | 17.9 |
| Tris | 0.2 |
| Sucra lose | 1.9 |
| Butter toffee | 2.0 |
| Total | 100 |
6. Reconstitution Approach
If the liquid pharmaceutical formulation of Compound (1) NA is to contain water as an excipient or co-solvent, a reconstitution approach is one additional method that has been 10 successfully used to control dégradation product formation. As the rate of hydrolytic
Compound X formation from Compound (l) NA is dépendent on the presence of water to drive the reaction, ultra dry formulations can minimize Compound X formation. This has been demonstrated, for example, by the development of the Compound (1) NA oral solution drug product formulation that consists of two solutions designed to be mixed at 15 time of patient use: Compound (1) NA dissolved in a dry solvent (e.g. PEG400 and propylene glycol) and an excipient vehicle containing water, the so-called “Reconstitution Approach”. By limiting or eliminating the association of Compound (1 ) NA with significant quantifies of water during the storage period, the rate of Compound X.formation during storage is greatly reduced.
In this method, a first non-aqueous concentrate formulation (the “first formulation premixture”) is prepared comprising only Compound (1), or a pharmaceutically acceptable sait thereof, and non-aqueous based excipients, along with a second aqueous formulation pre-mixture (the “second formulation pre-mixture”) comprising water as an excipient. The first and second formulation pre-mixtures are then mixed to préparé the final formulation prior to patient use.
In one general embodiment, if the liquid pharmaceutical composition is to contain water as an excipient material, the level of dégradation product X is controlled by first preparing a first formulation pre-mixture comprising only Compound (1), or pharmaceutically acceptable sait thereof, and non-aqueous based excipients and a second formulation premixture comprising water as an excipient, and then mixing the first and second formulation pre-mixtures to préparé the final formulation prior to patient use.
To demonstrate this effect, the below table provides the storage stability results (level of Compound X) under various storage conditions for two oral solution formulations: one having no Compound X control method applied (F248) and the other being a concentrate to be reconstituted (F412) in which Compound (1) NA is dissolved in a non-aqueous-based system (= a “first formulation pre-mixture” described above). The results demonstrate that there is a greatly reduced level of dégradation product formation in the concentrate as compared to the ready-to-use formulation having no control method applied.
| Balches | Description | 6m 40/75 | 12m 25/60 | 12m 30/75 |
| F 248 | Ready to use solution with no Compound X control method | < 2ppm | 3.3 ppm | 3.3 ppm |
| F412 | Concentrate lo be reconstituted | 0.1 ppm | ND | 0.1 ppm |
ND: non détectable
The formula for the F248 solution is as described above and below is the formula for the concentrate solution F412: v/
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Formula 412:
| INGREDIENT Compound (1) Na | g/lOOg |
| 14.9 | |
| PEG 400 | 67.6 |
| Propylene Glycol | 17.5 |
| Total | 100 |
Additional Embodiments of the Invention
1. Additional Method Embodiments
Additional embodiments of the présent invention includes control methods incorporating to any combination of one or more of the above-described control methods as suitable for the particular composition at hand.
For example, in one preferred embodiment, when the liquid pharmaceutical composition is contained within a capsule one or both ofthe following methods are applied to the capsule t5 to control the level of dégradation product X: (a) it is dried such that it has a water content of less than about 3.0 % w/w and stored under conditions sufficient to maintain a water content of less than about 3.0 % w/w; and/or (b) it is stored in at a température of between about 2 and 8 degrees Celsius. In sub-embodiments, the water content is less than about 2.5%, or less than about 2.0%, and is stored under conditions sufficient to maintain such 20 water content level. In additional preferred sub-embodiments, the composition contains a fatty acid excipient and/or the capsule shell material is substantially free of citric acid.
