WO2018060866A1 - Oral retinoid compositions - Google Patents
Oral retinoid compositions Download PDFInfo
- Publication number
- WO2018060866A1 WO2018060866A1 PCT/IB2017/055878 IB2017055878W WO2018060866A1 WO 2018060866 A1 WO2018060866 A1 WO 2018060866A1 IB 2017055878 W IB2017055878 W IB 2017055878W WO 2018060866 A1 WO2018060866 A1 WO 2018060866A1
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- WO
- WIPO (PCT)
- Prior art keywords
- oil
- glyceryl
- composition according
- retinoic acid
- mono
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 52
- 150000004492 retinoid derivatives Chemical class 0.000 title description 6
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 21
- 125000005456 glyceride group Chemical group 0.000 claims abstract description 18
- 235000015112 vegetable and seed oil Nutrition 0.000 claims abstract description 18
- 239000008158 vegetable oil Substances 0.000 claims abstract description 18
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 claims description 34
- 229960001445 alitretinoin Drugs 0.000 claims description 34
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 claims description 18
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 14
- 239000001993 wax Substances 0.000 claims description 13
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 11
- 239000003549 soybean oil Substances 0.000 claims description 11
- 235000012424 soybean oil Nutrition 0.000 claims description 11
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 9
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 9
- 239000003963 antioxidant agent Substances 0.000 claims description 9
- 229940074045 glyceryl distearate Drugs 0.000 claims description 9
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 9
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- ARIWANIATODDMH-UHFFFAOYSA-N rac-1-monolauroylglycerol Chemical compound CCCCCCCCCCCC(=O)OCC(O)CO ARIWANIATODDMH-UHFFFAOYSA-N 0.000 claims description 4
- WECGLUPZRHILCT-GSNKCQISSA-N 1-linoleoyl-sn-glycerol Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(=O)OC[C@@H](O)CO WECGLUPZRHILCT-GSNKCQISSA-N 0.000 claims description 3
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- OQQOAWVKVDAJOI-UHFFFAOYSA-N (2-dodecanoyloxy-3-hydroxypropyl) dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCC(CO)OC(=O)CCCCCCCCCCC OQQOAWVKVDAJOI-UHFFFAOYSA-N 0.000 claims description 2
- DRAWQKGUORNASA-UHFFFAOYSA-N (2-hydroxy-3-octadec-9-enoyloxypropyl) octadec-9-enoate Chemical compound CCCCCCCCC=CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC=CCCCCCCCC DRAWQKGUORNASA-UHFFFAOYSA-N 0.000 claims description 2
- LDVVTQMJQSCDMK-UHFFFAOYSA-N 1,3-dihydroxypropan-2-yl formate Chemical compound OCC(CO)OC=O LDVVTQMJQSCDMK-UHFFFAOYSA-N 0.000 claims description 2
- 235000019483 Peanut oil Nutrition 0.000 claims description 2
- 235000019484 Rapeseed oil Nutrition 0.000 claims description 2
- 235000019485 Safflower oil Nutrition 0.000 claims description 2
- 235000019486 Sunflower oil Nutrition 0.000 claims description 2
- 239000003240 coconut oil Substances 0.000 claims description 2
- 235000019864 coconut oil Nutrition 0.000 claims description 2
- 235000005687 corn oil Nutrition 0.000 claims description 2
- 239000002285 corn oil Substances 0.000 claims description 2
- 235000012343 cottonseed oil Nutrition 0.000 claims description 2
- 239000002385 cottonseed oil Substances 0.000 claims description 2
- 229940074049 glyceryl dilaurate Drugs 0.000 claims description 2
- 229940068939 glyceryl monolaurate Drugs 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 239000000944 linseed oil Substances 0.000 claims description 2
- 235000021388 linseed oil Nutrition 0.000 claims description 2
- 239000004006 olive oil Substances 0.000 claims description 2
- 235000008390 olive oil Nutrition 0.000 claims description 2
- 239000000312 peanut oil Substances 0.000 claims description 2
- 235000005713 safflower oil Nutrition 0.000 claims description 2
- 239000003813 safflower oil Substances 0.000 claims description 2
- 239000008159 sesame oil Substances 0.000 claims description 2
- 235000011803 sesame oil Nutrition 0.000 claims description 2
- 239000002600 sunflower oil Substances 0.000 claims description 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 claims 1
- 201000004624 Dermatitis Diseases 0.000 abstract description 8
- 208000010668 atopic eczema Diseases 0.000 abstract description 7
- 238000000034 method Methods 0.000 abstract description 6
- 208000017520 skin disease Diseases 0.000 abstract description 6
- 230000001684 chronic effect Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 3
- 125000002678 retinoid group Chemical group 0.000 abstract 1
- 239000007903 gelatin capsule Substances 0.000 description 9
- 230000003078 antioxidant effect Effects 0.000 description 8
- 235000006708 antioxidants Nutrition 0.000 description 8
- 238000009472 formulation Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- SHGAZHPCJJPHSC-UHFFFAOYSA-N Panrexin Chemical compound OC(=O)C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-UHFFFAOYSA-N 0.000 description 5
