WO2005011667A1 - Methods of therapeutic treatment using amounts of retinoid components - Google Patents
Methods of therapeutic treatment using amounts of retinoid components Download PDFInfo
- Publication number
- WO2005011667A1 WO2005011667A1 PCT/US2004/024966 US2004024966W WO2005011667A1 WO 2005011667 A1 WO2005011667 A1 WO 2005011667A1 US 2004024966 W US2004024966 W US 2004024966W WO 2005011667 A1 WO2005011667 A1 WO 2005011667A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tazarotene
- administered
- capsule
- acne
- human
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 69
- 238000011282 treatment Methods 0.000 title claims abstract description 51
- 150000004492 retinoid derivatives Chemical class 0.000 title abstract description 97
- 230000001225 therapeutic effect Effects 0.000 title description 27
- 206010000496 acne Diseases 0.000 claims abstract description 81
- 208000002874 Acne Vulgaris Diseases 0.000 claims abstract description 78
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 229960000565 tazarotene Drugs 0.000 claims description 85
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 claims description 78
- 230000000694 effects Effects 0.000 claims description 64
- 241001465754 Metazoa Species 0.000 claims description 42
- 241000282414 Homo sapiens Species 0.000 claims description 41
- IQIBKLWBVJPOQO-UHFFFAOYSA-N tazarotenic acid Chemical compound C1=C2C(C)(C)CCSC2=CC=C1C#CC1=CC=C(C(O)=O)C=N1 IQIBKLWBVJPOQO-UHFFFAOYSA-N 0.000 claims description 29
- 230000009885 systemic effect Effects 0.000 claims description 27
- 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 claims description 26
- 229960005280 isotretinoin Drugs 0.000 claims description 26
- 239000002775 capsule Substances 0.000 claims description 21
- -1 tazarotene compound Chemical class 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 239000007903 gelatin capsule Substances 0.000 claims description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 5
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000007909 solid dosage form Substances 0.000 claims 7
- 241000124008 Mammalia Species 0.000 claims 2
- 239000006186 oral dosage form Substances 0.000 claims 2
- 230000009467 reduction Effects 0.000 description 50
- 239000003795 chemical substances by application Substances 0.000 description 42
- 102000003702 retinoic acid receptors Human genes 0.000 description 31
- 108090000064 retinoic acid receptors Proteins 0.000 description 31
- 210000002374 sebum Anatomy 0.000 description 30
- 229940068196 placebo Drugs 0.000 description 29
- 239000000902 placebo Substances 0.000 description 29
- 108010038912 Retinoid X Receptors Proteins 0.000 description 27
- 102000034527 Retinoid X Receptors Human genes 0.000 description 27
- 230000028327 secretion Effects 0.000 description 25
- 150000001875 compounds Chemical class 0.000 description 24
- 230000003902 lesion Effects 0.000 description 23
- 230000002411 adverse Effects 0.000 description 17
- 239000000556 agonist Substances 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 14
- 230000001815 facial effect Effects 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 13
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 12
- 239000012071 phase Substances 0.000 description 12
- 108091008760 retinoic acid receptors γ Proteins 0.000 description 12
- 230000008901 benefit Effects 0.000 description 11
- 206010000503 Acne cystic Diseases 0.000 description 10
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 10
- 239000002243 precursor Substances 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- 108091008726 retinoic acid receptors α Proteins 0.000 description 10
- 102100033909 Retinoic acid receptor beta Human genes 0.000 description 9
- 108091008761 retinoic acid receptors β Proteins 0.000 description 9
- 206010013786 Dry skin Diseases 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000037336 dry skin Effects 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- 230000003389 potentiating effect Effects 0.000 description 7
- 238000001403 relative X-ray reflectometry Methods 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 150000003626 triacylglycerols Chemical class 0.000 description 7
- 208000003251 Pruritus Diseases 0.000 description 6
- 229960005339 acitretin Drugs 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000005755 formation reaction Methods 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 102000005962 receptors Human genes 0.000 description 6
- 108020003175 receptors Proteins 0.000 description 6
- 230000004044 response Effects 0.000 description 6
- 208000006820 Arthralgia Diseases 0.000 description 5
- 208000000112 Myalgia Diseases 0.000 description 5
- 206010033733 Papule Diseases 0.000 description 5
- 208000007287 cheilitis Diseases 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 210000002381 plasma Anatomy 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 238000007910 systemic administration Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 206010019233 Headaches Diseases 0.000 description 4
- 208000012659 Joint disease Diseases 0.000 description 4
- 201000004681 Psoriasis Diseases 0.000 description 4
- 206010037888 Rash pustular Diseases 0.000 description 4
- 210000000988 bone and bone Anatomy 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 231100000869 headache Toxicity 0.000 description 4
- 208000006575 hypertriglyceridemia Diseases 0.000 description 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 238000007449 liver function test Methods 0.000 description 4
- 208000029561 pustule Diseases 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 206010054196 Affect lability Diseases 0.000 description 3
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 3
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 206010051326 Ligament calcification Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 208000008558 Osteophyte Diseases 0.000 description 3
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229960002938 bexarotene Drugs 0.000 description 3
- 230000037182 bone density Effects 0.000 description 3
- 230000024279 bone resorption Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 208000031513 cyst Diseases 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 201000010934 exostosis Diseases 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 230000002989 hypothyroidism Effects 0.000 description 3
- 208000003532 hypothyroidism Diseases 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000007803 itching Effects 0.000 description 3
- 230000011164 ossification Effects 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 210000001732 sebaceous gland Anatomy 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 229960001727 tretinoin Drugs 0.000 description 3
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 3
- 238000002562 urinalysis Methods 0.000 description 3
- 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 2
- 206010001497 Agitation Diseases 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 239000004342 Benzoyl peroxide Substances 0.000 description 2
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 2
- 206010011878 Deafness Diseases 0.000 description 2
- 201000004624 Dermatitis Diseases 0.000 description 2
- 206010013710 Drug interaction Diseases 0.000 description 2
- 206010013774 Dry eye Diseases 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 241001635598 Enicostema Species 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 2
- 206010027626 Milia Diseases 0.000 description 2
- 208000002151 Pleural effusion Diseases 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 208000037656 Respiratory Sounds Diseases 0.000 description 2
- 206010040844 Skin exfoliation Diseases 0.000 description 2
- 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 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 238000013019 agitation Methods 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
- 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 2
- 231100000360 alopecia Toxicity 0.000 description 2
- 210000003423 ankle Anatomy 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 206010003549 asthenia Diseases 0.000 description 2
- 235000019400 benzoyl peroxide Nutrition 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 230000035618 desquamation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000032625 disorder of ear Diseases 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 201000005884 exanthem Diseases 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 210000004349 growth plate Anatomy 0.000 description 2
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical compound COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 2
- 230000010370 hearing loss Effects 0.000 description 2
- 231100000888 hearing loss Toxicity 0.000 description 2
- 208000016354 hearing loss disease Diseases 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000036543 hypotension Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002483 medication Methods 0.000 description 2
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 2
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 230000037390 scarring Effects 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 235000019155 vitamin A Nutrition 0.000 description 2
- 239000011719 vitamin A Substances 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- 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 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 208000010444 Acidosis Diseases 0.000 description 1
- 206010000501 Acne conglobata Diseases 0.000 description 1
- 206010049141 Acne fulminans Diseases 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 208000006888 Agnosia Diseases 0.000 description 1
- 241001047040 Agnosia Species 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 206010003547 Asterixis Diseases 0.000 description 1
- 208000008035 Back Pain Diseases 0.000 description 1
- 241000237519 Bivalvia Species 0.000 description 1
- 208000006386 Bone Resorption Diseases 0.000 description 1
- 206010006002 Bone pain Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 206010048962 Brain oedema Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 208000015879 Cerebellar disease Diseases 0.000 description 1
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 1