In another preferred embodiment, when the liquid pharmaceutical composition is a watercontaining solution designed for oral administration, one of the following methods are applied:
(1) adding a basifier to said composition to achieve an internai apparent pH of greater than about 7, preferably greater than about 8;
(2) first preparing a first formulation pre-mixture comprising only Compound (1), or pharmaceutically acceptable sait thereof, and non-aqueous based excipients and a second formulation pre-mixture comprising water as an excipient, and then mixing the first and second formulation pre-mîxtures to préparé the final formulation prior to patient use.
2. Additional Pharmaceutical Composition Embodiments
Additional embodiments are directed to a liquid pharmaceutical composition comprising a Compound (1), or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, wherein the amount of dégradation product Compound X in the composition is below a level of about 400 pg, or below a level of about 200 pg, or below a level of about 60 pg, or below a level of about 20 pg, when the composition contains a full daily dose of Compound (1) or pharmaceutically acceptable sait thereof in either single or multiple dosage units. In more spécifie embodiments, the amount of dégradation product Compound X in the composition is below a level of about 10 pg or below a level of about 1.5 pg when the composition contains a full daily dose of Compound (1 ) or pharmaceutically acceptable sait thereof in either single or multiple dosage units.
Additional embodiments ofthe présent invention are directed to the above-described liquid pharmaceutical compositions that may be prepared or treated using the above-described control methods, i.e., having low water content, low température, excipient controls and/or elevated pH.
Thus, additional embodiments of the présent invention include liquid pharmaceutical compositions as described above comprising Compound (1), or a pharmaceutically acceptable sait thereof, and having the stated low levels of Compound X, wherein the composition has one or more of the following properties: «y'-
-2316937 (a) a water content of less than about 3.0 % w/w, or less than about 2.5 % w/w, or less than about 2.0 % w/w, optionally stored in moisture résistant packaging and optionally further including a desiccant material;
(b) an internai température of between about 2 and 8 degrees Celsius (c) an internai apparent pH of greater than about 7, or greater than about 8;
(d) comprising a fatty acid excipient;
(e) contained within a capsule shell wherein the capsule shell material is substantially free of citric acid.
In additional more spécifie embodiments, the liquid pharmaceutical composition as described above comprising Compound (1), or a pharmaceutically acceptable sait thereof, and having the stated low levels of Compound X, has been stored for a period of at least 6 months, or at Ieast 1 year, or at Ieast 2 years, or at least 3 years, under conditions sufficient to maintain one or more of the following properties:
(a) a water content of less than about 3.0 % w/w;
(b) an internai température of between about 2 and 8 degrees Celsius;
(c) a internai apparent pH of greater than about 7.
In another preferred embodiment, the pharmaceutical composition has (a) a water content of less than about 3.0 % w/w, or less than about 2.5 % w/w, or less than about 2.0 % w/w and is stored in moisture résistant packaging optionally further including a desiccant material; and/or has (b) an internai température of between about 2 and 8 degrees Celsius. In a particular sub-embodiment, such composition is contained within a capsule. In another particular sub-embodiments thereof, the composition further comprises a fatty acid excipient and/or the capsule shell material is substantially free of citric acid.
In another preferred embodiment, the pharmaceutical composition has an internai apparent pH of greater than about 7, or greater than about 8. In a particular sub-embodiment, the liquid pharmaceutical composition is a water-containing solution designed for oral administration.
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The dégradation product control methods described herein can be used with various types of liquid formulations of Compound (I), including but not limited to the lipid-based SEDDS formulations described in US Publication 2011/0160149, and the oral solution formulations described in WO 2010/059667.
Additional embodiments are directed to the packaged dosage forms containing any of the aforementioned pharmaceutical compositions. Such embodiments include, for example, a liquid pharmaceutical composition in the form one or more discrète dosage units contained within a packaging, wherein the packaging further comprises written instructions for use indicating that the composition should be stored at a température in the range of from 2 to 8 degrees Celsius. In a preferred sub-embodiment thereof, the packaged dosage units are stored together with a température monitoring device to measure and record the environmental température during storage or shipment.
