# Patent

## Title
Self micro-emulsifying drug delivery system with increased bioavailability

## Abstract

The invention provides a formulation comprising (a) a drug that is poorly water-soluble, (b) at least one surfactant, and (c) at least one polar lipid, wherein the formulation is substantially free of a polar solvent, as well as methods of preparing the formulation and methods of increasing the bioavailability of a drug using the formulation.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This patent application is a divisional of U.S. patent application Ser. No. 13/989,687, filed Aug. 13, 2013, which is the U.S. national phase of International Application No. PCT/US2010/058106, filed Nov. 24, 2010, the disclosure of which is incorporated by reference.


BACKGROUND OF THE INVENTION
Many drugs are poorly soluble in water. Due to their low solubilities, these drugs have a correspondingly low degree of bioavailability. Therefore, it would be advantageous and desirable to have a method of increasing the dissolution and bioavailability of poorly water-soluble drugs.
BRIEF SUMMARY OF THE INVENTION
The invention provides a formulation for delivery of one or more poorly water-soluble drugs, wherein the formulation comprises (a) a drug that is poorly water-soluble, (b) at least one surfactant, and (c) at least one polar lipid, wherein the formulation is substantially free of a polar solvent.


DETAILED DESCRIPTION OF THE INVENTION
Poorly water-soluble drug delivery systems, such as traditional self micro-emulsifying drug delivery systems (SMEDDS), require the use of polar solvents (e.g., isopropanol or propylene glycol). In contrast, the inventive embodiment excludes the use of a polar solvent. In particular, the invention provides a formulation for delivery of one or more poorly water-soluble drugs, wherein the formulation comprises (a) a drug that is poorly water-soluble, (b) at least one surfactant, and (c) at least one polar lipid, wherein the formulation is substantially free of a polar solvent. Examples of polar solvents include, but are not limited to, water, methanol, acetic acid, acetone, isopropanol, propylene glycol, and ethyl acetate.
For the purposes of describing the invention, the term “substantially free” refers to less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%, less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, less than 0.2%, less than 0.1%, less than 0.5%, less than 0.1%, or 0%) (w/w) of the formulation.
For the purposes of describing the invention, the term “drug” refers to any compound which is biologically active, e.g., exhibits a therapeutic or prophylactic effect in vivo, or a biological effect in vitro. The term “poorly water-soluble” as used in conjunction with the present invention encompasses the terms sparingly water-soluble, slightly or very slightly water-soluble, and practically or totally water-insoluble compounds. A compound is poorly water-soluble for the purposes of this invention if it requires at least 30 parts solvent to dissolve one part solute.
Any poorly water-soluble drug, or combination of drugs including at least one poorly water-soluble drug, can be used in the inventive formulation. Suitable drugs include, but are not limited to, antihypertension drugs, antibiotic drugs, and anticancer or antitumor drugs. Examples of suitable drugs include, but are not limited to, peptides, nifedipine, glibencalmide, indomethacin, ursodeoxycholic acid, diphenyl hydrantoin, biphenyl dimethyl dicarboxylate, geldanamycin, mitotane, fenofibrate, simvastatin, idebenone, and camptothecin. In one embodiment of the invention, the poorly water-soluble drug is not mitotane.
Any surfactant or combinations of surfactants (e.g., combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more surfactants) can be used in the inventive formulation. Suitable surfactants include nonionic, cationic, and anionic surfactants that can be synthetic or natural. Surfactants for use in the invention may include, but are not limited to, ammonium lauryl sulfate, sodium lauryl sulfate (SDS), sodium laureth sulfate, also known as sodium lauryl ether sulfate (SLES), sodium myreth sulfate, dioctyl sodium sulfosuccinate, perfluorooctanesulfonate (PFOS), perfluorobutanesulfonate, alkyl ether phosphate, sodium stearate, sodium lauroyl sarcosinate, perfluorononanoate, perfluorooctanoate (PFOA or PFO), octenidine dihydrochloride, permanently charged quaternary ammonium cation, cetyl trimethylammonium bromide (CTAB) (i.e., hexadecyl trimethyl ammonium bromide), cetyl trimethylammonium chloride (CTAC), cetylpyridinium chloride (CPC), polyethoxylated tallow amine (POEA), benzalkonium chloride (BAC), benzethonium chloride (BZT), 5-bromo-5-nitro-1,3-dioxane, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB), CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate), cocamidopropyl hydroxysultaine, cocamidopropyl betaine, lecithin, cetyl alcohol, stearyl alcohol, cetostearyl alcohol (consisting predominantly of cetyl and stearyl alcohols), oleyl alcohol, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, polyoxypropylene glycol alkyl ethers, glucoside alkyl ethers, decyl glucoside, lauryl glucoside, octyl glucoside, polyoxyethylene glycol octylphenol, Triton X-100, polyoxyethylene glycol alkylphenol ethers, Nonoxynol-9, glyceryl laurate, polysorbates like polysorbate 20 (TweenTM20, SpanTM20), polysorbate 40 (TweenTM40, SpanTM40), polysorbate 60 (TweenTM60, polysorbate 65 (TweenTM65, SpanTM65), polysorbate 80 (TweenTM80, SpanTM80), sorbitan alkyl esters, cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide, and block copolymers of polyethylene glycol and polypropylene glycol.
Any polar lipid or combination of polar lipids (e.g., combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more polar lipids) can be used in the inventive formulation. Suitable polar lipids include mono- and di- glycerides, esters of fatty acids, and polysilane esters. Specific examples include propylene glycol monocaprylate (Capryol®90), propylene glycol monolaurate, propylene glycol oleate, propylene glycol myristate, propylene glycol monostearate, propylene glycol hydroxy stearate, propylene glycol ricinoleate, propylene glycol isostearate, propylene glycol monooleate, propylene glycol dicaprylate/dicaprate, propylene glycol dioctanoate, propylene glycol caprylate/caprate, propylene glycol dilaurate, propylene glycol distearate, propylene glycol dicaprylate, and propylene glycol dicaprate (Captex®100).
The at least one surfactant and at least one polar lipid can each be present in the formulation in an amount of 10-90% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, or 80% or ranges thereof, such as 10-30%, 15-20%, 15-17%, 20-60%, 35-50%, or 38-42%) weight/volume (w/w). In other words, the at least one surfactant can be present in the formulation in an amount of 10-90% (w/w) and the at least one polar lipid (e.g., two polar lipids) can be present in the formulation in an amount of 10-90% (w/w). For example, the inventive formulation can comprise 10-30% (w/w) of a first polar lipid, 20-60% (w/w) of a second polar lipid, and 10-30% (w/w) of a surfactant.
In one embodiment the first polar lipid is propylene glycol monocaprylate, the second polar lipid is propylene glycol dicaprate, and the surfactant is a polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, or mixtures thereof. Preferably, the polysorbate is polysorbate 80 (i.e., polyoxyethylene sorbitan monooleate). Accordingly, a particular example of the inventive formulation includes 10-30% (w/w) propylene glycol monocaprylate, 20-60% (w/w) propylene glycol dicaprate, and 10-30% (w/w) polysorbate (e.g., polysorbate 80). A second particular example of the inventive formulation includes 15-20% (w/w) propylene glycol monocaprylate, 35-50% (w/w) propylene glycol dicaprate, and 15-20% (w/w) polysorbate (e.g., polysorbate 80). A third particular example of the inventive formulation includes 15-17% (w/w) propylene glycol monocaprylate, 38-42% (w/w) propylene glycol dicaprate, and 15-17% (w/w) polysorbate (e.g., polysorbate 80).
The inventive formulation makes it possible to load a large amount of drug (e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, or more). In particular, the inventive formulation has a drug loading of at least 33%, preferably between 33% and 67%, and more preferably between 37% and 54%. In one embodiment, the formulation comprises 1 mg to 800 mg (e.g., 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 50 mg, 60 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg) of the drug.
The emulsion globules of the formulation are generally less than about 200 nm (e.g., less than about 180 nm, less than about 150 nm, less than about 120 nm, less than about 100 nm, less than about 90 nm, less than about 80 nm, less than about 70 nm, or less than about 60 nm) in diameter. The small size globules formed in the GI tract are designed to result in higher bioavailability of the drug compared to tablet formulations.
The inventive formulation (e.g., pharmaceutical formulation) also can comprise a carrier (e.g., a pharmaceutically acceptable carrier). The carrier can be any suitable carrier or mixture of carriers. For example, the pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the active compound (s), as well as by the route of administration. Preferably, the pharmaceutically acceptable carrier is chemically inert to the active compound (s) and has no detrimental side effects or toxicity under the conditions of use. Suitable pharmaceutically acceptable carriers, for example, vehicles, adjuvants, excipients, and diluents, are well-known in the art and are readily available.
The inventive formulation can be packaged in any pharmaceutical composition for oral administration. Suitable compositions that comprise the formulation are capsules, including hard gelatin capsules or soft gelatin capsules. Soft gelatin capsules are made with a gelatin shell, optionally in association with plasticizers, such as glycerine and/or sorbitol. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. The composition also can be formulated as a liquid suspension for administration directly into a patient's mouth. Alternatively, the formulation can be packaged into a solid dosage form (e.g., in a state readily converted to a microemulsion in vivo, thereby enhancing the dissolution of the drug).
Additional components that can be present in the dosage form include, but are not limited to, lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, and flavoring agents.
The inventive formulation can be used for any suitable purpose. For example, the inventive formulation can be used for scientific and research purposes, such as in determining the types of diseases or disorders, particularly cancers, which can be treated and for which their onset can be delayed, or progression slowed, by administration of the inventive formulation. The inventive formulation can be used in vitro in conjunction with cultured cells, tissues, organs, and the like.
The formulation can be used to deliver a drug to a host and has particular usefulness in applications in vivo. For example, the inventive formulation can be used in the prevention, delay of onset, slowing, or treatment of the progression of a disease or disorder, such as cancer.
The inventive method of delivering a drug to a host, especially an animal such as a mammal (e.g., mouse, rat, guinea pig, hamster, rabbit, cat, dog, pig, cow, horse, or simian, such as a human), comprises administering the inventive formulation to a host. Preferably, the inventive formulation is administered in an amount effective to treat or prevent a disease or disorder in the host (e. g., a therapeutically or prophylatically effective amount).
The method of delivering a drug to a host through administering the formulation of the invention can be made more effective in the treatment or prevention of disease by using it in conjunction with other known methods of treating or preventing diseases or disorders. For example, when the poorly water-soluble drug in the inventive formulation is an anticancer or antitumor drug, the formulation can be administered in conjunction with (i.e., sequentially or concurrently) with other anticancer or antitumor compounds, such as doxorubicin, bleomycin, vincristine, vinblastine, VP-16, VW-26, cisplatin, procarbazine, and taxol for solid tumors in general; alkylating agents, such as BCNU, CCNU, methyl-CCNU and DTIC, for brain or kidney cancers; and antimetabolites such as 5-FU and methotrexate for colon cancer.
One skilled in the art will appreciate that suitable methods of administering the inventive formulation to a host are known in the art, and, although more than one route can be used to administer a particular composition, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the described methods are merely exemplary and are in no way limiting.
The dose administered to the host should be sufficient to prevent the targeted disease or disorder, e. g., cancer, delay its onset, slow its progression, or treat the disease or disorder (e. g., reverse or negate the condition). One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular drug(s) employed, as well as the age, species, condition, and body weight of the host. The size of the dose will also be determined by the route, timing, and frequency of administration as well as the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular composition and the desired physiological effect.
Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
The invention also provides for a method for producing the inventive formulations using standard techniques, such as those set forth in the Example, as well as a method of increasing the bioavailability of a drug that is poorly water-soluble comprising preparing the inventive formulations.
The following example further illustrates the invention but, of course, should not be construed as in any way limiting its scope.
EXAMPLE
This example demonstrates the preparation of a Self Micro-Emulsifying Drug Delivery System (SMEDD) for mitotane (250 mg) soft gelatin capsule. Although the experiments described below employ mitotane as the water-soluble drug, one of ordinary skill in the art will appreciate that the inventive formulation can comprise any poorly water-soluble drug.
Development studies were performed to maximize drug loading in the dosage form while providing a system that was physically stable upon dilution with 20% weight/weight water, while minimizing the globule size upon 1:200 dilution with 0.01 N HCl or water, as determined by light scattering analysis.
After initial solubility screening, four formulations were developed. These formulations contained medium chain triglycerides, polar lipids, and surfactants. Drug loading of 25% was achieved in systems containing CapryolTM 90 (Propylene Glycol Monocaprylate, Type II), Captex® 100 (Propylene Glycol Dicaprate), and Labrasol® (Caprylocaproyl Macrogolglycerides); as well as Triethyl Citrate, Captex® 100, and Labrasol®. Generally, at 25% drug loading, the systems containing either CapryolTM 90 or Triethyl Citrate dispersed immediately upon dilution into a homogenous solution, and displayed minimum (or no) oily residue before and after centrifugation.
However, as drug loading was increased from 25% to 50%, the emulsions were increasingly unstable. For some systems at the highest drug loading, precipitates formed immediately upon dilution. In other cases, dispersion was delayed and/or a pellet was formed upon centrifugation.
In order to achieve a higher stable drug concentration within the selected solvents/systems, Polysorbate 80 was used to replace Labrasol® as the system surfactant. Polysorbate 80 enhanced dispersion and reduced globule sizes in the CapryolTM 90 system to a greater degree than in the Triethyl Citrate system. From these results, formulations containing CapryolTM 90, Captex® 100, and Polysorbate 80; in different proportions were selected for further development.