- 206010049047 Chapped lips Diseases 0.000 description 1
- 206010008469 Chest discomfort Diseases 0.000 description 1
- 206010008531 Chills Diseases 0.000 description 1
- 206010010071 Coma Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 208000002506 Darier Disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012373 Depressed level of consciousness Diseases 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013887 Dysarthria Diseases 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010014020 Ear pain Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010016029 Face oedema Diseases 0.000 description 1
- 208000004929 Facial Paralysis Diseases 0.000 description 1
- 208000002513 Flank pain Diseases 0.000 description 1
- 206010051283 Fluid imbalance Diseases 0.000 description 1
- 206010016936 Folliculitis Diseases 0.000 description 1
- 206010017577 Gait disturbance Diseases 0.000 description 1
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000288140 Gruiformes Species 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000035211 Heart Murmurs Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021113 Hypothermia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010022095 Injection Site reaction Diseases 0.000 description 1
- 206010022773 Intracranial pressure increased Diseases 0.000 description 1
- 206010023369 Keratosis follicular Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 206010023845 Laryngeal oedema Diseases 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 206010025102 Lung infiltration Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- 208000009525 Myocarditis Diseases 0.000 description 1
- 206010028740 Nasal dryness Diseases 0.000 description 1
- 206010028817 Nausea and vomiting symptoms Diseases 0.000 description 1
- 206010060860 Neurological symptom Diseases 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 206010031149 Osteitis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033425 Pain in extremity Diseases 0.000 description 1
- 206010033546 Pallor Diseases 0.000 description 1
- 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 1
- 208000005228 Pericardial Effusion Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 206010036018 Pollakiuria Diseases 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 208000029464 Pulmonary infiltrates Diseases 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010038540 Renal tubular necrosis Diseases 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 108010066463 Retinoid X Receptor alpha Proteins 0.000 description 1
- 108010006212 Retinoid X Receptor beta Proteins 0.000 description 1
- 206010040849 Skin fissures Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 208000032140 Sleepiness Diseases 0.000 description 1
- 206010071299 Slow speech Diseases 0.000 description 1
- 206010041349 Somnolence Diseases 0.000 description 1
- 208000029033 Spinal Cord disease Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000033809 Suppuration Diseases 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 208000036826 VIIth nerve paralysis Diseases 0.000 description 1
- 206010047555 Visual field defect Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 208000021017 Weight Gain Diseases 0.000 description 1
- 206010047924 Wheezing Diseases 0.000 description 1
- 206010048222 Xerosis Diseases 0.000 description 1
- 208000019790 abdominal distention Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229960001445 alitretinoin Drugs 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000003255 anti-acne Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 201000007201 aphasia Diseases 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004155 blood-retinal barrier Anatomy 0.000 description 1
- 230000004378 blood-retinal barrier Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000021152 breakfast Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 235000020639 clam Nutrition 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 229940124301 concurrent medication Drugs 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 230000002254 contraceptive effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 210000002249 digestive system Anatomy 0.000 description 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 206010013990 dysuria Diseases 0.000 description 1
- 208000007176 earache Diseases 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000001667 episodic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 229960002199 etretinate Drugs 0.000 description 1
- HQMNCQVAMBCHCO-DJRRULDNSA-N etretinate Chemical compound CCOC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)C=C(OC)C(C)=C1C HQMNCQVAMBCHCO-DJRRULDNSA-N 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 201000005219 extrinsic cardiomyopathy Diseases 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 210000001551 hemic and immune system Anatomy 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010019847 hepatosplenomegaly Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 201000009941 intracranial hypertension Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 201000004607 keratosis follicularis Diseases 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 208000027906 leg weakness Diseases 0.000 description 1
- 206010024378 leukocytosis Diseases 0.000 description 1
- 201000002364 leukopenia Diseases 0.000 description 1
- 230000004446 light reflex Effects 0.000 description 1
- 235000019626 lipase activity Nutrition 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 208000030500 lower respiratory tract disease Diseases 0.000 description 1
- 206010025135 lupus erythematosus Diseases 0.000 description 1
- 210000002751 lymph Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000035482 neurologic reaction Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000023603 positive regulation of transcription initiation, DNA-dependent Effects 0.000 description 1
- 238000009597 pregnancy test Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 206010037833 rales Diseases 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 108010079850 retinoic acid receptor beta Proteins 0.000 description 1
- 108010059301 retinoic acid receptor gamma Proteins 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 229940072291 soriatane Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 230000008833 sun damage Effects 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002344 surface layer Substances 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001839 systemic circulation Effects 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 229940036234 tazorac Drugs 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 238000009601 thyroid function test Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940042129 topical gel Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 208000011479 upper respiratory tract disease Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 208000014001 urinary system disease Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000004304 visual acuity Effects 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—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
- A61K9/4858—Organic compounds
-
- 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
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61P17/06—Antipsoriatics
-
- 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
- A61P17/10—Anti-acne agents
Definitions
- the present invention relates to methods of providing therapeutic effects using retinoid components. More particularly, this invention relates to systemically administering to patients, that is humans or animals, without regard to the body weights of the patients, amounts of certain retinoids effective to provide reduction in the severity of various medical conditions, while, at the same time achieving one or more of consistent bioavailability, reduced drug interactions, and reduced side effects relative to administering a reference retinoid agent effective to provide the same therapeutic effect.
- the invention relates to orally administering to patients retinoid components selected from the group consisting of tazarotene, tazarotenic acid, prodrugs of tazarotenic acid, and mixtures thereof in therapeutically effective amounts, for example amounts effective to reduce conditions such as psoriasis and nodulocystic acne, advantageously while resulting in one or more of the aforementioned advantages relative to a reference retinoid agent .
- retinoid components selected from the group consisting of tazarotene, tazarotenic acid, prodrugs of tazarotenic acid, and mixtures thereof in therapeutically effective amounts, for example amounts effective to reduce conditions such as psoriasis and nodulocystic acne, advantageously while resulting in one or more of the aforementioned advantages relative to a reference retinoid agent .
- Retinoid drugs exert their therapeutic activity by acting as ligands, and therefore stimulating, activating blocking or inhibiting the biological activities, of either or both of the retinoid- associated nuclear receptors RAR (retinoic acid receptors) and RXR (retinoid X receptors) .
- RAR retinoic acid receptors
- RXR retinoid X receptors
- each of these receptors is thought to undergo a conformational change when a cognitive agonist binds the receptor. This conformational change then results in the receptor stimulating or inhibiting the expression of a set of particular genes.
- RXR and RAR appear to bind separate sets of genes. This process is termed transactivation.
- there are myriad ligand- ediated effects such as involvement in the stimulation or mediation of cellular phosphorylation cascades, which may not be transactivational events.
- RAR and RXR receptors each have three major subtypes.
- RAR receptors comprise RAR alpha, RAR beta, and RAR gamma.
- RXR receptors comprise RXR alpha, RXR beta, and RXR gamma. Selective stimulation or inhibition of one or more subtype from among these 6 receptors can have different biological and therapeutic effects.
- a number of retinoid drugs are formulated for oral delivery.
- RAR agonists such as acitretin (Soriatane ® ) and etretinate can be administered orally to treat psoriasis.
- RXR agonists such as bexarotene (Tagretin”) can be administered orally to treat skin lymphoma.
