WO2012010942A2

WO2012010942A2 - Novel pharmaceutical composition(s) of hiv protease inhibitor(s)

Info

Publication number: WO2012010942A2
Application number: PCT/IB2011/001656
Authority: WO
Inventors: Ashish Ashokrao Deshmukh; Pravin Meghrajji Bhutada; Sajeev Chandran; Shirishkumar Kulkarni
Original assignee: Lupin Limited
Priority date: 2010-07-22
Filing date: 2011-07-18
Publication date: 2012-01-26
Also published as: WO2012010942A3

Abstract

The present invention provides an alcohol free, soluble, stable, taste masked pharmaceutical composition(s) for the administration of HIV protease inhibitors and pharmaceutically acceptable salts thereof. These compositions can optionally be encapsulated in hard or soft gelatin capsules.

Description

NOVEL PHARMACEUTICAL COMPOSITIONS) OF HIV

PROTEASE INHIBITOR(S)

Field of the Invention

The present invention provides an alcohol free, soluble, stable, taste masked pharmaceutical composition(s) for the administration of HIV protease inhibitors and pharmaceutically acceptable salts thereof.

More specifically the pharmaceutical composition(s) comprises a HIV protease inhibitor (s), which is essentially alcohol free. The pharmaceutical compositions of the present invention are suitable for the preparation of liquid oral composition(s) for the administration of HIV protease inhibitor(s) and optionally for the encapsulation in soft gelatin capsules or in hard gelatin capsules.

Background of the invention

Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). Antiretroviral (ARV) drugs are medications for the treatment of infection by retroviruses, primarily HIV and they are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. AIDS treatment ("Acquired Immunodeficiency Syndrome") employs medicines which have to be administrated daily; and which treatment preferably should not be interrupted at all for the rest of the infected individual's lives.

The success of AIDS treatment with antiretroviral drugs depends mainly upon the patient adherence to the therapy itself, consisting this therapy in the administration of significant amounts of different medicines several times a day.

One of the components from the anti-AIDS cocktail corresponds to a class of drugs known as protease inhibitors which act by inhibiting the retroviral protease. Proteases are enzymes that cleave proteins at specific peptide bonds, and many significant biological functions are controlled or mediated by proteases and their inhibitors. Protease inhibitors (Pi's) are substances with high molecular weight, with a lipophilic character, slightly or very slightly soluble in water and usually exhibit low absorption and low bioavailability profile when therapeutically administered in solid dosage form. Due to these characteristics, elevated dose and more frequent administration of dosage form are necessary for maintenance of an ideal therapeutically effective circulating level of the drugs like Pis.

Examples of HIV protease inhibitors include Saquinavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir, Ritonavir, Fosamprenavir, Atazanavir, Tipranavir and Darunavir. The administration of Protease inhibitors as liquid oral dosage forms are not well accepted by patients owing to its bad taste and stability issues.

Several attempts have been made to improve the formulations comprising protease inhibitor(s).

US Patent No. 5,948,436 and US 5,484,801 disclose the pharmaceutical compositions comprising a solution form of ritonavir in pharmaceutically acceptable alcohols.

Improved pharmaceutical compositions of ritonavir in a pharmaceutically acceptable medium and/or long chain fatty acids, ethanol or propylene glycol, and water are disclosed in US Patent No. 6,458,818; US 6,232,333; US 6,521,651 ; US 7,141,593 and US 7,432,594. WO 2005/007070 discloses stable pharmaceutical compositions comprising ritonavir, medium chain mono/triglycerides, surfactant, antioxidants, emulsion stabilizer and polarity corrector. US 7,632,853 describe soluble, stable pharmaceutical compositions comprising suitable pharmaceutical organic solvents, a surfactant and a bioavailability enhancer for the administration of HIV protease inhibitors.

The currently available liquid oral pharmaceutical compositions of HIV protease inhibitors include Ritonavir oral solution (commercially available as Norvir^®), Lopinavir and Ritonavir oral solution (commercially available as Kaletra ).

Alcohol is an essential part of the compositions as is evident from the products available in the market. These commercially available solutions have a high amount of alcohol (42-43% volume by volume) in the compositions.

Such compositions suffer from severe drawback of instability due to evaporation of a low boiling solvent like alcohol. This is particularly true as the products are used in home environment, can not be precisely controlled with respect to temperature.

It is also well known that the use of alcohol at such a high level has not been regarded as beneficial from an overall health standpoint.