TABLE 1







Qualitative Formula of Mitotane SMEDDS Soft Gelatin Capsules









Item




Number
Material
Function












1.
Gelatin USP/NF (150 Bloom Limed
Gelatin Shell



Bone, Type B)


2.
Glycerin, USP 99.7%
Plasticizer


3.
Sorbitol, 76% solution (Sorbitol
Plasticizer



Special TM)


4.
Purified Water, USP
Solvent


5.
FD&C Blue #1
Colorant


6.
Opatint White (G-18000)
Colorant


7.
Mitotane
Active Pharmaceutical




Ingredient (API)


8.
Propylene Glycol Monocaprylate,
Solubilizing Agent



Type II, NF (Capryol TM 90)


9.
Propylene Glycol Dicaprate
Solubilizing Agent



(Captex ® 100)


10.
Polysorbate 80, USP/NF
Surfactant
















TABLE 2







Quantitative Formula of Gelatin Mass for


Mitotane Soft Gel Capsules (250 kg Batch)













Batch


Item

% weight/
Quantity


Number
Ingredients
weight
(kg)













1.
Gelatin USP/NF (150 Bloom Limed
42.00
105.0



Bone, Type B)


2.
Glycerin, USP 99.7%
3.00
7.500


3.
Sorbitol, 76% solution (Sorbitol
18.00
45.00



Special TM)


4.
Purified Water, USP*
34.92*
104.8*


5.
FD&C Blue #1
0.08
0.200


6.
Opatint White (G-18000)
2.00
5.000



TOTAL
100.0
267.5





*Purified Water, USP includes a 7% excess (17.5 kg) of the 250 kg batch size, in order to compensate for evaporation during the manufacturing process.