- Tretinoin (Vesanoid ) , which binds and transactivates both RAR and RXR, can be administered orally to treat promoclocytic anemia, and isotretinoin (Accutane ) , which also affect both types of receptors, can be administered orally to treat acne.
- Drugs such as tretinoin and isotretinoin that affect both RAR and RXR receptors are associated with both RAR and RXR-type side effects.
- Retinoids are often formulated for topical administration to be therapeutically effective while reducing the occurrence and/or severity of side effects caused by systemic administration.
- Topical administration of retinoids results in reduced blood concentrations of the active drug, which can adversely impact the therapeutic effectiveness of the drug.
- the maximum blood concentration of tazarotenic acid obtained by topical administration of tazarotene is less than about 30 ng/ml .
- Tazarotene is currently marketed as a topical gel or cream under the brand names Tazorac" and Zorac".
- acne is a condition in which hair follicles, which usually permit the draining of sebum to the surface of the skin, become blocked.
- Acne occurs in different types and degrees of severity. Different types of acne include acne vulgaris, acne rosacea, acne conglobata, acne fulminans, pyroderma facialae and Gram-negative folliculitis . Mild to moderate acne may involve the appearance of whiteheads and or blackheads and can be treated by gentle cleansing and topical treatment with agents such as benzoyl peroxide . However such treatments are not generally effective in severe forms of acne such as those that involve large lesions which can result in scarring. In severe nodulocysic acne, these lesions can involve the formation of nodules (large hard bumps under the skin) or cysts (which are similar to nodules, but are pus-filled) .
- nodulocystic acne can cause extreme and disfiguring scarring.
- Treatment for severe acne has included the oral administration of steroids and antibiotics.
- Isotretinoin (Accutane" ) has also been used with success to treat severe nodulocystic acne, although it has a number of undesirable side effects, including teratogenic effects . Its mode of action has been thought to be due at least in part to the inhibition of sebum secretion. This reduction in sebum secretion, has been thought to be associated with the therapeutic effects of isotetinoin, see e.g., Accutane Product Monograph, revised May 15, 2003).
- Sebum secretion can be detrimental to the condition of the skin. Sebum is thought to provide a natural conditioning effect, keeping the skin smooth and supple and protecting against drying, scaling and itching. Patients using isotretinoin have reported chapped lips and dry, itchy skin. Such side effects can lead to a reduction in patent compliance in the therapeutic regimen, thereby limiting the number of patients who will benefit from oral retinoid treatment for nodulocystic acne. Chandraratna U.S.
- Patent 5,089,509 discloses a group of compounds which may be used to treat acne and other dermatoses such as Darier's disease, psoriasis, icthyosis, eczema, atopic dermatitis and epithelial cancers, as well as in treating arthritic diseases and other immunological disorders (e.g., lupus erythematosus) , in promoting wound healing, in treating dry eye syndrome and in reversing the effects of sun damage to skin.
- arthritic diseases and other immunological disorders e.g., lupus erythematosus
- lupus erythematosus immunological disorders
- the compounds disclosed by Chandraratna are the compounds known as tazarotene and tazarotenic acid.
- the patent discloses that when the retinoid-like compounds are used in the treatment of dermatoses, it will generally be preferred to administer the drug topically, though in certain cases such as treatment of severe cystic acne, oral administration may also be used.
- Firestone et al . U.S. Patent No. 6,248,354, (the "'354 patent") the disclosure of which is incorporated in its entirety herein by reference, discloses a capsule system for the oral delivery of an active agent, e.g., tazarotene, having low aqueous solubility and a vehicle for eliminating any need for initial active agent dissolution within the gastro-intestinal tract.
- the 354 patent discloses that orally administered tazarotene to provide maximum blood level concentrations of tazarotenic acid in healthy subjects of between 5.24 and 44.3 ng/ml may be sufficient to effect the treatment of acne in a patient.
- Neither the Chandraratna patent nor the Firestone et al patent specifically disclose the advantages of any of the disclosed compounds, such as tazarotene and tazarotenic acid, in reducing nodular, cystic, or nodulocystic acne, for example, to obtain specific therapeutic reductions in nodulocystic acne, e.g., halting or arresting or inhibiting the progression of cystic acne, reducing or substantially eliminating one or more of the symptoms of nodulocystic acne, reducing the size of one or more lesion, reducing the number of the cystic acne lesions, substantial or complete elimination of cystic acne lesions, and the like.
- neither of these patents discloses the advantages of using such compounds at specific blood concentrations and/or for specific periods of time. Further, neither patent specifically discloses the advantages of using such compounds, for example, in reducing severe acne, such as cystic acne, at specific daily doses in specific dosage forms.
- retinoids are administered to patients in amounts effective to provide therapeutic reductions in severe acne, such as nodular, cystic, or nodulosystic acne, while at the same time have less of an effect upon, for example, sebum secretion as compared to known systemically administered retinoids such as isotretinoin.
- the present methods involve systemic, preferably oral, administration to a human or animal of a retinoid component to provide a desired therapeutic effect.
- the present methods are useful in providing desired therapeutic effects, including, without limitation, the treatment, preferably the reduction of the extent of skin surface affected by pre-existing severe nodulocystic acne and the prevention of nodulocystic acne from becoming severe or widespread.
- the present invention is directed to methods for providing desired therapeutic effects to a human or animal which comprise systemically, preferably orally, administering to the human or animal a therapeutically effective amount of a retinoid component selected from active retinoid agents, precursors of active retinoid agents and mixtures thereof.
- a retinoid component selected from active retinoid agents, precursors of active retinoid agents and mixtures thereof.
- the desired therapeutic effect advantageously is provided as a result of the administering step.
- the administering is effective to provide for a maximum blood concentration in the human or animal of greater than about 40 ng/ml, greater than 45 ng/ml, or greater than about 50 ng/ml.
- the invention comprises new methods for treating nodulocystic acne employing retinoid components.
- the retinoid component comprises tazarotene, tazarotenic acid, and prodrugs of tazarotenic acid (hereinafter collectively referred to as a "tazarotene compound").
- the present methods involve systemic, preferably oral, administration to a human or animal having nodulocystic acne of such a retinoid component to provide the desired therapeutic effect, e.g., a reduction in nodulocystic acne, such as halting or arresting or inhibiting the progression of cystic acne, reducing or substantially eliminating one or more of the symptoms of cystic acne, reducing the size of one or more of the cysts, reducing the number of the cysts, substantial or complete curing of the severe cystic acne and the like.
- a reduction in nodulocystic acne such as halting or arresting or inhibiting the progression of cystic acne, reducing or substantially eliminating one or more of the symptoms of cystic acne, reducing the size of one or more of the cysts, reducing the number of the cysts, substantial or complete curing of the severe cystic acne and the like.
- the currently disclosed agents do not significantly reduce sebum secretion, as is observed with currently known oral retinoids, such as Accutane ® (isotretinoin) .
- a substantial reduction in sebum secretion often renders the patient's skin dry, itchy and irritated, thereby significantly contributing to patient discomfort. Indeed, these effects may reduce the degree of patient compliance with this medication.
- the advantages of reducing, or eliminating, the inhibitory effect on sebum secretion are reduced incidences of dry skin (xerosis) , scaling (desquamation) and itching relative to using other retinoids, such as isotretinoin, to treat nodulocystic acne with substantially equivalent efficacy.
- the present methods of effectively treating nodulocystic acne with a reduced effect on sebum secretion are quite unexpected, both in view of commonly held assumption that such a reduction is an important requirement in the treatment of nodulocystic acne, and in the prior use of isotretinoin to treat severe acne.