3. SEDDS Formulation Embodiments
Embodiments of the SEDDS lipid-based formulations, e.g. as described in US Publication 2011/0160149, include:
Pharmaceutical compositions comprising Compound (I), or a pharmaceutically acceptable sait thereof, together with one or more pharmaceutically acceptable lipids and hydrophilic surfactants. The compositions may optionaily include one or more additional ingrédients, e.g., pharmaceutically acceptable hydrophilic solvents, solidifying agents, antioxidants, etc., as will be discussed in more detail below. The pharmaceutical compositions are liquid or semi-solid and are preferably encapsulated in a capsule for oral administration.
The composition may be characterized by one or more of the following features:
(1) either substantially free of any amine compound, or not containing any amine compound;
(2) either substantially free of any alcohol compound, or not containing any alcohol compound; *7
-2516937 (3) either substantially free of any triglycéride compound, or not containing any triglycéride;
(4) either substantially free of any glyceride of a long chain fatty acid, or not containing any such glyceride;
(5) either substantially free of any additional surfactant compound, or not containing any additional surfactant compound;
A particular embodiment of this composition is directed to a pharmaceutical composition, comprising (or consisting essentially of):
| (a) | about 5% to 30% by weight of a compound of formula ( 1 ) or a pharmaceutically acceptable sait thereof; |
| (b) (c) | about 30% to 60% by weight of a pharmaceutically acceptable lipid; about 20% to 50% by weight of a pharmaceutically acceptable hydrophilic surfactant; |
| (d) | optionally up to about 30% by weight of a pharmaceutically acceptable hydrophilic solvent; |
A further particular embodiment of the composition is directed to a pharmaceutical composition, comprising (or consisting essentially of):
| (a) | about 10% to 20% by weight of a compound of formula ( 1 ) or a pharmaceutically acceptable sait thereof; |
| (b) (c) | about 40% to 50% by weight of a pharmaceutically acceptable lipid; about 25% to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant; |
| (d) | about 5% to 15% by weight of a pharmaceutically acceptable hydrophilic solvent; |
A further particular embodiment of the composition is directed to a pharmaceutical composition, comprising (or consisting essentially of):
| (a) | about 5% to 30% by weight of a compound of formula (1) or a pharmaceutically acceptable sait thereof; |
-2616937 (b) about 30% to 60% by weight of a pharmaceutically acceptable lipid selected from fatty acids, medium or long chain mono-, di- or triglycérides, propylene glycol fatty acid esters, sorbitol fatty acid esters, water insoluble vitamins, and mixtures thereof;
(c) about 20% to 50% by weight of a pharmaceutically acceptable hydrophilic surfactant selected from polyethoxylated vegetable oils, polyethoxylated tocopherols, polyethoxylated sorbitol fatty acid esters, bile salts, lecithins and mixtures thereof;
(d) optionally up to about 30% by weight of a pharmaceutically acceptable hydrophilic solvent selected from propylene glycol, polypropylene glycol, polyethylene glycol, glycerol, éthanol, dimethyl isosorbide, glycofùrol, propylene carbonate, dimethyl acetamide, water, or mixtures thereof;
A further particular embodiment of the composition is directed to a pharmaceutical composition, comprising (or consisting essentially of):
(a) about 10% to 20% by weight of a compound of formula ( 1 ) as the sodium sait;
(b) about 40% to 50% by weight of a pharmaceutically acceptable lipid selected from monoglycerides of caprylic and capric fatty acids; diglycerides of caprylic and capric fatty acids, and mixtures thereof;
(c) about 25% to 35% by weight of a pharmaceutically acceptable hydrophilic surfactant selected from tocopheryl polyethylene glycol succinate, polyoxyl 40 hydrogenated castor oil, and polyoxyl 35 castor oil and mixtures thereof;
(d) about 5% to 10% by weight of a pharmaceutically acceptable hydrophilic solvent selected from propylene glycol, polyethylene glycol, éthanol, water, and mixtures thereof.