TABLE 3







Quantitative Fill Solution Formula for Mitotane


SMEDD Soft Gel Capsules, 250 mg















Batch


Item

mg/
% weight/
Quantity


Number
Ingredient
capsule
weight
(kg)














7.
Mitotane
250.0
28.50
2.625


8.
Propylene Glycol
138.1
15.75
1.450



Monocaprylate,



Type II, NF



(Capryol TM 90)


9.
Propylene Glycol Dicaprate
350.8
40.00
3.684



(Captex ® 100)


10.
Polysorbate 80, USP/NF
138.1
15.75
1.450



TOTAL
877.0
100.0
9.209









Abbreviated manufacturing procedures included the following:
1. Fill Solution


    
    
        Mix CapryolTM90, Captex® 100, and Polysorbate 80, NF until a homogenous solution is obtained
        Heat to 45° C.±5° C.
        Slowly add mitotane into mixing solution, continue mixing until completely dissolved
        Deaerate final solution

2. Gelatin Mass

        Reserve approximately 3 kg of water
        Mix remaining water, Sorbitol SpecialTM, and Glycerin
        Heat to 85° C.±5° C.; add gelatin
        Maintain temperature at 85° C.±5° C. with continuous mixing until gelatin granules are completely dissolved, cook gelatin
        In separate container, mix Opatint White and FD&C Blue #1
        Add colorant mixture to gelatin mixture, rinse colorant container with reserved water and add to gelatin mixture
        Continue mixing until uniform color is obtained
        Deaerate the gel mass
        Determine water content of gel mass; adjust if needed (water addition or continued heating)
        Transfer to holding tank, maintain at 55°, use within 96 hours

3. Encapsulation

    
    


Encapsulate using size “20” oblong die roll

    
    
        Tumble dry the capsules
        Tunnel dry the capsules
        Inspect
        Polish
        Pack into bulk containers

Final Package into 100 count, 150 mL, HDPE bottles with heat seal caps.

4. Tentative Processing Parameter Targets

        Average Fill Weight: 877 mg±3%
        Ribbon Thickness: 0.81 mm±0.05 mm
        Tailing Edge Seam Thickness: NLT 0.25 mm
        Drying Conditions: 24° C. (21° C. to 28° C.); 20% Relative Humidity (12% to 26%)
        Drying End Point Moisture Content: ≧2% and ≦8% by LOD of capsule shell
    
    


Formulation Development included the following:
Solubility: Solubility in Single Solvents was determined either by incremental loading or by direct mixing.
Incremental loading is an addition of small portions of drug to a specific volume of solvent with mixing and gentle heating. Quantities of drug are listed below in two columns, with the highest weight of drug that dissolved in the “Soluble” column, and the lowest weight that did not dissolve listed in the “Precipitated” column. Although this method does not yield a maximum solubility of the drug in the solvent, it does give sufficient information to screen potential solvents for use in formulation.
Solvents of interest are then screened with direct loading of the drug in specific intermediate amounts, and are reported below in the same manner.
Drug loading screening studies are reported in grams of mitotane dissolved per volume of solvent. This screening method provides a quick evaluation of potentially useful solvents without correcting for the density of the individual solvents.







TABLE 4







Initial Solvent Screening Studies












Soluble (Clear
Insoluble




Solutions after
(Precipitant



Vehicle/Solvent
Mixing, g/mL)
observed, g/mL)







Capmul MCM
Not tested
0.250



Capryol TM 90
0.550
0.670



Captex ® 100
0.500
0.550



Captex ® 200
0.563
0.580



Cremophor ® EL
0.449
0.469



Ethanol
0.553
0.570



Labrafil ®
0.479
0.492



Labrasol ®
0.550
0.651



Miglyol Oil 812N
0.500
0.591



Poloxamer 124
0.189
0.204



Polyethylene Glycol 400
0.235
0.255



Polyethylene Glycol 600
0.345
0.365



Polysorbate 20
0.428
0.445



Polysorbate 80
0.475
0.495



Propylene Glycol
0.132
0.149



Soybean Oil
Not tested
0.250



Triethyl Citrate
0.750
0.837










Single vehicle solutions were selected at 50% drug loading for accelerated stability testing at 40° C./75% RH. These solutions were analyzed for assay and related substances at initial, two weeks, and four weeks.







TABLE 5







Stability Results of Single Vehicles Solutions at 50% Drug Load















Initial
2 Weeks
4 Weeks





Assay
40° C./
40° C./



Single
Batch
(% label
75% RH
75% RH



Vehicles
Number
claim)
Assay
Assay







Capryol TM
F-2772-
82.0
99.2
97.7



90
018A



Captex ®
F-2772-
90.0
77.1
77.4



100
018B



Labrasol ®
F-2772-
99.0
98.7
97.0




018C










Solvent Systems Solubility was then determined by selection of the solvents with the higher solubility, and combining them with materials of the types and ratios generally appropriate for production of SMEDD. The combinations below were tested either by incremental loading or by direct mixing, and are reported in the same manner as the single solvents. This screening method provides a quick evaluation of potentially useful solvent systems without correcting for the density of each solvent system as would be needed for reporting mitotane percent weight in each system.







TABLE 6







Solvent System Screening Studies










Clear Solutions




after Mixing
Precipitated


Solvent System (weight ratio)
(g/mL)
(g/mL)





Capmul MCM:PEG
Not tested
0.604


400:Polysorbate 80 (1:1:1)


Capryol TM 90:Captex ®
0.620
0.670


100 (1:1)


Capryol TM 90:Captex ®
0.550
0.600


100:Labrasol TM (56:22:22)


Capryol TM 90:Captex ®
0.550
0.600


100:Labrasol TM (3:1:1)


Capryol TM 90:Labrafil ®:Labrasol TM
0.527
0.546


(1:1:1)


Capryol TM 90:Labrasol TM (1:1)
0.520
0.570


Capryol TM 90:Labrasol TM:Captex ®
0.550
0.620


100 (56:22:22)


Capryol TM 90:Labrasol TM:Soybean
Not tested
0.687


Oil (1:1:1)


Capryol:Captex ® 100:Labrasol TM
0.550
0.803


(1:1:1)


Captex ® 100:Capryol TM
0.550
0.600


90:Labrasol TM (56:22:22)


Captex ® 100:Labrasol TM
0.550
0.570


(1:1)


Captex ® 100:Labrasol TM:Capryol TM
0.620
0.670


90 (56:22:22)


Labrasol TM:Capryol TM
0.600
0.650


90:Captex ® 100 (2:1:1)









Temperature dependent stability of selected mitotane solvents and solvent systems was explored by observing selected systems at 5° C. and at room temperature for 24 hours.