- the present invention is directed to methods for reducing, for example, as described elsewhere herein, nodulocystic acne, such as severe nodulocystic acne, in a human or animal which comprise systemically, preferably orally or transdermally administering to the human or animal having symptoms of nodulocystic acne a therapeutically effective amount of tazarotene.
- administration performed in such a manner so as to provide a maximum blood, i.e.
- concentration of an active retinoid agent in the human or animal of greater than 30 ng/ml or greater than 40 ng/ml or greater than 45 ng/ml or greater than about 50 ng/ml, and more preferably greater than about 60 ng/ml or greater than about 80 ng/ml or greater than about 100 ng/ml.
- the desired therapeutic effect e.g., a reduction in the symptoms, extent, and/or number of symptoms of nodulocystic acne, for example, as described elsewhere herein, advantageously is provided as a result of the administering step.
- prodrug refers to a compound or other substance which is capable of becoming converted in vivo to the compound or other substance of which it is a prodrug.
- prodrugs of tazarotenic acid may include esters, salts, and the like which are capble of being converted to tazarotenic acid in the GI tract, the blood, the skin, or in another tissue of the body. Such conversion may be by hydrolysis, metabolization, formation, or chemical reaction, for example, after being ingested' or introduced into a body of a human or animal .
- tazarotene and one or more derivatives of tazarotene can be considered precursors of active retinoid agents because tazarotene and one or more of its derivatives, after ingestion or introduction into the body of a human or animal, are converted into tazarotenic acid, an active retinoid agent, or one or more derivatives of tazarotenic acid, also active retinoid agents.
- a derivative of an active retinoid agent may be a precursor of an active retinoid agent and/or vice versa .
- the systemically administering step results in or is conducted at conditions effective to provide less attenuation of sebum secretion in the human or animal relative to employing a reference retinoid agent .
- the reference retinoid agent preferably is selected from pan RAR-active retinoids such as isotretinoin, and RXR- active retinoids, for example, bexarotene and the like.
- the systemically administering step using an amount of one of the reference retinoid agent is effective to provide the same reduction, for example, as described elsewhere herein, in nodulocystic acne as the present systemically administering step.
- the retinoid component is selected from active RAR agonists which are substantially ineffective to bind to or activate RXRs, precursors of active agonists which are substantially ineffective in binding to or activating RXRs and mixtures thereof .
- the systemically administering step of the present methods is effective in providing the desired therapeutic effect, and results in or is conducted at conditions effective to provide less reduction in sebum secretion in the human or animal relative to employing a RXR active retinoid agent which is effective in binding to RXRs in place of the retinoid component in a systemically administering step at a dose of the RXR active agent, or using an amount of the RXR active agent, effective to provide the same therapeutic effect, for example, the same reduction in the nodulocystic acne .
- the retinoid component is selected from active RAR agonists effective to selectively, or even specifically, affect, for example, activate, at least one, and preferably both, of RAR-beta and RAR-gamma relative to RAR-alpha, precursors of such active RAR agonists and mixtures thereof.
- active RAR agonists effective to selectively, or even specifically, affect, for example, activate, at least one, and preferably both, of RAR-beta and RAR-gamma relative to RAR-alpha, precursors of such active RAR agonists and mixtures thereof.
- the term "selectively" means that the presently useful RAR agonists precursors of RAR agonists and mixtures thereof are more effective, preferably at least about 10 or about 100 times to about 1000 times or more as effective, to affect times at least one, and preferably both, of RAR-beta and RAR-gamma relative to RAR-alpha.
- the systemically administering step is effective to provide the desired therapeutic effect, e.g., a reduction in the nodulocystic acne, and is conducted at conditions effective to result in or to provide less reduction in sebum secretion in the human or animal relative to employing a pan active or substantially non-selective RAR retinoid agent, such as described elsewhere herein, in place of the retinoid component in a systemically administering step using an amount of the pan active or substantially non-selective RAR retinoid agent to provide the same therapeutic effect, that is the same reduction in the nodulocystic acne.
- a pan active or substantially non-selective RAR retinoid agent such as described elsewhere herein
- nodulocystic acne reductions of at least about 60% or at least about 70% or at least about 80% or at least about 85% or at least about 90% are provided, with less reduction in sebum secretion, as described elsewhere herein.
- Administration e.g., systemically, preferably orally, administering of the presently useful retinoid components, often occurs for more than about 1 week, preferably at least about 4 weeks, or at least about 6 weeks, or about 12 weeks or about 20 weeks. Daily doses of the retinoid component can vary over a wide range.
- the daily dose advantageously is in a range of about 1 mg to about 6 mg of the retinoid component .
- the administering step comprises orally administering the retinoid.
- a capsule for example, a hard gel capsule or a soft gel capsule, containing the retinoid component to the human or animal .
- the capsule systems useful in accordance with the present invention are those disclosed in Firestone et al . , U.S. Patent 6,248,354.
- Firestone et al. discloses capsules, including soft gel capsules with the following fill formulations:
- formulations can be effectively used for oral administration of the presently useful retinoid components; in addition to hard gelatin capsules, tablets or powders (encapsulated or not) may be used.
- the formulations including the presently useful retinoid components may be chosen or selected depending, for example, on the mode of systemic administration of the composition.
- formulations for ' oral administration, transdermal administration, rectal (suppository) administration, administration by injection and other non-oral systemic administration advantageously have different chemical compositions one from the other. Accordingly, each formulation is made to provide the drug in a manner that suits the purpose and mode of administration, for which the drug is to be used.
- formulations for use in the same mode of administration may be employed, for example, to effectively or more effectively meet the needs and/or requirements of the patient and/or the application involved.
- formulations for oral administration can be in forms including soft capsules, hard capsules, powders, pills, tablets, liquids, syrups, elixirs and the like and mixtures or combinations thereof .
- the present methods provide desired therapeutic effects employing certain retinoid components, particularly when administered systemically, for example, orally, to treat severe acne, for example nodular acne, cystic acne, and nodulocystic acne, in a manner that reduces the attenuation of sebum secretion at a dose that will provide substantially the same efficacy as a reference retinoid agent administered in the same manner.
- other side effects commonly seen in other systemic retinoid drugs that can be reduced in severity or substantially eliminated in accordance with the present invention include, but are not limited to, metabolic and nutritional side effects, whole body side effects, endocrine side effects, hemic and lymphatic system side effects, digestive system side effects, ocular side effects, cardiovascular side effects, nervous system side effects, psychiatric side effects, typical retinoid toxicity side effects, respiratory system side effects, ear side effects, gastrointestinal tract side effects, and urinary system side effects.
- Typical Retinoid Toxicity this side effect is similar to that in patients taking high doses of .
- vitamin A includes headache, fever, skin mucous membrane dryness, bone pain, nausea/vomiting, rash, mucositis, pruritus, increased sweating, visual disturbances, ocular disorders, alopecia, skin changes, changed visual acuity, bone inflammation, and visual field defects .
- RA-APL Syndrome characterized by fever, dyspnea, weight gain, radiographic pulmonary infiltrates and pleural or pericardial effusions. This syndrome is occasionally accompanied by impaired myocardial contractility and episodic hypotension and is observed with or without concomitant leukocytosis.
- Body as a Whole general disorders includes malaise, shivering, hemorrhage, infections, peripheral edema, pain, chest discomfort, edema, disseminated intravascular coagulation, weight increase, injection site reactions, anorexia, weight decrease, myalgia, flank pain, cellulitis, face edema, fluid imbalance, pallor, lymph disorders, acidosis, hypothermia, and ascites .