Especially in geriatrics, chronic exposure has been found to result in gum "burn" by the alcohol. Alcoholic solutions often result in a "dry mouth" sensation, while recovering alcoholics cannot be subjected to alcohol in any form. Similarly, accidental ingestion of the product containing high level of alcohol by children could result in significant alcohol-related toxicity and could approach the potential lethal dose of alcohol. Moreover, severe incidences of vomiting and nausea can occur if one is taking metronidazole or disulfuram along with Norvir and Kaletra solution.

Propylene glycol based HIV protease inhibitor solution such as Agenerase^® [Amprenavir] is available in market. However, propylene glycol has been linked to many severe health problems including contact dermatitis (irritation), auto toxicity, kidney damage and liver abnormalities.

Although much progress has been made toward treating AIDS, none of the current treatments have proven to be totally effective in reversing the disease. In addition, many of the pharmaceutically active agents useful in treating AIDS have a bitter taste that discourages patients from complying with their drug taking regimen.

There exists a need to develop a soluble, stable, taste masked pharmaceutical composition(s) of HIV protease inhibitor(s) which is alcohol free.

Object of the Invention

In accordance, an object of the invention is to provide a soluble, stable, taste masked pharmaceutical composition(s) of HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which is alcohol free.

Yet another object of the invention is to provide a soluble, stable, taste masked, pharmaceutical composition(s) of HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which is essentially alcohol free. Yet another object of the present invention is to provide a soluble, stable, taste masked pharmaceutical composition(s) which comprises (a) an HIV protease inhibiting compound or a combination of HIV protease inhibiting compounds (preferably, Ritonavir or Saquinavir or Nelfinavir or Indinavir or Amprenavir or Fosamprenavir or Atazanavir or Tipranavir or Darunavir or Lopinavir) or a pharmaceutical acceptable salts or solvates thereof and (b) a pharmaceutically acceptable organic solvent or a mixture of pharmaceutically acceptable organic solvents, wherein the solvent is essentially free of alcohol.

Yet another object of the invention is to provide a soluble, stable, taste masked pharmaceutical composition(s) of HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which is essentially alcohol free wherein the composition(s) is encapsulated in a soft gelatin capsules or in a hard gelatin capsule.

Yet another object of the invention is to provide a soluble, stable, taste masked pharmaceutical composition(s) of HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which can find utility in pediatric and geriatric patient populations.

Detailed Description of the Invention

The novel pharmaceutical composition(s) of the present invention typically contains HIV Protease inhibitor(s) or its pharmaceutically acceptable complexes, salts, polymorphs, hydrates, solvates, racemate, single enantiomer, in base form or in acid addition salts thereof.

Herein, the term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. Also it means that which is useful in preparing a pharmaceutical composition(s) that is generally safe and neither biologically nor otherwise undesirable and includes that which is acceptable for human pharmaceutical use. This invention provides HIV protease inhibitor composition(s) free of alcohols such as ethanol, propanol, alkyl alcohols and alkylene alcohols for oral use and a process for preparation of the same. The invention further provides composition(s) comprising HIV protease inhibitors which are stable under varying temperature and humidity.

For the purposes of the present invention, the term "alcohol-free" shall mean that alcohol is completely absent.

The term "essentially alcohol free" as used herein refers to the presence of alcohol in the pharmaceutical composition up to 10% w/w.

The term "pharmaceutically acceptable organic solvent" as used herein refers to polyoxyethylene castor oil derivatives (for example, polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (Cremophor RTM EL), polyoxyethyleneglycerol oxystearate (Cremophor^®RH 40 (polyethyleneglycol 40 hydrogenated castor oil) or Cremophor^® RH 60 (polyethyleneglycol 60 hydrogenated castor oil), and the like; saturated polyglycolized glycerides (for example, Gelucire^® 35/10, Gelucire^® 44/14, Gelucire^® 46/07, Gelucire^® 50/13 or Gelucire^® 53/10 and the like; polyoxyethylene alkyl ethers (for example, cetomacrogol 1000 and the like); polyoxyethylene stearates (for example, PEG-6 stearate, PEG-8 stearate, polyoxyl 40 stearate NF, polyoxyethyl 50 stearate NF, PEG- 12 stearate, PEG-20 stearate, PEG- 100 stearate, PEG- 12 distearate, PEG-32 distearate, PEG- 150 distearate and the like); ethyl oleate, isopropyl palmitate, isopropyl myristate and the like; dimethyl isosorbide; N- methylpyrrolidinone; paraffin; cholesterol; lecithin; suppository bases; pharmaceutically acceptable waxes (for example, carnauba wax, yellow wax, white wax, microcrystalline wax, emulsifying wax and the like); pharmaceutically acceptable silicon fluids; sorbitan fatty acid esters (including sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate and the like); pharmaceutically acceptable saturated fats or pharmaceutically acceptable saturated oils (for example, hydrogenated castor oil (glyceryl-tris-12-hydroxystearate), cetyl esters wax (a mixture of primarily Ci₄-C₁₈ saturated esters of C₁ -Ci₈ saturated fatty acids having a melting range of about 43-47°C), glyceryl monostearate and the like);