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 238000005538 encapsulation Methods 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 150000004665 fatty acids Chemical class 0.000 description 4
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 3
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 3
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 3
- 239000013029 homogenous suspension Substances 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 229960000984 tocofersolan Drugs 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 2
- 102000034527 Retinoid X Receptors Human genes 0.000 description 2
- 108010038912 Retinoid X Receptors Proteins 0.000 description 2
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000013022 formulation composition Substances 0.000 description 2
- 230000002519 immonomodulatory effect Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 239000011369 resultant mixture Substances 0.000 description 2
- 229930002330 retinoic acid Natural products 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 1
- 239000005635 Caprylic acid (CAS 124-07-2) Substances 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 1
- 229930002945 all-trans-retinaldehyde Natural products 0.000 description 1
- 229940100609 all-trans-retinol Drugs 0.000 description 1
- 239000011717 all-trans-retinol Substances 0.000 description 1
- 235000019169 all-trans-retinol Nutrition 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000007765 cera alba Substances 0.000 description 1
- 239000007766 cera flava Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 239000008184 oral solid dosage form Substances 0.000 description 1
- 229940096763 panretin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N retinal group Chemical group C\C(=C/C=O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 102000003702 retinoic acid receptors Human genes 0.000 description 1
- 108090000064 retinoic acid receptors Proteins 0.000 description 1
- 229960003471 retinol Drugs 0.000 description 1
- 235000020944 retinol Nutrition 0.000 description 1
- 239000011607 retinol Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000004671 saturated fatty acids Chemical class 0.000 description 1
- 235000003441 saturated fatty acids Nutrition 0.000 description 1
- 210000002374 sebum Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 1
- 150000002266 vitamin A derivatives Chemical class 0.000 description 1
- 229940045997 vitamin a Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/203—Retinoic acids ; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
Definitions
- the present invention relates to novel oral pharmaceutical compositions of retinoids. Methods of preparing such compositions are also provided.
- Retinoids are a class of compounds structurally related to vitamin A. The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation.
- Alitretinoin or 9-cis retinoic acid is a first generation retinoid.
- the chemical name of alitretinoin is (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-l-yl)nona- 2,4,6,8-tetraenoic a
- Alitretinoin is an endogenous metabolite of vitamin A.
- Alitretinoin binds to RARs and the so-called retinoid X receptors (RXRs).
- RXRs retinoid X receptors
- alitretinoin is commercially available as oral soft gelatin capsules 10 & 30 mg (TOCTINO ® ) for use in adults who have severe chronic hand eczema.
- Alitretinoin is also available in US and Europe as 0.1% topical gel (PANRETIN ) for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma.
- EP 0552624 Al discloses a soft gelatin capsule formulation of 9-cis retinoic acid with a fill mass formulation consisting of oil and wax mixture.
- WO 99/24024 discloses a soft gelatin capsule preparation of retinoids containing hydrogenated castor oil, synthetic triglycerides, medium chain triglycerides and DL-alpha- tocopherol.
- US 20100136108 discloses improved soft gelatin capsule formulation of 9-cis retinoic acid as an active ingredient and a fill mass comprising natural vegetable oil, partially hydrogenated natural vegetable oil and medium chain triglycerides.
- the formulation also comprises a natural wax.
- the composition exhibits improved dissolution rate and avoids pellicles formation after long-term storage at temperatures above 5°C.
- the present specification relates to novel oral pharmaceutical compositions of retinoids.
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising: (i) 9-cis retinoic acid,
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.
- the present specification relates to novel oral pharmaceutical compositions of retinoids.
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- the present specification relates to an oral pharmaceutical composition
- an oral pharmaceutical composition comprising:
- oral pharmaceutical composition refers to an oral dosage form comprising tablets, pills, sachets, or capsules.