- Respiratory System Disorders include upper respiratory tract disorders, dyspnea, respiratory insufficiency, pleural effusion, pneumonia, rales, expiratory wheezing, lower respiratory tract disorders, pulmonary infiltration, bronchial asthma, pulmonary edema, larynx edema, and unspecified pulmonary disease.
- Ear Disorders ear disorders are consistently reported, with earache or feeling of fullness in the ears also reported. Hearing loss or other unspecified auricular disorders are observed, with infrequent reports of irreversible hearing loss .
- Gastrointestinal Tract (GI) Disorders include GI hemorrhage, abdominal pain, other gastrointestinal tract disorders, diarrhea, constipation, dyspepsia, abdominal distention, hepatosplenomegaly, hepatitis, ulcer, and unspecified liver disorder.
- Cardiovascular and Heart Rate and Rhythm Side Effects arrhythmias, flushing, hypotension, hypertension, phlebitis, cardiac failure, cardiac arrest, myocardial infarction, enlarged heart, heart murmur, ischemia, stroke, myocarditis, pericarditis, pulmonary hypertension, and secondary cardiomyopathy .
- Central and Peripheral Nervous System Disorders and Psychiatric Side Effects dizziness, paresthesias, anxiety, insomnia, depression, confusion, cerebral hemorrhage, intracranial hypertension, agitation, hallucination, abnormal gait, agnosia, aphasia, asterixis, cerebellar edema, cerebellar disorders, convulsions, coma, CNS depression, dysarthria, encephalopathy, facial paralysis, hemiplegia, h poreflexia, hypotaxia, no light reflex, neurologic reaction, spinal cord disorder, tremor, leg weakness, unconsciousness, dementia, forgetfulness, somnolence, and slow speech.
- Urinary System Disorders renal insufficiency, dysuria, acute renal failure, micturition frequency, renal tubular necrosis, and enlarged prostate.
- the systemically, preferably orally, administering step is effective to provide a maximum plasma concentration of an active retinoid agent in the human or animal of greater than about 30 ng/ml, preferably greater than about 40 ng/ml or 45 ng/ml or about 60 ng/ml or about 80 ng/ml, for example, greater than about 100 ng/ml.
- concentration of active retinoid agent in the blood of the human or animal must be therapeutically effective and present in a concentration less than that amount which would cause substantial harm or toxicity in the patient .
- the concentration of the retinoid, including a tazarotene compound, in blood may be determined using a liquid chromatography-mass spectroscopy-mass spectroscopy ( C-MS/MS) .
- C-MS/MS liquid chromatography-mass spectroscopy-mass spectroscopy
- the systemically administering advantageously comprises other than topically administering the retinoid component (preferably the tazarotene compound, to the human or animal.
- the administering comprises a step selected from the group consisting of orally administering to the human or animal the retinoid component, transdermally administering to the human or animal the retinoid component, intravenously administering to the human or animal the retinoid component, subcutaneously administering to the human or animal the retinoid component, intramuscularly administering to the human or animal the retinoid component, intraperitoneally administering to the human or animal the retinoid component, rectally administering to the human or animal the retinoid component, one or more of like administering steps and combinations thereof.
- the administering comprises systemically, preferably orally, administering to the human or animal the retinoid component .
- the retinoid component is not topically administered to the skin of the human or animal in an amount effective to treat the patient's condition while, or during the time, the retinoid component is being systemically administered to the human or animal, for instance, to treat the same condition.
- the retinoid component preferably includes a tarzarotene compound effective to selectively activate at least one of RAR-beta and RAR-gamma relative to RAR- alpha .
- the terms “selectively” or “more selectively” refer to the ability of an active retinoid agent to act as an agonist at RAR-beta and RAR-gamma relative to RAR-alpha.
- the presently useful active retinoid agents are at least about 5 times more potent as an agonist of RAR-beta and RAR-gamma than RAR-alpha, or at least about 10 times more potent, or at least about 20 times more potent, or at least about 50 times more potent, or at least about 100 times mopre potent, or about 1000 times more potent than RAR-alpha.
- the term “specifically” refers to the ability of an active retinoid agent to affect RAR-beta and RAR-gamma at a therapeutically effective dose without detectably agonizing RAR alpha (to a statistically significant extent) using the assays disclosed in this specification.
- the retinoid component includes an active retinoid agent or a precursor of an active retinoid agent effective to selectively or even specifically affect both RAR-beta and RAR-gamma relative to RAR-alpha.
- the retinoid component advantageously includes an active retinoid agent or a precursor of an active retinoid agent effective to selectively or even specifically activate or inhibit the activation of or block at least one or both of RAR- beta and RAR-gamma relative to RAR-alpha.
- the retinoid component includes an active retinoid agent or a precursor of an active retinoid agent effective to selectively or even specifically activate at least one of or both RAR-beta and RAR-gamma relative to RAR-alpha.
- the retinoid component comprises a tazarotene compound.
- the retinoid component includes, or upon systemic administration is able to be converted to, an active retinoid agent having a substantial degree of water solubility.
- an active retinoid agent may be more water soluble than isotretinoin, or may be metabolically converted in the human or animal into an active retinoid agent having a substantial degree of water solubility. In this way, it is possible to design the active retinoid agent to avoid having the active agent cross lipid barriers, such as the blood brain barrier and the retinal-blood barrier.
- the retinoid component comprises an active RAR ligand which is substantially ineffective to bind to or activate or block RXRs and/or a precursor of an active RAR ligand substantially ineffective to bind to or activate or block RXRs .
- the retinoid compound is a tazarotene compound.
- any compound can be tested for RAR activity, for example, using conventional and well known techniques, for example, without limitation, those described in the above-noted patents, each of which is incorporated in its entirety herein by reference.
- a compound Once a compound has been determined to have suitable RAR activity, it can be administered to a test animal with appropriate monitoring for drug interactions and/or side effects . Comparing the results of such monitoring with similar monitoring of test animals given reference retinoid agents allows one to determine if the compound is useful in accordance with the present invention.
- one or more compounds for example, from a screening library of compounds, which are known to have or have been tested, using conventional and well known techniques, and found to have useful RAR activity, can be individually or collectively tested for RXR activity using conventional and well known testing procedures. See, for example, the above-noted Evans et al . patents, in particular U.S. Patent 5,906,920, hereby incorporated by reference herein.
- the methods of the present invention are useful in the treatment of nodulocystic acne, for instance, severe nodulocystic acne, and are particularly beneficial because they result in less reduction, or even substantially no reduction, in sebum secretion.
- a reduction in sebum secretion often occurs upon use of other oral or systemic retinoid agents, resulting in itching, and dry, chapped skin.
- Such use of retinoid components, particularly tazarotene compounds, in accordance with the present invention effectively provides treatment of nodulocystic acne without subjecting the patient to undue reduction in sebum secretion previously associated with treating nodulocystic acne with other retinoid active agents, for example, isotretinoin.
- Especially useful retinoid components useful in the present methods include tazarotene, tazarotenic acid and mixtures thereof.
- Tazarotene is an ethyl ester prodrug that is metabolized to the corresponding free acid, tazarotenic acid.
- Tazarotene has a rigid ring-locked structure that offers limited conformational flexibility compared to all- rans- retinoic acid, the natural ligand for the retinoic acid receptors (RARs) . This structural change confers tazarotenic acid with specificity for the RARs and selectivity for RAR- ⁇ and RAR- ⁇ . As RAR- ⁇ is the major receptor found in skin, tazarotene exerts its pharmacological effects through RAR- ⁇ .