4. Oral Solution Formulation Embodiments
Embodiments of the SEDDS lipid-based formulations, e.g. as described in WO 2010/059667, include:
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A liquid composition comprising:
(a) Compound (1), or a pharmaceutically acceptable sait thereof:
(b) at least one surfactant; and (c) at least one pharmaceutically acceptable solvent; and wherein the composition is substantially free of lipid.
Additional embodiments ofthe composition may include:
(a) compositions wherein the weight ratio of surfactant to drug substance is greater than or equal to 1.4;
(b) compositions wherein the weight ratio of surfactant to drug substance is greater than or equal to 2.7; and (c) compositions wherein the weight ratio of surfactant to drug substance is greater than or equal to 4.3.
Additional preferred embodiments under embodiments (a) to (c) above include:
(d) wherein under embodiment (b) above the compositions contain drug substance in an amount less than or equal to 4.6% and the weight ratio of surfactant to drug substance is greater than or equal to 2.7; and (e) wherein under embodiment (c) above the compositions contain drug substance in an amount less than or equal 6.3% and the weight ratio of surfactant to drug substance is greater than or equal to 4.3.
In one preferred embodiment, the pharmaceutical composition comprises:
(a) 1% to 40% by weight of Compound (1), or a pharmaceutically acceptable sait thereof;
(b) 2% to 50% by weight of surfactant; and (c) 10% to 90% by weight of solvent or mixture of solvents; and wherein the composition is substantially free of lipid, or more preferably does not contain any lipid.
In another preferred embodiment, the pharmaceutical composition comprises:
-2816937 (a) 2% to 10% by weight of Compound (1), or a pharmaceutically acceptable sait thereof;
(b) 10% to 30% by weight of surfactant; and (c) 60% to 90% by weight of solvent or mixture of solvents; and wherein the composition is substantially free of lipid, or more preferably does not contain 5 any lipid.
In another preferred embodiment, the pharmaceutical composition comprises:
(a) 2% to 10% by weight of Compound (1), or a pharmaceutically acceptable sait thereof;
(b) 10% to 30% by weight of Vitamin E TPGS; and (c) 60% to 90% by weight of a mixture of water, propylene glycol and polyethylene glycol
400 ; and wherein the composition is substantially free of lipid, or more preferably does not contain any lipid.
In another preferred embodiment, the pharmaceutical composition comprises:
(a) 2% to 10% by weight of Compound (1), or a pharmaceutically acceptable sait thereof;
(b) 10% to 30% by weight of Vitamin E TPGS; and (c) 60% to 90% by weight of a mixture of water and polyethylene glycol 400; and wherein the composition is substantially free of lipid, or more preferably does not contain any lipid.
Additional embodiments include any ofthe above fourembodiments, wherein the composition is (1) substantially free of propylene glycol or does not contain propylene glycol, and/or (2) substantially free of an amine or does not contain an amine.
4. Kit Embodiments
The invention also comprises a kit comprising two formulation pre-mixtures to be used in connection with the above-described Reconstitution Approach. The formulation pre-29 mixtures are packaged and sold together and the patient reconstitutes the final formulation by mixing together the two pre-mixtures prior to use. In a general embodiment, therefore, the kit comprises:
(a) a first formulation pre-mixture comprising a Compound (1), or a pharmaceutically acceptable sait thereof, and one or more non-aqeous based excipients; and;
(b) a second formulation pre-mixture comprising water as an excipient, and optionally one or more additional excipients.
Examples of final formulations that may be prepared using the reconstitution method include the oral solution formulations set forth above and those described in WO 2010/059667.
Figure 7 sets forth three examples of different oral solution formulations designed for empioying three different dégradation control methods as described herein: wherein “Control by Refrigerated Storage” = température control method; “Control by pH” = basification control method; “Control by Reconstitution” = reconstitution control method.