- the preferred oral dosage form is in the form of capsule.
- the capsule may be a hard gelatin capsule or a soft gelatin capsule.
- the oral pharmaceutical composition of the present specification includes retinoids as an active ingredient.
- the retinoids are selected from the group of retinol, retinal, retinoic acid and derivatives thereof. Specific examples are all-trans retinol, all-trans retinoic acid, 13- cis retinoic acid and 9-cis retinoic acid.
- 9-cis retinoic acid refers to 9-cis retinoic acid and esters, salts, or derivatives thereof.
- the amount of 9-cis retinoic acid employed in the composition is in the range of 1% to 10% (w/w), 2% to 9% (w/w) of the total composition, e.g. 8.6% (w/w).
- the term "mono glyceride” includes mono ester of glycerol with fatty acid.
- the term “di glycerides” includes di esters of glycerol with fatty acids.
- the fatty acids are long chain fatty acids containing 12 to 20 carbon atoms. The fatty acids could be saturated or unsaturated.
- Examples of mono or di glycerides include but are not limited to glyceryl monolaurate, glyceryl dilaurate, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, glyceryl dioleate, glyceryl monolinoleate.
- the amount of mono and/or di glycerides employed in the composition is in the range of 1% to 15% (w/w), 1% to 8% (w/w), 1% to 7% (w/w) of the total composition, e.g. 5.9 % (w/w).
- vegetable oil includes any pharmaceutically acceptable vegetable oil selected from the group comprising soybean oil, corn oil, sunflower oil, rape seed oil, linseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil and cottonseed oil or mixtures of two or more of these oils.
- the amount of vegetable oil employed in the composition is in the range of 60% to 90% (w/w), 70% to 85% (w/w), 72%) to 78%) (w/w) of the total composition, e.g. 73%> (w/w).
- medium chain triglycerides includes triglycerides of saturated fatty acids containing 8 to 10 carbon atoms, e.g. triglycerides of caprylic acid and/or capric acid.
- the amount of medium chain triglycerides employed in the composition is in the range of 5% to 10% (w/w), 6% to 8% (w/w) of the total composition, e.g. 7.8 % (w/w).
- wax includes any pharmaceutically-acceptable natural wax. Examples include but are not limited to natural wax, yellow bees wax, white bees wax, carnauba wax.
- the amount of wax employed in the composition is in the range of 1% to 10% (w/w), 2% to 8% (w/w), 2% to 4% (w/w), e.g. 3.7% (w/w).
- the composition of the present specification may include an antioxidant.
- the antioxidant may be selected from one or more of DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and propyl gallate.
- BHT butylhydroxy toluene
- BHA butylhydroxy anisole
- ascorbyl palmitate ascorbic acid and propyl gallate.
- the amount of antioxidant employed in the composition is in the range of 0.01 to about 0.5% (w/w) of the total composition, e.g. 0.09% (w/w).
- the pharmaceutical composition of present specification may be prepared by any conventional process for oral solid dosage forms.
- the soft gelatin capsules may be prepared by using the following process steps: The vegetable oil, mono or di glyceride, medium chain triglyceride and wax are taken in to a suitable vessel, heated to a temperature of 65°C -70°C. The resultant mixture is cooled to 40°C with constant stirring. An antioxidant may be added to the resulting mixture followed by stirring. Subsequently, the retinoid is added to the above blend and stirred until a homogeneous suspension is obtained which is then stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules is then carried out on a rotary-die machine.
- compositions of present specification were subjected to accelerated and long term stability studies.
- compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.
- the pharmaceutical compositions of present specification may be subjected to pharmaceutical bioequivalence testing in comparison with the reference product (TOCTINO ® ) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.
- the above test formulations of Table 1 were prepared by the following method: Soybean oil, glyceryl distearate/ glyceryl monooleate/ glyceryl monolinoleate, medium chain triglyceride and wax were weighed in a suitable stainless steel vessel, heated to a temperature of 65°C -70°C and stirred constantly to get a homogeneous mixture. The resultant mixture was cooled to 40°C under constant stirring. DL-alpha Tocopherol was added to the resulting mixture. Subsequently, 9-cis retinoic acid was added to the above blend and stirred until a homogeneous suspension was obtained. The homogenous suspension was stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules was then carried out on a rotary-die machine.
- Stability study The stability of the oral retinoid compositions of present specification was evaluated through accelerated stability studies.
- the composition prepared according to the formula and process of Example 4 was subjected to stability study at various temperature and humidity conditions.