- Tazarotene is also a potent API antagonist. API regulates the transcription of many genes involved in proliferation and inflammation. Tazarotenic acid does not activate the RXR retinoid receptors and its major metabolite, a sulfoxide derivative, does not activate either the RARs or the RXRs. As it has no isomerizable double bonds, tazarotene cannot be converted into RXR-active compounds .
- polyolefinic retinoids such as isoretinoin and acitretin can be isomerized, and if isomerization occurs metabolically the isomers could potentially activate the RARs and/or RXRs.
- RXR agonists cause transient elevation of triglycerides by inhibiting peripheral tissue lipoprotein lipase activity.
- RAR and RXR ligands act synergistically to induce hypertriglyceridemia.
- RAR pan agonists also induce hypertriglyceridemia by increasing hepatic triglyceride output, and this effect is primarily mediated by the RAR- ⁇ receptor.
- RAR- ⁇ is not implicated in hypertriglyceridemi .
- tazarotenic acid has minimal RAR- ⁇ activity and substantially no RXR activity, it would not be expected to elevate triglycerides - by either of the pathways.
- Clinical use of RXR agonists has also been associated with hypothyroidism.
- tazarotene is RAR specific, and cannot be either metabolized or isomerized to RXR active compounds, it would not be expected to cause either significant elevation of triglycerides or hypothyroidism.
- RXR activity and the minimal RAR- ⁇ activity of tazarotenic acid are important factors that reduce the potential for some toxicities, such as hypertriglyceridemia and hypothyroidism, that are typically associated with oral or systemic retinoids .
- the LC-MS/MS test for simultaneous detection of tazarotene and tazarotenic acid may be run as follows.
- One ml of plasma (EDTA-treated) is diluted with 1.0 ml of water.
- Diluted plasma is extracted using solid phase extraction (SPE) on a C18 cartridge.
- the eluate is evaporated, reconstituted in a water/methanol-based mobile phase, and injected onto a 4.6 x 50 mm, 3 ⁇ m pore size C-8 reverse phase high pressure liquid chromatography (HPLC) column (Agilent, Wilmington, DE) .
- Compounds are gradient-eluted at 1.2 m / in and detected using an API 3000 triple quadrupole mass spectrometer with an Atmospheric Pressure Chemical lonization (APCI) source (PE-Sciex, Concord, Ontario, Canada) .
- API 3000 triple quadrupole mass spectrometer with an Atmospheric Pressure Chemical lonization (APCI) source (PE-Sciex, Concord, Ontario, Canada) .
- APCI Atmospheric Pressure Chemical lonization
- Molecular reaction monitoring enhances the sensitivity and selectivity of this assay by collisionally dissociating the protonated molecules for the analyte and an internal standard thereby forming the product ions.
- the specific precursor-product ion pair monitored are m/z 352—>324 for tazarotene, m/z 359—>331 for the tazarotene internal standard, m/z 324—>294 for tazarotenic acid, and m/z 331 ⁇ 298 for the tazarotenic acid internal standard.
- the lower limit of quantitation at assay range tested is 0.1 ng/mL, with a coefficient of variation and deviation from nominal concentration of ⁇ 15%.
- Retinoid components useful in the present invention may be included in a composition with one or more other suitable pharmaceutically acceptable ingredients .
- suitable pharmaceutically acceptable ingredients include, but are not limited to antioxidants, such as burylated hydroxyanisole NF and the like; emulsifiers, such as sorbitanmonoolate NF, polysorbate 80 NF and the like and mixtures thereof; vehicle components, such as conventional vehicles and the like; and other materials which are useful to provide one or more benefits to the composition to be administered and/or to the subject to whom the composition is administered.
- the retinoid component may be coadministered, either in separate composition or together in a single composition, with one or more active ingredient.
- tazarotene compounds may be coadministered with an antibiotic or other agent effective for the treatment of nodulocystic acne.
- Daily dosages of the presently useful retinoid components may vary from patient to patient depending, for example, on the specific activity of the particular compound, on the desired therapeutic effect to be achieved, on the condition of the patient, on the mode of systemic administration, on the frequency of administration and the like factors. Such dosages advantageously are selected to provide the desired therapeutic effect, preferably substantially without unduly harming or interfering with the patient. Examples, without limitation, of such daily dosages may be in a range of about 0.1 g/day or less or about 0.3 mg/day to about 7 mg/day or about 10 mg/day or more. Each oral dose may contain about 0.2 mg, or about 0.7 mg, or about 1 mg, or about 4.5 mg.
- the desired therapeutic effect is a reduction in nodulocystic acne, for example, severe nodulocystic acne
- daily dosages are often within +the above-noted ranges.
- the daily dosage of tazarotene preferably is in a range of about 0.3 mg/day to about 7 mg/day or about 8 mg/day, more preferably in a range of about 0.6 mg/day to about 6.5 mg/day or about 7 mg/day.
- Clinical trials using orally administered tazarotene to effect reductions, as described elsewhere herein, in nodulocystic acne have employed daily dosages of tazarotene including 0.4 mg/day, 0.75 mg/day, 1.5 mg/day, 2.8 mg/day, 3 mg/day, 4.5 mg/day, 6 mg/day and 6.3 mg/day.
- Each oral dose may contain about 0.4 mg, or about 0.75 mg, or about 1.5 mg, or about 2.8 mg, or about 3 mg or about 6 mg of tazarotene.
- the presently useful retinoid components can be advantageously administered on a once daily basis, other dosing frequencies may be employed.
- the presently useful retinoid components may be administered twice or three or more times daily, or once every two or three or more days .
- Coadministration of 6.3 mg oral tazarotene with a high-fat meal in normal healthy subjects following single and multiple dose administrations does not substantially affect the bioavailability or pharmacokinetics of tazarotenic acid, the primary active retinoid species in the systemic circulation. This result is based on comparing the pharmacokinetics of tazarotenic acid when administered within 30 minutes after consuming a high fat breakfast vs. when administered after an 8-10 hour fast. The 90% confidence intervals (CI) of AUC ratios (test/reference) are completely within the 80-125% boundary.
- EXAMPLE 3 Two multicenter, double-blind, randomized, placebo-controlled 24-week studies of identical design are conducted to evaluate the safety of oral tazarotene. In addition, 16- to 24-week dose-response evaluations are performed.
- tazarotene was associated with an increased incidence of psychiatric disorders -- depression (1% with tazarotene vs 2% with placebo) , psychosis (0% vs ⁇ 1%) , psychotic depression (0% vs ⁇ 1%) , emotional lability (3% vs 3%) , anxiety (1% vs ⁇ 1%) , and agitation ( ⁇ 1% vs 0%) .
- Two placebo-controlled dose-ranging studies are conducted to evaluate the safety of oral tazarotene in patients having nodulocystic acne.
- patients receive orally administered tazarotene at daily doses of 0.4 mg to 2.8 mg in 96 (71 + 25) patients (12 weeks treatment plus 12 weeks post- treatment) .
- daily doses of 0.75 mg to 6 mg tazarotene are administered to 181 patients (24 weeks treatment plus 12 weeks post-treatment) .
- Oral tazarotene is well tolerated, with only 2.5% (7/277) of patients withdrawing from either study due to adverse events (2 each with placebo, 0.75 mg, and 3 mg, and 1 with 6 mg) .
- cheilitis is mild in 25 and 27 patients, respectively, moderate in 3 and 6 patients, and severe in 1 patient in each group.
- dry skin is mild in 11 and 17 patients, respectively, and moderate in 2 and 1 patient. No patient has severe dry skin. Emotional lability occurs in 1 (3%) patient in the 3 mg group and 5 (14%) in the 6 mg group compared with
- Tazarotene treatment is also not associated with any clinically significant ligament calcification, osteophyte formation, or changes in serum bone alkaline phosphatase, serum amino terminal telopeptides, or bone density.