Pharmaceutically acceptable solvents also include pharmaceutically acceptable oils such as mineral oil or a vegetable oil (for example, safflower oil, peanut oil, olive oil, fractionated coconut oil), mixed triglycerides with caprylic acid and capric acid (for example, IMWITOR 307 & 988, Capmul MCM C8), propyleneglycol monolaurate and the like.

Preferably, the pharmaceutically acceptable organic solvent comprises from about 5 to 85% by weight of the total solution. More preferably pharmaceutically acceptable organic solvent or mixture of pharmaceutically acceptable organic solvents comprises from about 10 to about 50% by weight of the total solution.

The pharmaceutical composition(s) of the present invention may include but not limited to one or more pharmaceutically acceptable additives such as surfactants, stabilizers, antioxidants, flavoring agents, viscosity controlling agents, preservatives and sweeteners or combinations thereof.

The pharmaceutical composition(s) of the present invention may further include viscosity- controlling agents and optionally emulsifiers.

Suitable surfactants/emulsifiers include, but are not limited to, polyoxyethylene castor oil derivatives (for example, polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (Cremophor^® EL, BASF Corp.) or polyoxyethyleneglycerol oxystearate (Cremophor^® RH 40 (polyethylene glycol 40 hydrogenated castor oil)) or Cremophor^® RH 60 (polyethylene glycol 60 hydrogenated castor oil), BASF Corp. and the like) or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropylene glycol, such as Poloxamer^®124, Poloxamer^®188, Poloxamer^®237, Poloxamer^®388, Poloxamer^®407 and the like, (BASF Wyandotte Corp.) or a mono fatty acid ester of polyoxyethylene (20) sorbitan (for example, polyoxyethylene (20) sorbitan monooleate (Tween^®80), polyoxyethylene (20) sorbitan monostearate (Tween^®60), polyoxyethylene (20) sorbitan monopalmitate (Tween^®40), polyoxyethylene (20) sorbitan monolaurate (Tween^®20) and the like) or a sorbitan fatty acid ester (including sorbitan laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate and the like). A preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil (Cremophor^®EL, BASF Corp.), polyoxyethylene (20) sorbitan monolaurate (Tween^®20), polyoxyethylene (20) sorbitan monooleate (Tween^®80) or a sorbitan fatty acid ester, for example sorbitan oleate. A most preferred pharmaceutically acceptable surfactant is polyoxyl 35 castor oil (Cremophor^®EL, BASF Corp.).

The concentration of the surfactants may range from 1 to 70% w/w, particularly from 5 to 50% w/w, and most particularly is about 6.5% w/w in oral solution and 45% w/win capsules. The most preferred surfactant is CREMOPHORE EL and RH 40 used alone or in combinations.

Suitable stabilizers include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid and the like, (ii) an organic mono-, di- or tri-carboxylic acid (for example, formic acid, acetic acid, adipic acid, alginic acid, citric acid, ascorbic acid, aspartic acid, benzoic acid, butyric acid, camphoric acid, gluconic acid, glucuronic acid, galactaronic acid, glutamic acid, heptanoic acid, hexanoic acid, fumaric acid, lactic acid, lactobionic acid, malonic acid, maleic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, succinic acid, tartaric acid, undecanoic acid and the like) or (iii) a sulfonic acid (for example, benzenesulfonic acid, sodium bisulfate, sulfuric acid, camphorsulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, methanesulfonic acid, isethionic acid, naphthalenesulfonic acid, p-toluenesulfonic acid and the like. The concentration of the stabilizers may range from 0.1 to 0.3 % w/w, particularly from 0.15 to 0.25 % w/w, and most particularly is about 0.2 % w/w.