- the composition was found to be chemically stable under accelerated conditions.
- Table 2 presents the stability study data.
- the pharmaceutical bioequivalence of the oral compositions of present specification was studied through comparative pharmacokinetic study against the reference product (TOCTINO ® capsules).
- the pharmaceutical composition of the present invention (Test; 30 mg of 9-cis retinoic acid composition) was compared with the marketed formulation of 9- cis retinoic acid (Reference; 30 mg TOCTINO ® capsules) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Botany (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to novel oral pharmaceutical compositions of retinoid as an active ingredient. The compositions comprise one or more mono and/or di glycerides, and one or more vegetable oils. Methods of preparing such compositions are also provided. The compositions may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.
Description
ORAL RETINOID COMPOSITIONS
FIELD OF THE INVENTION
The present invention relates to novel oral pharmaceutical compositions of retinoids. Methods of preparing such compositions are also provided.
BACKGROUND OF THE INVENTION
Retinoids are a class of compounds structurally related to vitamin A. The pharmacological action of retinoids may be explained by their effects on cell proliferation, cell differentiation, apoptosis, angiogenesis, keratinization, sebum secretion and immunomodulation.
Alitretinoin or 9-cis retinoic acid is a first generation retinoid. The chemical name of alitretinoin is (2E,4E,6Z,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-l-yl)nona- 2,4,6,8-tetraenoic a
Alitretinoin is an endogenous metabolite of vitamin A. Alitretinoin binds to RARs and the so-called retinoid X receptors (RXRs). Alitretinoin has demonstrated immunomodulatory and anti-inflammatory effects that are relevant to skin inflammation.
In Europe & Canada alitretinoin is commercially available as oral soft gelatin capsules 10 & 30 mg (TOCTINO®) for use in adults who have severe chronic hand eczema.
Alitretinoin is also available in US and Europe as 0.1% topical gel (PANRETIN ) for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi's sarcoma.
EP 0552624 Al discloses a soft gelatin capsule formulation of 9-cis retinoic acid with a fill mass formulation consisting of oil and wax mixture.
WO 99/24024 discloses a soft gelatin capsule preparation of retinoids containing hydrogenated castor oil, synthetic triglycerides, medium chain triglycerides and DL-alpha- tocopherol.
US 20100136108 discloses improved soft gelatin capsule formulation of 9-cis retinoic acid as an active ingredient and a fill mass comprising natural vegetable oil, partially hydrogenated natural vegetable oil and medium chain triglycerides. Optionally, the formulation also comprises a natural wax. The composition exhibits improved dissolution rate and avoids pellicles formation after long-term storage at temperatures above 5°C.
In an attempt to develop novel oral 9-cis retinoic acid compositions, the present inventors have surprisingly found that use of mono and/or di glycerides resulted in compositions which are found to be chemically stable and having immediate release characteristics. To our knowledge, none of the prior arts disclose the use of mono and/or di glycerides in a retinoid formulation for oral administration.
SUMMARY OF THE INVENTION
The present specification relates to novel oral pharmaceutical compositions of retinoids.
In one aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides, and
(iii) one or more vegetable oils.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides,
(iii) one or more vegetable oils, and
(iv) one or more medium chain triglycerides.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides,
(iii) one or more vegetable oils,
(iv) one or more medium chain triglycerides,
(v) one or more wax, and
(vi) one or more antioxidant.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 1% to 10% (w/w) 9-cis retinoic acid,
(ii) 1% to 15% (w/w) mono and/or di glycerides,
(iii) 60% to 90% (w/w) vegetable oils,
(iv) 5% to 10%) (w/w) medium chain triglycerides,
(v) 1% to 10 % (w/w) wax, and
(vi) an antioxidant.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl monooleate, and
(iii) soybean oil.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl distearate, and
(iii) soybean oil.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl monooleate,
(iii) glyceryl distearate,
(iv) soybean oil, and
(v) medium chain triglycerides.
The pharmaceutical compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.
DESCRIPTION OF THE INVENTION
The present specification relates to novel oral pharmaceutical compositions of retinoids.
In one aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides, and
(iii) one or more vegetable oils.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides,
(iii) one or more vegetable oils, and
(iv) one or more medium chain triglycerides.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides,
(iii) one or more vegetable oils,
(iv) one or more medium chain triglycerides,
(v) one or more wax, and
(vi) one or more antioxidant.