TABLE 7







Physical Stability of Mitotane Solutions at 5° and Room Temperature











Drug Loading





(g Drug/g
5° C. (minimum
Room Temperature


Vehicle/System (w/w)
Solvent)
24 hours)
(minimum 24 hours)





Capmul MCM
0.25
Precipitate
Clear Solution


Capmul MCM:PEG 400:Polysorbate
0.25
Clear Solution
Clear Solution


80 (1:1:1)


Capryol TM 90
0.50
Clear Solution
Clear Solution


Capryol TM 90:Captex ® 100
0.25
Clear Solution
Clear Solution


(1:1)


Capryol TM 90:Captex ®
0.50
Clear Solution
Clear Solution


100:Labrasol TM (1:1:1)


Capryol TM 90:Captex ®
0.50
Clear Solution
Not Tested


100:Labrasol TM (56:22:22)


Capryol TM 90:Captex ®
0.25
Clear Solution
Clear Solution


100:Labrasol TM (2:2:1)


Capryol TM 90:Labrasol TM:Captex ®
0.25
Clear Solution
Clear Solution


100 (2:2:1)


Capryol TM 90:Captex ®
0.25
Clear Solution
Clear Solution


100:Polysorbate 80 (1:1:1)


Capryol TM 90:Captex ®
0.40
Clear Solution
Clear Solution


100:Polysorbate 80 (1:1:1)


Capryol TM 90:Captex ®
0.40
Clear Solution
Clear Solution


100:Polysorbate 80 (22:56:22)


Capryol TM 90:Labrasol TM:Soybean
0.25
Clear Solution
Clear Solution


Oil (1:1:1)


Captex ® 100
0.50
Clear Solution
Clear Solution


Captex ® 100:Capryol TM
0.50
Clear Solution
Not Tested


90:Labrasol TM (56:22:22)


Labrafil ®
0.25
Clear Solution
Clear Solution


Labrasol TM
0.50
Clear Solution
Clear Solution


Labrasol TM:Capryol TM
0.50
Clear solution
Not Tested


90:Captex ® 100 (56:22:22)


Miglyol Oil 812N
0.25
Clear Solution
Clear Solution


Polyethylene Glycol 600
0.25
Clear Solution
Clear Solution


Polysorbate 20
0.25
Clear Solution
Clear Solution


Polysorbate 80
0.25
Clear Solution
Clear Solution


Soybean Oil
0.25
Precipitate
Clear Solution


Triethyl Citrate
0.25
Clear Solution
Clear Solution









Temperature Cycling of Selected Solvents and Solubility Systems was studied. Systems were prepared at ambient temperature, with mixed solvent in the weight ratios reported in brackets. Mitotane, 0.25 grams, was then added to 1 gram of each solvent or solvent mixture. Samples were placed in the refrigerator (5° C.±3° C.) and observations were recorded. The samples were then left at ambient temperature for 24 hours, and observations recorded. The samples were then placed in a 40° C. oven, and final observation was made after another 24 hours. These observations are recorded in the table below.
Water Tolerance was evaluated since water migration often occurs as the fill solution is exposed to wet gelatin mass during the soft gelatin encapsulation process. Therefore, portions of water were added to the mitotane solutions to determine if they would precipitate upon exposure to quantities of water that typically may migrate into the capsule fill solution.
Solvent systems were prepared at ambient temperature, with mixed solvent in the weight ratios reported in brackets in the table below. Mitotane was then added to 3 grams of each solvent or solvent mixture. (For the samples reported as 25% Drug loading, 0.75 grams of mitotane was added to the 3 grams of solvent. For samples reported as 50% Drug loading, 1.5 grams were added to 3 grams of solvent.) After the mitotane solution was obtained, 300 milligrams of water was added to the sample with vortex mixing. If the sample remained as a clear solution, a second portion of 300 milligrams of water was added and mixing repeated. (If the sample precipitated after the first addition, a second addition of water was not performed.)







TABLE 8







Water Tolerance of Mitotane Solutions










Vehicle/System
Drug
Appearance following
Appearance following


(w/w)
Loading*
addition of 10%* w/w water
addition of 20%* w/w water





Capmul MCM
25%
Hazy liquid
Not tested


Capmul MCM:PEG
25%
Hazy liquid
Not tested


400:Polysorbate 80


(1:1:1)


Capryol TM 90
50%
Hazy, precipitation
Not tested


Capryol TM 90:Captex ®
25%
Hazy, precipitation
Not tested


100 (1:1)


Capryol TM 90:Captex ®
50%
Hazy liquid
Not tested


100:Labrasol TM (1:1:1)


Capryol TM 90:Captex ®
50%
Hazy, precipitation
Not tested


100:Labrasol TM


(56:22:22)


Capryol TM 90:Captex ®
25%
Hazy, precipitation
Not tested


100:Labrasol TM (2:2:1)


Capryol TM 90:Labrasol TM:Captex ®
25%
Hazy liquid
Not tested


100 (2:2:1)


Capryol TM 90:Labrasol TM:Soybean
25%
Hazy, precipitation
Not tested


Oil (1:1:1)


Captex ® 100
50%
Immiscible/precipitation
Not tested


Captex ® 100:Capryol TM
50%
Hazy, precipitation
Not tested


90:Labrasol TM (56:22:22)


Captex ® 200
25%
Immiscible/precipitation
Not tested


Labrafil ®
25%
Hazy/precipitation
Not tested


Labrasol TM
50%
Hazy liquid
Not tested


Labrasol TM:Capryol TM
50%
Hazy, precipitation
Not tested


90:Captex ® 100


(56:22:22)


Miglyol Oil 812N
25%
Hazy, precipitation
Not tested


Polyethylene Glycol
25%
Clear liquid
Clear liquid


600


Polysorbate 20
25%
Clear yellow liquid
Clear yellow liquid


Polysorbate 80
25%
Clear yellow liquid
Clear yellow liquid


Soybean Oil
25%
Hazy, precipitation
Not tested


Triethyl Citrate
25%
Hazy liquid
Not tested





*Percent relative to the weight of solvent in the sample, not the total weight of sample.






Dilution of Mitotane Systems
Mitotane systems were tested in a 1:200 dilution (v/v) with purified water, USP or N/100 HCl. Mitotane systems (1.0 mL) were charged into 200 mL of either purified water, USP or N/100 HCl, with continuous mixing for five minutes. Samples were transferred in a glass jar. Liquids were then centrifuged for 30 minutes at 5000 rpm to prepare a pellet (if present). Drug loading ranged from 25% to 50%.
Differential Scanning Calorimetry (DSC)
After dilutions were centrifuged, pellets were evaluated using DSC. The testing method used in the evaluation of the pellets was 25° C. to 85° C.







TABLE 9







Differential Scanning Calorimetry of Mitotane Dilutions (Pellets)












Drug

Onset
Peak


System (w/w)
Loading
Media
(° C.)
(° C.)





Capryol TM 90:Captex ®
50%
Purified Water,
72.91
80.17


100:Labrasol TM (56:22:22)

USP


Capryol TM 90:Captex ®
50%
0.01N HCl
54.81
70.85


100:Labrasol TM (56:22:22)


Captex ® 100:Capryol TM
50%
Purified Water,
31.78
74.92


90 Labrasol TM (56:22:22)

USP


Captex ® 100:Capryol TM
50%
0.01N HCl
70.32
80.79


90 Labrasol TM (56:22:22)


Labrasol TM:Capryol TM
50%
Purified Water,
43.39
66.38


90:Captex ® 100:

USP


(56:22:22)


Labrasol TM:Capryol TM
50%
0.01N HCl
57.79
66.26


90:Captex ® 100:


(56:22:22)





Note:


No pellets formed from Capryol TM 90:Captex ® 100:Labrasol TM (1:1:1), with either dilulent.






Dynamic Light Scattering of Mitotane Dilutions
The supernatant liquids decanted after centrifugation were evaluated using a Nicomp ZLS Particle Sizer for Dynamic Light Scattering. DLS was tested to evaluate the globule size in the supernatant liquids. Samples were examined for two minutes at an intensity set point of approximately 300 KHz.
Formulation Selection
Based on these studies, several formulations were prepared (see Tables 10 and 11). Temperature cycling was tested to evaluate the physical stability of the three formulations F-2772-054 (33.3% drug w/w), F-2772-055 (20.0% drug w/w), and F-2772-057 (33.3% drug w/w) as well as formulations F-2772-054 and 057 at 28.5% drug w/w. F-2772-056 was eliminated because of the amount of precipitate. Temperature cycling consisted of three stages for 24 hour periods; refrigeration (5° C.), 40° C. conventional oven, and room temperature. After each 24 hour cycle, solutions were evaluated for clarity. Formulations containing 28.5% drug w/w remained in solution after temperature cycling showing the solutions were physically stable.