Suitable preservatives include, but are not limited to, benzoic acid, sorbic acid, methylparaben, propylparaben, imidazolidinyl urea and diazolidinyl urea, phenoxetol, benzyl alcohol, quaternary compounds, e.g. benzylalkonium chloride, and the like.

The preservatives, such as benzoic acid, sorbic acid, imidazolidinyl urea and diazolidinyl urea and benzyl alcohol are preferred as they yield clear, transparent solutions which do not show any clouding upon storage.

The concentration of the preservatives may range from 0.01 to 2 % w/w, particularly from 0.1 to 0.5 % w/w, and most particularly is about 0.5 % w/w. Suitable antioxidants include, but are not limited to ascorbic acid, BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), vitamin E, vitamin E PEG 1000 succinate and the like.

The concentration of the antioxidants may range from 0.001 to 0.08 % w/w, particularly from 0.01 to 0.05 % w/w, and most particularly is about 0.025 % w/w.

Suitable flavoring agents include, but are not limited to cherry flavor, artificial banana flavor, caramel, chocolate mint flavor, grape flavor, wild cherry flavor, raspberry flavor, strawberry flavor, citrus flavor, orange flavor, pineapple flavor, citrus lime flavor, citrus cream flavor, cherry vanilla flavor, creme de menthe flavor.

The concentration of the flavoring agent may range from 0.1 to 20 % w/w, particularly from 0.5 to 10 % w/w, and most particularly is about 2 % w/w. The viscosity-controlling agents suspending agents are selected from the group consisting of guar gum, agar, xanthan gum, sodium alginate, povidone, PVP, various cellulose derivatives such as hydroxyethyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and hydroxypropyl cellulose and the like and mixtures thereof.

These agents may be employed in an amount ranging from 0.5 to 5 % w/w, preferably 1 to 3.5 % w/w and most preferably from 1 to 2 % w/w.

Suitable sweeteners used as an additive are selected from the group consisting of sucrose, fructose, dipotassium glycyrrrhizinate, artificial sweeteners like saccharin, saccharin sodium, aspartame, mannitol, xylitol or acesulfame potassium and mixtures thereof.

The sweeteners may be employed in an amount ranging from 0.5 to 5 % w/w preferably 0.5 to 3 % w/w and most preferably from 1 to 2 % w/w.

As used in this specification and in the claims which follow, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an ingredient" includes mixtures of ingredients; reference to "an active pharmaceutical agent" includes more than one active pharmaceutical agent, and the like.

The following are the non-limiting examples of the invention.

Example 1:

The weighed quantity of Lopinavir and Ritonavir were dissolved in weighed quantity of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl 35 Castor Oil (CREMOPHORE EL) under continuous stirring and sonication at 40°C. The resulting solution was filled into soft elastic capsules (SEC)/ empty hard gelatin capsule.

Example 2:

The weighed quantity of Lopinavir and Ritonavir were dissolved in weighed quantity of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl 35 Castor Oil (CREMOPHORE EL) under continuous stirring and sonication at 40°C. The resulting solution was filled into soft elastic capsules (SEC)/ empty hard gelatin capsule shell. Example 3:

The weighted quantity of Lopinavir and Ritonavir were dissolved in weighed quantity of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl Castor Oil (CREMOPHORE EL/ RH 40). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to empty hard gelatin capsule shell/ soft gelatin capsules shell.

Example 4:

S.No Ingredients Qty (% w/w)

1 Lopinavir 21

2 Ritonavir 5

3 Glyceryl Caprylate 53

Polyoxyl Castor Oil

(CREMOPHORE

4 EL/CREMOPHORE RH 40) 10.5

5 Glyceryl Monostearate 10.5

Total 100

Empty hard gelatin capsule

5 shell/ 1

Soft gelatin capsules shell The weighted quantity of Lopinavir and Ritonavir were dissolved in weighed quantity of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl Castor Oil (CREMOPHORE EL/ RH 40). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to empty hard gelatin capsule shell/ soft gelatin capsules shell.

Example 5:

The weighed quantity of Lopinavir and Ritonavir were dissolved in weighed quantity of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl Castor Oil (CREMOPHORE EL/RH 40) and lecithin. Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to empty hard gelatin capsule shell/ soft gelatin capsules shell. Example 6:

The weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl Castor Oil (CREMOPHORE EL/ RH 40) and poloxamer. Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to Empty hard gelatin capsule shell/ Soft gelatin capsules shell. Example 7:

The weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl Castor Oil (CREMOPHORE RH 40 & EL). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to Empty hard gelatin capsule shell/ Soft gelatin capsules shell.