- oral tazarotene has a good safety and tolerability profile in the treatment of nodulocystic acne and does not appear to result in clinically significant changes in liver enzymes, cholesterol or triglyceride levels, or bone density.
- a multicenter, double-blind, randomized, placebo- controlled parallel-group study is undertaken to determine the efficacy of orally administered tazarotene in treating severe nodulocystic acne.
- the main inclusion criteria for this study include: at least 7 facial nodulocystic acne lesions (>5 mm); an age of at least 16 years; stable doses of any concurrent medication that might significantly affect hepatic or renal excretion; if taking oral contraceptives, stable dose for last 3 months; and negative urine pregnancy test for females of childbearing potential.
- the main exclusion criteria for this study include: females of childbearing potential not committed to using highly effective contraceptive during the study; pregnant or lactating females; 8-hour fasting triglyceride levels ⁇ 500 mg/dL, serum calcium levels >11 mg/dL; likelihood of prolonged exposure to ultraviolet light during the study; and uncontrolled systemic disease.
- washout periods for other medications for this study are: 1 week for vitamin A supplements >5000 IU; 2 weeks for topical anti-acne medications (e.g., retinoids, azelaic acid, benzoyl peroxide); 2 weeks for topical or systemic antibiotic therapy that may alter the course of acne; and 6 months for systemic retinoids.
- topical anti-acne medications e.g., retinoids, azelaic acid, benzoyl peroxide
- topical or systemic antibiotic therapy that may alter the course of acne
- 6 months for systemic retinoids 6 months for systemic retinoids.
- Patients are randomized to receive placebo or oral tazarotene (0.75, 1.5, 3, or 6 mg) , in a 1:1:1:1:1 ratio once daily for 24 weeks. After this, the patients are followed without treatment for an additional 12 weeks. Patients discontinuing from the treatment period due to adverse effects or lack of efficacy are eligible for entry into the post-treatment phase .
- acne severity is rated as: none (no inflammatory acne lesions) ; mild (few to several papules or pustules, no nodulocystic lesions) ; moderate (several to many papules or pustules, few to several nodulocystic lesions) ; and severe (numerous or extensive papules or pustules, many, for example, at least about 5 or at least about 10, nodulocystic lesions) .
- Treatment success is defined as at least moderate (about 50%) improvement on the following 7-point global response scale:
- facial nodulocystic lesion count includes lesions greater than 5mm in size.
- Facial papular/pustular lesion count includes lesions less than or equal to 5 mm in size.
- Facial non-inflammatory lesion count includes open and closed comedones .
- Sebum output is assessed every 4 weeks at selected centers using the Sebutape® patches, sold by Cuderm Corporation. Urinalysis, chemistry, and hematology values are monitored. Bone formation and resorption assessments (serum bone alkaline phosphatase and serum amino terminal telopeptides, respectively) at selected centers are monitored.
- Bone mineral density of spine and proximal femur at selected centers is monitored.
- Ligament calcification or osteophyte formation is monitored.
- Epiphyseal growth plate closure is monitored.
- the withdrawing patients are as follows: 0% (0/36) of placebo group; 6% (2/35) of 0.75 mg group (anxiety attack, mild leucopenia); 0% (0/37) of 1.5 mg group; 5% (2/37) of 3 mg group (infectious mononucleosis, depression) ; and 3% (1/36) of 6 mg group (spinal stiffness and joint and muscle pain) .
- Patients withdrawing due to lack of efficacy are primarily in the placebo or lowest dose groups: 17% (6/36) of placebo group; 20% (7/35) of 0.75 mg group;
- results of this study are that tazarotene at 6 mg reduces the overall acne severity significantly more than placebo from week 16 until the end of the post- treatment phase (p ⁇ O.01). More than 45% of the patients in the three highest dose groups have either no acne or mild acne by the end of the treatment phase, compared with 34% in the tazarotene 0.75 mg group and 19% in the placebo group. At the end of the post- treatment phase, these levels of acne have been maintained in 53% of the 6 mg group and 43% of the 3 mg group .
- Tazarotene at 3 mg and 6 mg have a significantly higher incidence of treatment success ( ⁇ 50% global improvement) than placebo at week 24 and throughout the post-treatment phase (p ---0.05). Treatment success is achieved by week 12 in more than 70% of patients treated with the three highest doses of tazarotene and by week 24 in more than 86% of patients treated with the two highest doses . Tazarotene achieves consistently greater reductions in the number of total facial nodulocystic lesions than placebo from week 8 onward.
- the mean total facial nodulocystic lesion count is reduced from: 11.6 to 5.2 in the placebo group (a 55% reduction) ; 12.2 to 4.2 in the 0.75 mg group (a 66% reduction) ; 11.8 to 3.2 in the 1.5 mg group (a 73% reduction); 10.8 to 2.3 in the 3 mg group (a 79% reduction); and 11.6 to 1.6 in the 6 mg group (an 86% reduction) .
- the percentage of patients with at least a 90% reduction in facial nodulocystic lesion count is significantly greater in the higher-dose tazarotene groups (1.5, 3, and 6 mg) than in the placebo group at week 24.
- the 6 mg group also shows significant superiority over placebo at the end of the post- treatment phase.
- tazarotene results in consistently greater reductions in the number of facial papules or pustules, and facial non-inflammatory acne lesions, compared with placebo.
- the mean facial papule or pastule count is reduced from: 32.4 to 22.3 in the placebo group (a 31% reduction) ; 32.3 to 20.3 in the 0.75 mg group (a 37% reduction) ; 29.1 to 13.3 in the 1.5 mg group (a 54% reduction) ; 25.4 to 10.0 in the 3 mg group (a 61% reduction); and 24.6 to 11.1 in the 6 mg group (a 55% reduction).
- the mean facial non-inflammatory lesion count is reduced from: 62.3 to 34.2 in the placebo group (a 45% reduction) ; 56.3 to 30.3 to 30.3 in the 0.75 mg group (a 46% reduction) ; 59.2 to 17.8 in the 1.5 mg group (a 70% reduction); 56.1 to 21.3 in the 3 mg group (a 62% reduction); and 47.7 to 13.5 in the 6 mg group (a 72% reduction) .
- Sebum secretion output is assessed in a maximum of 86 patients (with successively fewer patients at each timepoint - e.g., 60 patients at week 24, 46 patients at week 36) .
- the oral administration of tazarotene does not substantially reduce sebum secretion relative to placebo, even when such tazarotene administration is effective to reduce or even eliminate severe nodulocystic acne.
- Bone formation and resorption do not appear to be altered. There are no statistically significant differences between groups in the mean change from baseline in serum bone alkaline phosphatase (bone formation) or serum amino terminal telopeptides (bone resorption) .
- oral tazarotene has a better tolerability profile than other oral retinoids.
- Oral isotretinoin has been associated with several adverse events that did not occur as frequently — or at all — with oral tazarotene.
- the only adverse effects reported with an incidence of ---15% with oral tazarotene are cheilitis, dry skin, headache, arthralgia, myalgia, infection, asthenia, and joint disorder.
- oral tazarotene is not generally associated with abnormalities in liver function test results or elevated levels of triglycerides, total cholesterol, or high-density lipoprotein cholesterol.
- Oral tazarotene is efficacious at once-daily doses of 1.5, 3, and 6 mg.
- the higher doses are associated with the greatest efficacy, the most rapid clearing of facial nodulocystic lesions, and maintenance of response for at least 12 weeks post-treatment.