TABLE 10







Mitotane Formulations










Item

Drug
Intensity Diameter


No.
System (w/w)
Loading
(Gaussian) nm





1.
Capryol TM 90:Captex ®
25%
149.49 (Water)



100:Labrasol TM (1:1:1)

251.24 (0.01N HCl)


2.
Capryol TM 90:Captex ®
25%
246.63 (Water)



100:Labrasol TM

399.85 (0.01N HCl)



(56:22:22)


3.
Capryol TM 90:Captex ®
50%
 93.68 (Water)



100:Polysorbate 80

 81.03 (0.01N HCl)



(1:1:1)


  3B.
Capryol TM 90:Captex ®
25%
120.82 (Water)



100:Polysorbate 80

138.62 (0.01N HCl)



(1:1:1)


4.
Capryol TM 90:Captex ®
50%
104.48 (Water)



100:Polysorbate 80

143.95 (0.01N HCl)



(56:22:22)


5.
Capryol TM 90:Captex ®
25%
547.98 (Water)



100:Polysorbate 80

640.09 (0.01N HCl)



(22:56:22)


6.
Capryol TM 90:Captex ®
50%
125.84 (Water)



100:Polysorbate 80

138.68 (0.01N HCl)



(22:56:22)
















TABLE 11







Mitotane Formulations










Formulation












F-2772-054
F-2772-055
F-2772-057


Ingredient (s)
% w/w
% w/w
% w/w













Mitotane
28.5
20.0
28.5


Capryol TM 90
23.8
26.7
15.7


Captex ® 100
23.8
26.7
40.0


Polysorbate 80
23.8
26.7
15.7


TOTAL
100.0
100.0
100.0


Density (g/cm3)
1.05
1.03
1.04


Assay by External
99.8
99.5
97.3


Std.









SUMMARY
Drug loading of 25% wt/wt was achieved in systems containing a mixture of CapryolTM 90, Captex® 100, and LabrasolTM as well as a mixture containing Triethyl Citrate, Captex® 100, and LabrasolTM. These systems dispersed immediately upon dilution (1:200, water or dilute HCl) into a homogenous suspension, and displayed minimum (or no) oily residue before and after centrifugation, indicating an appropriate ratio of ingredients for SMEDDS formation.
In trials to achieve a stable, higher drug concentration, Polysorbate 80 was used in addition to and as a replacement for LabrasolTM as the system surfactant. Addition of Polysorbate 80 enhanced dispersion and reduced globule sizes in the CapryolTM 90 system, however this system was found to be an unstable.







TABLE 12







Observations upon Dilution of Mitotane Systems












Drug
Dilution
Observations after
Observations after


System (expressed as w/w)
Loading
(1:200 v/v)
Dilution
Centrifugation





Capryol TM 90:Captex ®
25%
Purified
Milky white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)

Water, USP
immediate emulsion
no oily residue


Capryol TM 90:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)


immediate emulsion
no oily residue


Capryol TM 90:Captex ®
30%
Purified
Cloudy white liquid,
Drug crystals- rod


100:Labrasol TM, (1:1:1)

Water, USP
immediate dispersion
shaped side of the






tube (very few crystals)


Capryol TM 90:Captex ®
30%
0.01N HCl
Cloudy white liquid,
Drug crystals- rod


100:Labrasol TM, (1:1:1)


immediate dispersion,
shaped side of the





oily residue
tube (very few crystals)


Capryol TM 90:Captex ®
40%
Purified
Cloudy white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)

Water, USP
immediate dispersion
no oily residue


Capryol TM 90:Captex ®
40%
0.01N HCl
Cloudy white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)


immediate dispersion
oily residue at bottom


Capryol TM 90:Captex ®
50%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)


precipitation, oily
oily residue at bottom





residue


Capryol TM 90:Captex ®
50%
Purified
Milky white liquid,
No pellet formation,


100:Labrasol TM, (1:1:1)

Water, USP
precipitation, oily
oily residue at bottom





residue


Capryol TM 90:Captex ®
25%
Purified
Milky white liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)

Water, USP
immediate emulsion
no oily residue


Capryol TM 90:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)


immediate emulsion
no oily residue


Capryol TM 90:Captex ®
30%
Purified
Cloudy white liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)

Water, USP
immediate dispersion
oily residue at bottom


Capryol TM 90:Captex ®
30%
0.01N HCl
Hazy liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)


delayed dispersion
oily residue at bottom


Capryol TM 90:Captex ®
40%
Purified
Hazy liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)

Water, USP
delayed dispersion
oily residue at bottom


Capryol TM 90:Captex ®
40%
0.01N HCl
Clear solution, oily
No pellet formation,


100:Labrasol TM, (56:22:22)


residue
oily residue at bottom


Capryol TM 90:Captex ®
50%
Purified
Clear solution,
Pellet formation


100:Labrasol TM, (56:22:22)

Water, USP
precipitation, oily
(precipitate)





residue


Capryol TM 90:Captex ®
50%
0.01N HCl
Clear solution,
Pellet formation


100:Labrasol TM, (56:22:22)


precipitation, oily
(precipitate)





residue


Capryol TM 90:Captex ®
25%
Purified
Milky white liquid,
No pellet formation,


100:Labrasol TM:Polysorbate 80,

Water, USP
immediate dispersion
hazy liquid


(1:1:1):1


Capryol TM 90:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Labrasol TM:Polysorbate 80,


immediate dispersion
hazy liquid


(1:1:1):1


Capryol TM 90:Captex ®
50%
Purified
Milky white liquid,
No pellet formation,


100:Labrasol TM:Polysorbate 80,

Water, USP
immediate dispersion,
gel residue


(1:1:1):1


emulsion breaking


Capryol TM 90:Captex ®
50%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Labrasol TM:Polysorbate 80,


immediate dispersion,
gel residue


(1:1:1):1


emulsion breaking


Capryol TM 90:Captex ®
25%
Purified
Milky white liquid,
No pellet formation,


100:Polysorbate 80, (1:1:1)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Polysorbate 80, (1:1:1)


immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
50%
Purified
Cloudy white liquid,
No pellet formation,


100:Polysorbate 80, (1:1:1)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
50%
0.01N HCl
Cloudy white liquid,
No pellet formation,


100:Polysorbate 80, (1:1:1)


immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
25%
Purified
Cloudy white liquid,
No pellet formation,


100:Polysorbate 80, (56:22:22)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
25%
0.01N HCl
Cloudy white liquid,
No pellet formation,


100:Polysorbate 80, (56:22:22)


immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
50%
Purified
Milky white liquid,
No pellet formation,


100:Polysorbate 80, (56:22:22)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Capryol TM 90:Captex ®
50%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Polysorbate 80, (56:22:22)


immediate dispersion
oily reside at bottom






(excessive)


Captex ® 100:Polysorbate
25%
Purified
Milky white liquid,
No pellet formation,


80:Triethyl Citrate:(1:1:1)

Water, USP
immediate dispersion
oily residue at bottom






(excessive)


Captex ® 100:Capryol TM
25%
0.01N HCl
Milky white liquid,
No pellet formation,


90:Labrasol TM, (56:22:22)


immediate emulsion
oily residue at bottom


Captex ® 100:Capryol TM
30%
Purified
Cloudy white liquid,
No pellet formation,


90:Labrasol TM, (56:22:22)

Water, USP
immediate dispersion
no oily residue


Captex ® 100:Capryol TM
30%
0.01N HCl
Cloudy white liquid,
No pellet formation,


90:Labrasol TM, (56:22:22)


immediate dispersion
oily residue at bottom


Captex ® 100:Capryol TM
40%
Purified
Cloudy white liquid,
No pellet formation,


90:Labrasol TM, (56:22:22)