Example 8:

The weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988), Polysorbate 80 (Tween 80) and Polyoxyl Castor Oil (CREMOPHORE EL). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to Empty hard gelatin capsule shell/ Soft gelatin capsules shell.

Example 9:

The weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988), and Polyoxyl Castor Oil (CREMOPHORE EL & RH 40). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to Empty Hard Gelatin Capsule shell /Soft Gelatin capsules shell.

Example 10:

S.No Ingredients Qty (% w/w)

1 Lopinavir 21

2 Ritonavir 5

3 Glyceryl Caprylate 37

Polyoxyl Castor Oil

4 (CREMOPHORE RH 40) 5

5 Tween 80 28

6 Glyceryl Monostearate 4

Total 100

Empty hard gelatin capsule

7 shell/ 1

Soft gelatin capsules shell The weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988), Polysorbate 80 (Tween 80) and Polyoxyl Castor Oil (CREMOPHORE RH 40). Glyceryl monostearate was melted under continuous stirring and add it in step 1 with sonication at 40°C. The resulting solution was filled in to Empty hard gelatin capsule shell/ Soft gelatin capsules shell each containing 200 mg of Lopinavir and 50 mg of Ritonavir.

Example 11:

Dissolve weighed quantity of Lopinavir and Ritonavir in weighed qty of Glyceryl Caprylate (IMWITOR 988) and Polyoxyl 35 Castor Oil (CREMOPHORE EL) under continuous stirring and sonication at 40°C. Dissolve Saccharin and Benzoic Acid in MCT in separate vessel with continuous stirring and sonication. Mix weighed qty to the solution of step 2 under continuous stirring. Mix solution of step 3 with solution step 1 under continuous stirring under sonication. Mix weighed qty of Caramel Flavor & Orange Juicy Flavor Solution with Step 4 under continuous stirring. Filter the prepared solution of step 5 through 75 micron filter. Fill the filtered solution in suitable container.

Claims

A pharmaceutical composition comprising (a) an HIV protease inhibiting compound or combinations thereof, wherein the composition is alcohol free.

A pharmaceutical composition of claim 1 comprising a solution of an HIV protease inhibiting compound or combinations thereof, wherein the composition is essentially alcohol free.

The composition of claim 1, wherein the HIV protease inhibiting compounds are selected from lopinavir, ritonavir, nelfinavir, indinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, darunavir or saquinavir or their pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, polymorphs or prodrugs.

The composition of claim 1 further comprising one or more additives independently selected from pharmaceutically acceptable organic solvents, pharmaceutically acceptable oils, pharmaceutically acceptable viscosity controlling agents, pharmaceutically acceptable sweetening agents, pharmaceutically acceptable flavoring agents, pharmaceutically acceptable surfactants and antioxidants.

The composition of claim 4, wherein the organic solvent is selected from the group consisting of polyoxyethylene castor oil derivatives, saturated polyglycolized glycerides, polyoxyethylene alkyl ethers, polyoxyethylene stearates, ethyl oleate, isopropyl palmitate, isopropyl myristate, dimethyl isosorbide, N-methylpyrrolidinone, paraffin, cholesterol, lecithin, suppository bases, waxes, silicon fluids, sorbitan fatty acid esters, saturated fats or saturated oils, cetyl esters wax, Glyceryl monostearate and combinations thereof.

6. The pharmaceutical composition according to claim 1 comprising HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which is alcohol free wherein the composition is encapsulated in a soft elastic gelatin capsules or a hard gelatin capsule.

7. The pharmaceutical composition according to claim 1 comprising HIV protease inhibitor(s) and pharmaceutically acceptable salts thereof which is essentially alcohol free wherein the composition is encapsulated in a soft elastic gelatin capsules or a hard gelatin capsule.

8. A pharmaceutical composition comprising lopinavir and ritonavir in a pharmaceutically acceptable organic solvent comprising a mixture of solvent selected from glyceryl caprylate, polyoxyl 35 castor oil and medium chain triglycerides.

A pharmaceutical composition comprising lopinavir and ritonavir in a pharmaceutically acceptable organic solvent comprising a mixture of solvent selected from glyceryl caprylate, polyoxyl castor oil, polyoxyl 35 castor oil and glyceryl monostearate.