5. Dégradation Product Level Embodiments
The various techniques described herein may be employed, either separately or one or more of them together, to control the level of Compound X in the composition. In one embodiment ofthe invention the level of dégradation product X is controlled to below a level of about 400 pg, or below a level of about 200 pg, or below a level of about 60 pg, or below a level of about 20 pg, when the composition contains a full daily dose ofthe active ingrédient, and in another embodiment below a level ofabout 10 pg. Thus, spécifie embodiments of the présent invention are directed to empioying one or more of the methods described herein wherein the resulting amount of dégradation product X in the composition is below a level of about 400 pg, or below a level of about 200 pg, or below a level of about 60 gg, or below a level of about 20 gg, or below a level of about 10 gg, when the composition contains a full daily dose of Compound (1), or pharmaceutically acceptable sait thereof, in either single or multiple dosage units.
As described above, the EMEA (European Medicines Agency) Guideline on the Limits of Genotoxic Impurities (28 June 2006) spécifiés a maximum intake value of 1.5 gg/day of a genotoxic impurity as being associated with an acceptable risk for most pharmaceuticals. Accordingly, one additional preferred embodiment of the présent invention is directed to employing one or more of the methods described herein wherein the resulting amount of dégradation product X in the composition is below a level of about 1.5 gg when the composition contains a full daily dose of Compound (1), or pharmaceutically acceptable sait thereof, in either single or multiple dosage units.
For example, when a full daily dose is 240 mg of Compound (1), this intake value (1.5 ts gg/day) calculâtes to a level of 6 ppm (parts-per-million). Thus, an additional embodiment is wherein the resulting amount of dégradation product X in the composition is below a level of about 6 ppm for each 240 mg of Compound (l) or pharmaceutically acceptable sait thereof. Preferred subembodiments at such dosage include upper limits of 3 ppm, or 2 ppm or 1 ppm.
As an additional example, when a full daily dose is 120 mg of Compound (1), this intake value (1.5 gg/day) calculâtes to a level of 12 ppm (parts-per-million). Thus, an additional embodiment is wherein the resulting amount of dégradation product X in the composition is below a level of about 12 ppm for each 120 mg of Compound (1 ) or pharmaceutically acceptable sait thereof. Preferred subembodiments at such dosage include upper limits of 8 ppm, or 4 ppm or 2 ppm.
Claims (25)
1. A liquid pharmaceutical composition comprising a compound of formula ( 1 ):
-3116937 or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, wherein the amount of dégradation product Compound X:
in the composition is below a level of about 400 pg when the composition contains a full daily dose of Compound (1) or pharmaceutically acceptable sait thereof in either single or multiple dosage units.
2. A liquid pharmaceutical composition according to claim 1, wherein the composition has one or more of the following properties:
(a) a water content ofless than about 3.0 % w/w;
(b) an internai température of between about 2 and 8 degrees Celsius;
-3216937 (c) a internai apparent pH of greater than about 7.
3. A liquid pharmaceutical composition according to claim 2, wherein the
5 composition has been stored for a period of at least 6 months under conditions sufficient to maintain one or more of the following properties:
(a) a water content of less than about 3.0 % w/w;
(b) an internai température of between about 2 and 8 degrees Celsius;
(c) a internai apparent pH of greater than about 7.
4. A liquid pharmaceutical composition according to any of daims 1 to 3, wherein lhe composition has a water content of less than about 3.0 % w/w.
5. A liquid pharmaceutical composition according to claim 4, wherein the
15 composition is stored in moisture résistant packaging optionally further including a desiccant material.
6. A liquid pharmaceutical composition according to any of claîms 1 to 3, wherein the composition has an internai température of between about 2 and 8 degrees Celsius
7. A liquid pharmaceutical composition according any of daims 1 to 3, wherein the liquid pharmaceutical composition is contained within a capsule and has one or both ofthe following properties: (a) a water content of less than about 3.0 % w/w; and (b) an interna! température of between about 2 and 8 degrees Celsius.
8. A liquid pharmaceutical composition according to daim 7, wherein the capsule shell material is substantially free of citric acid
9. A liquid pharmaceutical composition according to any of daims 1 to 8, wherein the composition contains a fatty acid excipient
-3316937
10. A liquid pharmaceutical composition according to claim 2, wherein the composition has an internai apparent pH of greater than about 7.