Water, USP
immediate dispersion
oily residue at bottom


Captex ® 100:Capryol TM
40%
0.01N HCl
Cloudy white liquid,
Drug crystals- rod


90:Labrasol TM, (56:22:22)


immediate dispersion
shaped side of the






tube (very few crystals)


Captex ® 100:Capryol TM
50%
Purified
Clear solution,
Pellet formation


90:Labrasol TM, (56:22:22)

Water, USP
precipitation, oily
(semi-solid)





residue


Captex ® 100:Capryol TM
50%
0.01N HCl
Clear solution,
Pellet formation


90:Labrasol TM, (56:22:22)


precipitation, oily
(semi-solid)





residue


Captex ® 100:Capryol TM
25%
Purified
Milky white liquid,
No pellet formation,


90:Labrasol TM, (56:22:22)*

Water, USP
immediate emulsion
oily residue at bottom


Captex ® 100:Capryol TM
25%
Purified
Cloudy white liquid,
No pellet formation,


90:Polysorbate 80, (56:22:22)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Captex ® 100:Capryol TM
25%
0.01N HCl
Cloudy white liquid,
No pellet formation,


90:Polysorbate 80, (56:22:22)


immediate dispersion
oily reside at bottom






(excessive)


Captex ® 100:Capryol TM
50%
Purified
Milky white liquid,
No pellet formation,


90:Polysorbate 80, (56:22:22)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Captex ® 100:Capryol TM
50%
0.01N HCl
Milky white liquid,
No pellet formation,


90:Polysorbate 80, (56:22:22)


immediate dispersion
oily reside at bottom






(excessive)


Captex ® 100:Labrasol TM:Triethyl
25%
Purified
Cloudy white liquid,
No pellet formation,


Citrate, (1:1:1)

Water, USP
immediate dispersion,
no oily residue





oily residue


Captex ® 100:Labrasol TM:Triethyl
25%
0.01N HCl
Cloudy white liquid,
No pellet formation,


Citrate, (1:1:1)


immediate dispersion,
no oily residue





oily residue


Captex ® 100:Labrasol TM:Triethyl
50%
Purified
Cloudy white liquid,
No pellet formation,


Citrate, (1:1:1)

Water, USP
delayed dispersion,
no oily residue





oily residue


Captex ® 100:Labrasol TM:Triethyl
50%
0.01N HCl
Milky white liquid,
Pellet formation


Citrate, (1:1:1)


delayed dispersion,
(semi-solid)





oily residue


Captex ® 100:Labrasol TM:Triethyl
25%
Purified
Hazy liquid, delayed
No pellet formation,


Citrate, (56:22:22)

Water, USP
dispersion, oily
oily residue at bottom





residue


Captex ® 100:Labrasol TM:Triethyl
25%
0.01N HCl
Cloudy white liquid,
No pellet formation,


Citrate, (56:22:22)


immediate dispersion,
oily residue at bottom





oily residue


Captex ® 100:Labrasol TM:Triethyl
50%
Purified
Cloudy white
Drug crystals- rod


Citrate, (56:22:22)

Water, USP
liquid, delayed
shaped side of the





dispersion, oily
tube (very few crystals)





residue


Captex ® 100:Labrasol TM:Triethyl
50%
0.01N HCl
Cloudy white liquid,
Pellet formation


Citrate, (56:22:22)


delayed dispersion,
(precipitation)





oily residue


Captex ® 100:Polysorbate
25%
Purified
Milky white liquid,
No pellet formation,


80:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion
oily residue at bottom






(excessive)


Captex ® 100:Polysorbate
25%
0.01N HCl
Milky white liquid,
Pellet formation


80:Triethyl Citrate, (56:22:22)


immediate dispersion
(semi-solid)


Captex ® 100:Polysorbate
50%
Purified
Milky white liquid,
Pellet formation


80:Triethyl Citrate, (1:1:1)

Water, USP
immediate dispersion,
(semi-solid)





oily residue


Captex ® 100:Polysorbate
50%
0.01N HCl
Milky white liquid,
Pellet formation


80:Triethyl Citrate, (1:1:1)


immediate dispersion,
(semi-solid)





oily residue


Labrasol TM:Capryol TM
25%
Purified
Milky white liquid,
No pellet formation,


90:Captex ® 100, 22:22:56

Water, USP
immediate emulsion
oily residue at bottom


Labrasol TM:Capryol TM
25%
0.01N HCl
Milky white liquid,
No pellet formation,


90:Captex ® 100, 22:22:56


immediate emulsion
oily residue at bottom


Labrasol TM:Capryol TM
30%
Purified
Milky white liquid,
No pellet formation,


90:Captex ® 100, (56:22:22)

Water, USP
immediate dispersion,
oily residue at bottom





oily residue


Labrasol TM:Capryol TM
30%
0.01N HCl
Milky white liquid,
No pellet formation,


90:Captex ® 100, (56:22:22)


immediate dispersion,
no oily residue





oily residue


Labrasol TM:Capryol TM
40%
Purified
Milky white liquid,
Pellet formation


90:Captex ® 100, (56:22:22)

Water, USP
immediate dispersion
(semi-solid)


Labrasol TM:Capryol TM
40%
0.01N HCl
Milky white liquid,
Pellet formation


90:Captex ® 100, (56:22:22)


immediate dispersion,
(semi-solid)





oily residue


Labrasol TM:Capryol TM
50%
Purified
Clear solution,
Pellet formation


90:Captex ® 100, (56:22:22)

Water, USP
precipitation, oily
(semi-solid)





residue


Labrasol TM:Capryol TM
50%
0.01N HCl
Clear solution,
Pellet formation


90:Captex ® 100, (56:22:22)


precipitation, oily
(semi-solid)





residue


Labrasol TM:Captex ®
25%
Purified
Cloudy white liquid,
No pellet formation,


100:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion,
no oily residue





oily residue


Labrasol TM:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Triethyl Citrate, (56:22:22)


immediate dispersion,
no oily residue





oily residue


Labrasol TM:Captex ®
50%
Purified
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion,
(semi-solid)





oily residue


Labrasol TM:Captex ®
50%
0.01N HCl
Cloudy white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)


delayed dispersion,
(semi-solid)





oily residue


Polysorbate 80:Capryol TM
25%
Purified
Milky white liquid,
No pellet formation,


90:Captex ® 100, (56:22:22)

Water, USP
immediate dispersion
oily reside at bottom






(excessive)


Polysorbate 80:Capryol TM
25%
0.01N HCl
Milky white liquid,
No pellet formation,


90:Captex ® 100, (56:22:22)


immediate dispersion
oily reside at bottom






(excessive)


Polysorbate 80:Capryol TM
50%
Purified
Milky white liquid,
Pellet formation


90:Captex ® 100, (56:22:22)

Water, USP
immediate dispersion
(semi-solid)


Polysorbate 80:Capryol TM
50%
0.01N HCl
Milky white liquid,
Pellet formation


90:Captex ® 100, (56:22:22)


immediate dispersion
(semi-solid)


Polysorbate 80:Captex ®
50%
Purified
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion,
(semi-solid)





oily residue


Polysorbate 80:Captex ®
50%
0.01N HCl
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)


immediate dispersion,
(semi-solid)





oily residue


Polysorbate 80:Captex ®
25%
0.01N HCl
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)


immediate dispersion
(semi-solid)


Polysorbate 80:Captex ®
25%
0.01N HCl
Milky white liquid,
No pellet formation,


100:Triethyl Citrate, (56:22:22)


immediate dispersion
oily residue at bottom






(excessive)