- the superiority of the 6-mg dose of oral tazarotene over placebo is significant from week 16 onward.
- oral administration of tazarotene does not substantially reduce sebum secretion, even when such administration is effective to reduce or even eliminate severe nodulocystic acne.
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP04779893A EP1653941A1 (en) | 2003-07-30 | 2004-07-29 | Methods of therapeutic treatment using amounts of retinoid components |
CA002534005A CA2534005A1 (en) | 2003-07-30 | 2004-07-29 | Methods of therapeutic treatment using amounts of retinoid components |
AU2004261286A AU2004261286A1 (en) | 2003-07-30 | 2004-07-29 | Methods of therapeutic treatment using amounts of retinoid components |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US49114303P | 2003-07-30 | 2003-07-30 | |
US60/491,143 | 2003-07-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005011667A1 true WO2005011667A1 (en) | 2005-02-10 |
Family
ID=34115472
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2004/024966 WO2005011667A1 (en) | 2003-07-30 | 2004-07-29 | Methods of therapeutic treatment using amounts of retinoid components |
Country Status (7)
Country | Link |
---|---|
US (1) | US20050026958A1 (en) |
EP (1) | EP1653941A1 (en) |
AR (1) | AR045177A1 (en) |
AU (1) | AU2004261286A1 (en) |
CA (1) | CA2534005A1 (en) |
TW (1) | TW200509922A (en) |
WO (1) | WO2005011667A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007065289A2 (en) * | 2005-12-09 | 2007-06-14 | Basilea Pharmaceutica Ag | 4-oxo-(iso)tretinoin for the topical treatment of severe dermatological disorders |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070060620A1 (en) * | 2005-09-09 | 2007-03-15 | John Sefton | Use of RAR retinoid agonists to increase sperm count and sperm mobility in males |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4322438A (en) * | 1979-08-06 | 1982-03-30 | United States Of America | Method for the use of orally administered 13-cis-retinoic acid in the treatment of acne |
US5089509A (en) * | 1988-09-15 | 1992-02-18 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
WO2000051571A2 (en) * | 1999-03-04 | 2000-09-08 | Allergan Sales, Inc. | Capsule system |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5776699A (en) * | 1995-09-01 | 1998-07-07 | Allergan, Inc. | Method of identifying negative hormone and/or antagonist activities |
US5958954A (en) * | 1995-09-01 | 1999-09-28 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5877207A (en) * | 1996-03-11 | 1999-03-02 | Allergan Sales, Inc. | Synthesis and use of retinoid compounds having negative hormone and/or antagonist activities |
US5919970A (en) * | 1997-04-24 | 1999-07-06 | Allergan Sales, Inc. | Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity |
-
2004
- 2004-07-29 CA CA002534005A patent/CA2534005A1/en not_active Abandoned
- 2004-07-29 WO PCT/US2004/024966 patent/WO2005011667A1/en active Application Filing
- 2004-07-29 US US10/902,719 patent/US20050026958A1/en not_active Abandoned
- 2004-07-29 EP EP04779893A patent/EP1653941A1/en not_active Withdrawn
- 2004-07-29 AU AU2004261286A patent/AU2004261286A1/en not_active Abandoned
- 2004-07-30 AR ARP040102722A patent/AR045177A1/en not_active Application Discontinuation
- 2004-07-30 TW TW093122946A patent/TW200509922A/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4322438A (en) * | 1979-08-06 | 1982-03-30 | United States Of America | Method for the use of orally administered 13-cis-retinoic acid in the treatment of acne |
US5089509A (en) * | 1988-09-15 | 1992-02-18 | Allergan, Inc. | Disubstituted acetylenes bearing heteroaromatic and heterobicyclic groups having retinoid like activity |
WO2000051571A2 (en) * | 1999-03-04 | 2000-09-08 | Allergan Sales, Inc. | Capsule system |
Non-Patent Citations (3)
Title |
---|
"New therapies for psoriasis produce impressive responses", FORMULARY 01 MAY 2003 UNITED STATES, vol. 38, no. 5, 1 May 2003 (2003-05-01), pages 267+270, XP009039267, ISSN: 1082-801X * |
LEE EDWARD ET AL: "Pharmacokinetics and dose proportionality of tazarotene following oral administration in healthy subjects", PHARMACOTHERAPY, vol. 22, no. 10, October 2002 (2002-10-01), & ANNUAL MEETING OF THE AMERICAN COLLEGE OF CLINICAL PHARMACY; ALBUQUERQUE, NEW MEXICO, USA; OCTOBER 20-23, 2002, pages 1364, XP009039324, ISSN: 0277-0008 * |
NAGPAL SUNIL ET AL: "Recent developments in receptor-selective retinoids", CURRENT PHARMACEUTICAL DESIGN, vol. 6, no. 9, June 2000 (2000-06-01), pages 919 - 931, XP009039340, ISSN: 1381-6128 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007065289A2 (en) * | 2005-12-09 | 2007-06-14 | Basilea Pharmaceutica Ag | 4-oxo-(iso)tretinoin for the topical treatment of severe dermatological disorders |
WO2007065289A3 (en) * | 2005-12-09 | 2007-08-02 | Basilea Pharmaceutica Ag | 4-oxo-(iso)tretinoin for the topical treatment of severe dermatological disorders |
Also Published As
Publication number | Publication date |
---|---|
AU2004261286A1 (en) | 2005-02-10 |
CA2534005A1 (en) | 2005-02-10 |
TW200509922A (en) | 2005-03-16 |
EP1653941A1 (en) | 2006-05-10 |
AR045177A1 (en) | 2005-10-19 |
US20050026958A1 (en) | 2005-02-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Rolf et al. | Intra-articular absorption and distribution of ketoprofen after topical plaster application and oral intake in 100 patients undergoing knee arthroscopy. | |
DE60116256T2 (en) | COMPOSITIONS FOR THE DELIVERY OF CORTISOLANTAGONISTS | |
US20070105954A1 (en) | Formulation containing a carboxylic acid or an ester thereof | |
KR20210151816A (en) | Cannabinoid acid ester compositions and uses thereof | |
US20200261427A1 (en) | Topical rapamycin formulations and their use in treating facial angiofibromas and other skin disorders | |
KR20240052856A (en) | Compositions comprising 15-hepe and methods of using the same | |
JP2013502411A (en) | Skin improvement composition containing hexamidines and retinoids | |
US7060729B2 (en) | Composition and method for treating skin | |
US20050026958A1 (en) | Methods of therapeutic treatment using amounts of retinoid components | |
WO2020152350A1 (en) | Compositions for use in preventing acne | |
US10123970B2 (en) | Topical retinoid solutions | |
US20050026950A1 (en) | Methods of therapeutic treatment using retinoids to achieve consistent bioavailability | |
US20050027003A1 (en) | Methods of therapeutic treatment using retinoids with reduced side effects | |
US10022348B2 (en) | Topical solution of isotretinoin | |
EP2991653A1 (en) | Minoxidil for suppressing androgen receptor function | |
EP3386516A1 (en) | Pharmaceutical formulations for treating skin disorders and methods for fabricating and using thereof | |
US20050026949A1 (en) | Methods of therapeutic treatment using amounts of retinoids without regard to body weight | |
Anadkat et al. | 3 Systemic Retinoids |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref document number: 2534005 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004779893 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004261286 Country of ref document: AU |
|
ENP | Entry into the national phase |
Ref document number: 2004261286 Country of ref document: AU Date of ref document: 20040729 Kind code of ref document: A |
|
WWP | Wipo information: published in national office |
Ref document number: 2004779893 Country of ref document: EP |