In another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 1% to 10% (w/w) 9-cis retinoic acid,
(ii) 1% to 15% (w/w) mono and/or di glycerides,
(iii) 60% to 90% (w/w) vegetable oils,
(iv) 5% to 10% (w/w) medium chain triglycerides,
(v) 1% to 10 % (w/w) wax, and
(vi) an antioxidant.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl monooleate, and
(iii) soybean oil.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl distearate, and
(iii) soybean oil.
In yet another aspect, the present specification relates to an oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) glyceryl monooleate,
(iii) glyceryl distearate,
(iv) soybean oil, and
(v) medium chain triglycerides.
As used herein, the term "oral pharmaceutical composition" refers to an oral dosage form comprising tablets, pills, sachets, or capsules. The preferred oral dosage form is in the form of capsule. The capsule may be a hard gelatin capsule or a soft gelatin capsule.
The oral pharmaceutical composition of the present specification includes retinoids as an active ingredient. The retinoids are selected from the group of retinol, retinal, retinoic acid and derivatives thereof. Specific examples are all-trans retinol, all-trans retinoic acid, 13- cis retinoic acid and 9-cis retinoic acid.
The term 9-cis retinoic acid refers to 9-cis retinoic acid and esters, salts, or derivatives thereof. The amount of 9-cis retinoic acid employed in the composition is in the range of 1% to 10% (w/w), 2% to 9% (w/w) of the total composition, e.g. 8.6% (w/w).
As used herein, the term "mono glyceride" includes mono ester of glycerol with fatty acid. As used herein, the term "di glycerides" includes di esters of glycerol with fatty acids. The fatty acids are long chain fatty acids containing 12 to 20 carbon atoms. The fatty acids could be saturated or unsaturated. Examples of mono or di glycerides include but are not limited to glyceryl monolaurate, glyceryl dilaurate, glyceryl monostearate, glyceryl distearate, glyceryl monooleate, glyceryl dioleate, glyceryl monolinoleate. The amount of mono and/or di glycerides employed in the composition is in the range of 1% to 15% (w/w), 1% to 8% (w/w), 1% to 7% (w/w) of the total composition, e.g. 5.9 % (w/w).
As used herein, the term "vegetable oil" includes any pharmaceutically acceptable vegetable oil selected from the group comprising soybean oil, corn oil, sunflower oil, rape seed oil, linseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil and cottonseed oil or mixtures of two or more of these oils. The amount of vegetable oil employed in the composition is in the range of 60% to 90% (w/w), 70% to 85% (w/w), 72%) to 78%) (w/w) of the total composition, e.g. 73%> (w/w).
As used herein, the term "medium chain triglycerides" includes triglycerides of saturated fatty acids containing 8 to 10 carbon atoms, e.g. triglycerides of caprylic acid and/or capric acid. The amount of medium chain triglycerides employed in the composition is in the range of 5% to 10% (w/w), 6% to 8% (w/w) of the total composition, e.g. 7.8 % (w/w).
As used herein, the term "wax" includes any pharmaceutically-acceptable natural wax. Examples include but are not limited to natural wax, yellow bees wax, white bees wax, carnauba wax. The amount of wax employed in the composition is in the range of 1% to 10% (w/w), 2% to 8% (w/w), 2% to 4% (w/w), e.g. 3.7% (w/w).
The composition of the present specification may include an antioxidant. The antioxidant may be selected from one or more of DL-alpha-tocopherol, butylhydroxy toluene (BHT), butylhydroxy anisole (BHA), ascorbyl palmitate, ascorbic acid and propyl gallate. The amount of antioxidant employed in the composition is in the range of 0.01 to about 0.5% (w/w) of the total composition, e.g. 0.09% (w/w).
The pharmaceutical composition of present specification may be prepared by any conventional process for oral solid dosage forms. For example, the soft gelatin capsules may be prepared by using the following process steps: The vegetable oil, mono or di glyceride, medium chain triglyceride and wax are taken in to a suitable vessel, heated to a temperature of 65°C -70°C. The resultant mixture is cooled to 40°C with constant stirring. An antioxidant may be added to the resulting mixture followed by stirring. Subsequently, the retinoid is added to the above blend and stirred until a homogeneous suspension is obtained which is then stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules is then carried out on a rotary-die machine.
The pharmaceutical compositions of present specification were subjected to accelerated and long term stability studies.
The pharmaceutical compositions of present specification may be used for the treatment of eczema, chronic hand eczema or other skin disorders or diseases.