Polysorbate 80:Captex ®
25%
Purified
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion
(semi-solid)


Polysorbate 80:Captex ®
50%
Purified
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)

Water, USP
immediate dispersion,
(semi-solid)





oily residue


Polysorbate 80:Captex ®
50%
0.01N HCl
Milky white liquid,
Pellet formation


100:Triethyl Citrate, (56:22:22)


immediate dispersion,
(semi-solid)





oily residue


Triethyl Citrate:Captex ®
25%
Purified
Hazy liquid,
No pellet formation,


100:Labrasol TM, (56:22:22)

Water, USP
immediate dispersion,
no oily residue





oily residue


Triethyl Citrate:Captex ®
50%
Purified
Hazy liquid,
Pellet formation


100:Labrasol TM, (56:22:22)

Water, USP
delayed dispersion,
(semi-solid)





oily residue


Triethyl Citrate:Captex ®
50%
0.01N HCl
Cloudy white liquid,
Pellet formation


100:Labrasol TM, (56:22:22)


delayed dispersion,
(semi-solid)





oily residue


Triethyl Citrate:Captex ®
25%
0.01N HCl
Hazy liquid, delayed
No pellet formation,


100:Labrasol TM, (56:22:22)


dispersion, oily
no oily residue





residue


Triethyl Citrate:Captex ®
50%
Purified
Milky white liquid,
Pellet formation


100:Polysorbate 80 (56:22:22)

Water, USP
immediate dispersion,
(semi-solid)





oily residue


Triethyl Citrate:Captex ®
50%
0.01N HCl
Milky white liquid,
Pellet formation


100:Polysorbate 80 (56:22:22)*


immediate dispersion,
(semi-solid)





oily residue


Triethyl Citrate:Captex ®
25%
Purified
Cloudy white liquid,
Pellet formation


100:Polysorbate 80, (56:22:22)

Water, USP
immediate dispersion
(semi-solid)


Triethyl Citrate:Captex ®
25%
0.01N HCl
Cloudy white liquid,
No pellet formation,


100:Polysorbate 80, (56:22:22)


immediate dispersion
oily residue at bottom






(excessive)









The highest mitotane concentration trial that was found to be the most stable was 28.5% weight/weight, or 40% drug loading (28.5/(100-28.5)=40% drug loading).
Due to the drug precipitation overnight in some samples, selected systems were retested at 50% and 55% drug loading in a direct loading solubility study.







TABLE 13







Dynamic Light Scattering of Supernatant Liquids

















Intensity








Dilution
Diameter
Standard


System
Drug
1:200
(Gaussian)
Deviation


Fit


(expressed as w/w)
Loading
(v/v)
nm
nm
Chi2
Decay
Error

















Capryol TM 90:Captex ®
25%
Purified
149.49
78.03
2.299
2.172
5.105


100:Labrasol TM, (1:1:1)

Water, USP


Capryol TM 90:Captex ®
25%
0.01N
251.24
96.22
3.139
2.355
8.831


100:Labrasol TM, (1:1:1)

HCl


Capryol TM 90:Captex ®
50%
Purified
192.04
46.47
0.34
2.599
11.317


100:Labrasol TM, (1:1:1)

Water, USP


Capryol TM 90:Captex ®
50%
0.01N
579.06
216.57
6.344
2.408
5.511


100:Labrasol TM, (1:1:1)

HCl


Capryol TM 90:Captex ®
25%
Purified
246.63
148.72
6.079
2.394
5.655


100:Labrasol TM, (56:22:22)

Water, USP


Capryol TM 90:Captex ®
25%
0.01N
399.85
170.34
1.91
2.532
10.43


100:Labrasol TM, (56:22:22)

HCl


Capryol TM 90:Captex ®
50%
Purified
197.87
50.06
1.142
2.431
22.115


100:Labrasol TM, (56:22:22)

Water, USP


Capryol TM 90:Captex ®
50%
0.01N
380.41
159.52
0.883
2.33
15.389


100:Labrasol TM, (56:22:22)

HCl


Capryol TM 90:Captex ®
25%
Purified
148.99
89.24
2.885
2.435
6.165


100:Labrasol TM:Polysorbate 80,

Water, USP


(1:1:1:1)


Capryol TM 90:Captex ®
25%
0.01N
153.44
94.52
6.007
2.363
8.267


100:Labrasol TM:Polysorbate 80,

HCl


(1:1:1:1)


Capryol TM 90:Captex ®
50%
Purified
249.86
176.15
104.628
2.439
6.835


100:Labrasol TM:Polysorbate 80,

Water, USP


(1:1:1:1)


Capryol TM 90:Captex ®
50%
0.01N
273.31
209.08
122.608
2.372
6.275


100:Labrasol TM:Polysorbate 80,

HCl


(1:1:1:1)


Capryol TM 90:Captex ®
25%
Purified
120.82
55.94
2.273
2.37
9.598


100:Polysorbate 80, (1:1:1)

Water, USP


Capryol TM 90:Captex ®
25%
0.01N
138.62
61.96
1.725
2.48
7.598


100:Polysorbate 80, (1:1:1)

HCl


Capryol TM 90:Captex ®
50%
Purified
93.68
36.44
1.307
2.439
10.223


100:Polysorbate 80, (1:1:1)

Water, USP


Capryol TM 90:Captex ®
50%
0.01N
81.03
36.95
5.457
2.351
4.614


100:Polysorbate 80, (1:1:1)

HCl


Capryol TM 90:Captex ®
25%
Purified
131.31
71.56
23.15
2.484
7.392


100:Polysorbate 80, (56:22:22)

Water, USP


Capryol TM 90:Captex ®
25%
0.01N
392.44
313.95
133.58
2.45
5.42


100:Polysorbate 80, (56:22:22)

HCl


Capryol TM 90:Captex ®
50%
Purified
104.48
57.36
11.872
2.558
10.424


100:Polysorbate 80, (56:22:22)

Water, USP


Capryol TM 90:Captex ®
50%
0.01N
143.95
82.05
36.573
2.52
9.186


100:Polysorbate 80, (56:22:22)

HCl


Captex ® 100:Capryol TM
25%
Purified
127.65
66.88
2.57
2.395
7.469


90:Polysorbate 80, (56:22:22)

Water, USP


Captex ® 100:Capryol TM
25%
0.01N
225.36
159.55
37.175
2.809
8.54


90:Polysorbate 80, (56:22:22)

HCl


Captex ® 100:Capryol TM
50%
Purified
125.84
70.47
10.714
2.411
8.912


90:Polysorbate 80, (56:22:22)

Water, USP


Captex ® 100:Capryol TM
50%
0.01N
138.68
83.76
9.857
2.624
8.937


90:Polysorbate 80, (56:22:22)

HCl


Captex ® 100:Labrasol TM:Triethyl
50%
0.01N
1080.6
637.55
14.632
2.491
1793.64


Citrate, (1:1:1)

HCl


Captex ® 100:Labrasol TM:Triethyl
25%
Purified
142.51
44.03
0.44
2.551
13.836


Citrate, (56:22:22)

Water, USP


Captex ® 100:Labrasol TM:Triethyl
25%
Purified
136.98
35.2
1.919
2.513
20.442


Citrate (1:1:1)

Water, USP


Captex ® 100:Polysorbate
25%
Purified
131.92
54.48
2.263
2.455
7.245


80:Triethyl Citrate, (1:1:1)

Water, USP


Captex ® 100:Polysorbate
25%
0.01N
127
82.27
0.999
2.561
10.035


80:Triethyl Citrate, (1:1:1)

HCl


Captex ® 100:Polysorbate
50%
Purified
98.43
52.27
4.069
2.518
7.942


80:Triethyl Citrate, (1:1:1)