11. A liquid pharmaceutical composition according to claim 10, wherein the
5 composition is a water-contaïning solution designed for oral administration and wherein the composition is optionally stored at a température of between about 2 and 8 degrees Celsius.
12. A liquid pharmaceutical composition according to any of the preceding claims,
10 wherein the composition is in the form one or more discrète dosage units contained within a packaging, wherein the packaging further comprises written instructions for use indicating that the composition should be stored at a température in the range of from 2 to 8 degrees Celsius
15
13. A liquid pharmaceutical composition according to claim 12, wherein the packaged dosage units are stored together with a température monitoring device to measure and record the environmentai température during storage or shipment.
14. A method for controlling the level of dégradation product Compound X:
X in a liquid pharmaceutical composition comprising a compound of formula (1):
-3416937 or a pharmaceutically acceptable sait thereof, and at least one pharmaceutically acceptable excipient, said method comprising one or more ofthe following:
(a) drying said composition such that it has a water content of less than about 3.0 %
5 w/w and storing the composition under conditions sufficient to maintain a water content of less than about 3.0 % w/w;
(b) storing said composition at a température of between about 2 and 8 degrees Celsius;
(c) adding a basifier to said composition to achieve an internai apparent pH of
10 greater than about 7; or (d) if the liquid pharmaceutical composition is to contain water as an excipient material, first preparing a first formulation pre-mixture comprising only Compound (1), or pharmaceutically acceptable sait thereof, and non-aqueous based excipients and a second formulation pre-mixture comprising water as an
15 excipient, and then mixing the first and second formulation pre-mixtures to préparé the final composition just prior to patient use.
15. A method according to claim 14, wherein the resulting amount of dégradation product Compound X in the composition is below a level ofabout 400 pg when the u/ composition contains a fui! daily dose of Compound (I) or pharmaceutically acceptable sait thereof in either single or multiple dosage units.
16. A method according to claim 15, wherein the composition, or in the case of (d) the 5 first-formulation pre-mixture, has been stored for a period of at least 6 months under conditions sufïîcient to maintain one or more of the following properties:
(a) a water content of less than about 3.0 % w/w;
(b) an internai température of between about 2 and 8 degrees Celsius;
(c) a internai apparent pH of greater than about 7.
17. A method according to any of claims 14 to 16, wherein said composition is dried such that ît has a water content of less than about 3.0 % w/w and stored under conditions sufïîcient to maintain a water content of less than about 3.0 % w/w.
15
18. A method according to any of claims 14 to 17, wherein the composition is stored in moisture résistant packaging, optionally further including a desiccant material.
19. A method according to any of claims 14 to 18, wherein said composition is stored at a température of between about 2 and 8 degrees Celsius.
20. A method according any of claims 14 to 19, wherein the liquid pharmaceutical composition is conlained within a capsule and one or both of the following methods are applied to the capsule: (a) it is dried such that it has a water content of less than about 3.0 % w/w and stored under conditions sufïîcient to maintain a water content of less than
25 about 3.0 % w/w; and/or (b) it is stored in at a température of between about 2 and 8 degrees Celsius.
21. A method according to claim 20, wherein the capsule shell material is substantially free ofcitric acid
-3616937
22. A method according to any of claims 14 to 21, wherein the composition contains a fatty acid excipient.
23. A method according to claim 14 comprising adding a basifier to said composition 5 to achieve an internai apparent pH of greater than about 7.
24. A method according to claim 23, wherein the composition is a water-containing solution designed for oral administration and wherein the composition is optionally stored at a température of between about 2 and 8 degrees Celsius.
25. A kit comprising:
(a) a first formulation pre-mixture comprising a compound of formula (1):
15 or a pharmaceutically acceptable sait thereof, and one or more non-aqueous based excipients; and (b) a second formulation pre-mixture comprising water as an excipient, and optionally one or more additional excipients,
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61/586087 | 2012-01-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA16937A true OA16937A (en) | 2016-01-25 |
Family
ID=
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