The pharmaceutical compositions of present specification may be subjected to pharmaceutical bioequivalence testing in comparison with the reference product (TOCTINO®) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.
The specifications will now be described in greater detail by reference to the following non-limiting examples.
Table 1 : Formulation compositions
The above test formulations of Table 1 were prepared by the following method: Soybean oil, glyceryl distearate/ glyceryl monooleate/ glyceryl monolinoleate, medium chain triglyceride and wax were weighed in a suitable stainless steel vessel, heated to a temperature of 65°C -70°C and stirred constantly to get a homogeneous mixture. The resultant mixture was cooled to 40°C under constant stirring. DL-alpha Tocopherol was added to the resulting mixture. Subsequently, 9-cis retinoic acid was added to the above blend and stirred until a homogeneous suspension was obtained. The homogenous suspension was stored in a stainless steel vessel under inert gas, tightly sealed and protected from light until encapsulation. The encapsulation of the homogenous suspension into soft gelatin capsules was then carried out on a rotary-die machine.
Stability study
The stability of the oral retinoid compositions of present specification was evaluated through accelerated stability studies. The composition prepared according to the formula and process of Example 4, was subjected to stability study at various temperature and humidity conditions. The composition was found to be chemically stable under accelerated conditions. Table 2 presents the stability study data.
Table 2: Stability data for Example 4 formulation composition
Bioequivalence Study
The pharmaceutical bioequivalence of the oral compositions of present specification was studied through comparative pharmacokinetic study against the reference product (TOCTINO® capsules). The pharmaceutical composition of the present invention (Test; 30 mg of 9-cis retinoic acid composition) was compared with the marketed formulation of 9- cis retinoic acid (Reference; 30 mg TOCTINO® capsules) in an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, crossover study in healthy adult human male subjects under fasting and fed conditions.
Values for various pharmacokinetic parameters, including observed Cmax, AUCo-t, and AUCo-inf for fasting and fed conditions were calculated and the composition was found to be bioequivalent against the reference product. The results are provided in Table 3 and Table 4 below.
Table 3 : Results of bioequivalence study in fasted conditions
Parameter Ratio[%Ref] CI 90 Lower CI_90 Upper CV %
Cmax 102.14 81.81 127.51 45
AUCt 106.49 89.97 126.04 33
AUCinf 111.73 94.06 132.73 33
Table 4: Results of bioequivalence study in fed conditions
Claims
An oral pharmaceutical composition comprising:
(i) 9-cis retinoic acid,
(ii) one or more mono and/or di glycerides,
(iii) one or more vegetable oils, and
(iv) one or more medium chain triglycerides.
The composition according to claim 1, wherein the mono glycerides are selected from one or more of glyceryl monolaurate, glyceryl monostearate, glyceryl monooleate, glyceryl monolinoleate or mixtures thereof.
The composition according to claim 1, wherein the di glycerides are selected from one or more of glyceryl dilaurate, glyceryl distearate, glyceryl dioleate, or mixtures thereof.
The composition according to claim 2, wherein the mono glyceride is glyceryl monooleate.
The composition according to claim 3, wherein the di glyceride is glyceryl distearate.
The composition according to claim 1, wherein the vegetable oil is selected from one or more of soybean oil, corn oil, sunflower oil, rape seed oil, linseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil, cottonseed oil or mixtures thereof.
The composition according to claim 6, wherein the vegetable oil is soybean oil.
The composition according to claim 1, further comprising one or more waxes.
The composition according to claim 1, further comprising one or more antioxidants.
10. The composition according to claim 1, compri
(i) 9-cis retinoic acid,
(ii) glyceryl monooleate,
(iii) glyceryl distearate,
(iv) soybean oil, and
(v) medium chain triglycerides.
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Citations (2)
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US20100136108A1 (en) * | 2003-11-03 | 2010-06-03 | Ditzinger Guenter | Formulation for retinoid-containing soft gelatin capsules |
US20130029957A1 (en) * | 2011-07-28 | 2013-01-31 | Chandrashekar Giliyar | 17-Hydroxyprogesterone Ester-Containing Oral Compositions and Related Methods |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100136108A1 (en) * | 2003-11-03 | 2010-06-03 | Ditzinger Guenter | Formulation for retinoid-containing soft gelatin capsules |
US20130029957A1 (en) * | 2011-07-28 | 2013-01-31 | Chandrashekar Giliyar | 17-Hydroxyprogesterone Ester-Containing Oral Compositions and Related Methods |
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