Water, USP


Captex ® 100:Polysorbate
50%
0.01N
103.26
54.11
2.981
2.587
7.047


80:Triethyl Citrate, (1:1:1)

HCl


Captex ® 100:Polysorbate
25%
Purified
126.43
62.08
1.564
2.886
5.675


80:Triethyl Citrate, (56:22:22)

Water, USP


Captex ® 100:Polysorbate
25%
0.01N
139.7
77.11
5.804
2.46
9.841


80:Triethyl Citrate, (56:22:22)

HCl


Captex ® 100:Polysorbate
50%
Purified
126.67
70.05
1.874
2.415
7.452


80:Triethyl Citrate, (56:22:22)

Water, USP


Captex ® 100:Polysorbate
50%
0.01N
117.53
60.17
0.971
2.443
6.369


80:Triethyl Citrate, (56:22:22)

HCl


Captex ® 100:Capryol TM
50%
Purified
213.42
45.03
0.93
2.356
5.465


90:Labrasol TM, (56:22:22)

Water, USP


Captex ® 100:Capryol TM
50%
0.01N
569.76
394.84
1.358
2.361
10.067


90:Labrasol TM, (56:22:22)

HCl


Captex ® 100:Capryol TM
25%
Purified
547.98
415.92
42.277
2.343
3.88


90:Labrasol TM, (56:22:22)

Water, USP


Captex ® 100:Capryol TM
25%
0.01N
640.09
410.3
15.47
2.37
5.327


90:Labrasol TM, (56:22:22)

HCl


Captex ®100:Labrasol TM:Triethyl
25%
0.01N
512.67
309.65
28.203
2.595
5.787


Citrate, (56:22:22)

HCl


Captex ® 100:Labrasol TM:Triethyl
50%
Purified
151.03
24.62
0.855
2.403
9.435


Citrate, (56:22:22)

Water, USP


Captex ®100:Labrasol TM:Triethyl
25%
0.01N
967.49
521.47
17.912
2.579
1843.23


Citrate, (1:1:1)

HCl


Captex ®100:Labrasol TM:Triethyl
50%
0.01N
1256.38
741.27
116.546
2.107
1572.65


Citrate, (56:22:22)

HCl


Labrasol TM:Capryol TM
25%
Purified
121.46
50.77
1.4
2.522
6.999


90:Captex ® 100, (56:22:22)

Water, USP


Labrasol TM:Capryol TM
25%
0.01N
267.43
23.27
0.185
3.067
9.94


90:Captex ® 100, (56:22:22)

HCl


Labrasol TM:Capryol TM
50%
Purified
162.18
24.65
0.652
2.498
11.071


90:Captex ® 100, (56:22:22)

Water, USP


Labrasol TM:Capryol TM
50%
0.01N
2140.74
1485.67
7.137
1.821
1506.17


90:Captex ® 100, (56:22:22)

HCl


Labrasol TM:Captex ®
25%
Purified
119.93
20.51
1.825
2.387
12.02


100:Triethyl Citrate, (56:22:22)

Water, USP


Labrasol TM:Captex ® 100:Triethyl
50%
0.01N
281.59
144.74
0.449
2.448
6.331


Citrate, (56:22:22)

HCl


Labrasol TM:Captex ® 100:Triethyl
50%
Purified
171.38
71.64
1.226
2.451
8.004


Citrate, (56:22:22)

Water, USP


Labrasol TM:Captex ® 100:Triethyl
25%
0.01N
858.78
490.36
18.004
2.236
1476.04


Citrate, (56:22:22)

HCl


Polysorbate 80:Capryol TM
25%
Purified
116.29
51.52
1.541
2.466
8.594


90:Captex ® 100, (56:22:22)

Water, USP


Polysorbate 80:Capryol TM
25%
Purified
116.29
51.52
1.541
2.4665
8.594


90:Captex ® 100, (56:22:22)

Water, USP


Polysorbate 80:Capryol TM
25%
0.01N
93.68
36.44
1.307
2.439
10.233


90:Captex ® 100,(56:22:22)

HCl


Polysorbate 80:Capryol TM
50%
Purified
101.75
33.07
0.635
2.438
8.903


90:Captex ® 100, (56:22:22)

Water, USP


Polysorbate 80:Capryol TM
50%
0.01N
100.78
20.96
0.599
2.463
8.643


90:Captex ® 100, (56:22:22)

HCl


Polysorbate 80:Captex ®
25%
Purified
104.37
51.87
1.281
2.376
8.822


100:Triethyl Citrate, (56:22:22)

Water, USP


Polysorbate 80:Captex ®
25%
0.01N
106.35
31.59
1.422
2.517
15.046


100:Triethyl Citrate, (56:22:22)

HCl


Polysorbate 80:Captex ®
50%
Purified
110.01
49.17
0.462
2.44
7.309


100:Triethyl Citrate, (56:22:22)

Water, USP


Polysorbate 80:Captex ®
50%
0.01N
114.97
37.59
7.5
2.492
11.166


100:Triethyl Citrate, (56:22:22)

HCl


Triethyl Citrate:Captex ®
50%
Purified
136.66
16.67
0.814
2.523
9.782


100:Labrasol TM, (1:1:1)

Water, USP


Triethyl Citrate:Captex ®
25%
Purified
154.92
84.59
4.659
2.357
11.19


100:Labrasol TM, (56:22:22)

Water, USP


Triethyl Citrate:Captex ®
25%
0.01N
541.6
298.96
2.746
2.654
5.985


100:Labrasol TM, (56:22:22)

HCl


Triethyl Citrate:Captex ®
50%
Purified
158.37
46.09
1.002
2.29
14.573


100:Labrasol TM, (56:22:22)

Water, USP


Triethyl Citrate:Captex ®
50%
0.01N
965.26
412.17
0.862
2.77
2314.71


100:Labrasol TM, (56:22:22)

HCl


Triethyl Citrate:Captex ®
25%
Purified
126.57
77.33
7.996
2.71
10.059


100:Polysorbate 80, (56:22:22)

Water, USP


Triethyl Citrate:Captex ®
25%
0.01N
112.11
44.17
0.686
2.388
6.75


100:Polysorbate 80, (56:22:22)

HCl


Triethyl Citrate:Captex ®
50%
Purified
164.69
102.6
3.606
2.318
6.345


100:Polysorbate 80, (56:22:22)

Water, USP


Triethyl Citrate:Captex ®
50%
0.01N
187.73
121.09
18.036
2.642
7.277


100:Polysorbate 80, (56:22:22)

HCl









All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

## Claims

1. A method of increasing the bioavailability of mitotane comprising preparing a formulation comprising (a) between 33% and 67% (w/w) mitotane, (b) 10-30% (w/w) polysorbate, (c) 10-30% (w/w) propylene glycol monocaprylate, and (d) 20-60% (w/w) propylene glycol dicaprate, wherein the formulation is substantially free of a polar solvent, and administering the formulation to a host.

2. The method of claim 1, wherein the formulation comprises between 37% and 54% (w/w) mitotane.

3. The method of claim 2, wherein the formulation comprises about 50% (w/w) mitotane.

4. The method of claim 1, wherein the formulation comprises 15-20% (w/w) propylene glycol monocaprylate, 35-50% (w/w) propylene glycol dicaprate, and 15-20% (w/w) polysorbate.

5. The method of claim 2 wherein the formulation comprises 15-17% (w/w) propylene glycol monocaprylate, 38-42% (w/w) propylene glycol dicaprate, and 15-17% (w/w) polysorbate.

6. The method of claim 1 wherein the polysorbate is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and mixtures thereof.

7. The method of claim 6, wherein the polysorbate is polysorbate 80.