WO2006014669A2 - Methodes et compositions pour le traitement de la neoplasie intra-epitheliale - Google Patents
Methodes et compositions pour le traitement de la neoplasie intra-epitheliale Download PDFInfo
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- WO2006014669A2 WO2006014669A2 PCT/US2005/025639 US2005025639W WO2006014669A2 WO 2006014669 A2 WO2006014669 A2 WO 2006014669A2 US 2005025639 W US2005025639 W US 2005025639W WO 2006014669 A2 WO2006014669 A2 WO 2006014669A2
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- 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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
Definitions
- inhibitory compounds such as those that inhibit SpI binding to promoters of genes involved in cell cycle regulation or cell survival, for example, catecholic butanes that include nordihydroguaiaretic acid derivatives
- IEN Intraepithelial neoplasia
- the AACR Task Force indicates that "[although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk.”
- the Task Force suggests that the "incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population . . . .”
- the Task Force concludes that there is "an urgent need to rapidly develop new treatment and prevention agents for IEN.”
- the Task Force recommends such treatment because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive intervention.
- O'Shaughnessy et al. (2002) describes the stages of progression from normal tissue to cancer as including the stages of: initiation of dysplasia, development of mild dysplasia, development of moderate dysplasia, development of severe dysplasia, development of carcinoma in situ ("CIS"), and finally development of cancer (invasive neoplasia).
- - 40 cigarette pack-years.
- normal tissues progress to the IEN stage in about 30 - 40 years, and then to cancer in about another 10 years.
- tissues exhibiting characteristics of atypical hyperplasia progress to ductal CIS ("DCIS") in about 14 - 18 years, and from DCIS to cancer in about another 6 - 10 years.
- DCIS ductal CIS
- prostate tumors it takes about 20 years to progress from normal to prostatic intraepithelial neoplasia ("PIN”), then another 10 years or more to progress to latent cancer stage, and a further 3 - 15 years to progress to invasive cancer stage.
- PIN prostatic intraepithelial neoplasia
- Colon cancer and rectal cancer (collectively, “colorectal cancer” or
- CRC cancer-related death in the United States, after lung and prostate cancer in men, and lung and breast cancer in women. Colorectal carcinogenesis is believed to be a multistage process.
- the first clinically detectable evidence of IEN consists of subtle alterations in the regular pattern of the intestinal crypts known as aberrant crypt foci ("ACF").
- ACF may show loss of wild-type adenomatous polyposis coli (“APC”) protein, as well as mutations of K-ras .”
- HNSCC Head and neck squamous cell carcinoma
- the primary risk factors for HNSCC include smoking tobacco and alcohol consumption.
- the overall survival rate for these cancers (-55%) is not significantly improved over the last three decades. It is believed that although many different changes contribute to epithelial carcinogenesis, histologically, defined IEN lesions are still considered to be a better predictor of cancer risk than any individual genetic lesion.
- the oral IEN lesions (“OPLs”) are white and/or red mucosal patches in the oral cavity or oropharynx that occur in about 1 - 10% of the adult population in the Western world.
- Barrett's esophagus is "a condition in which normal esophageal squamous epithelium is replaced by a metaplastic columnar lining resembling intestinal epithelium," and is believed to be “strongly associated with chronic GERD (gastroesophageal reflux disease).”
- Cervical cancer is believed to be the third most common cancer in women worldwide.
- the precursor lesion to invasive cervical cancer, CIN, is also known as SIL (squamous intraepithelial lesion) of the cervix.
- LGSIL low grade
- HGSIL high grade
- LGSILs include CIN 1 lesions
- HGSILs include CIN 2 and 3 and CIS, according to the Bethesda System. (The Bethesda System for reporting cervical/vaginal cytological diagnoses (1989)) and Kurman, RJ. et al. (1994).
- Bronchial intraepithelial neoplasia is the precursor to lung cancer.
- lung cancer is the most common cause of cancer death in both men and women. It is believed that more patients die from lung cancer than from breast, colon, and prostate cancers combined. Like other epithelial malignancies, lung cancers are preceded by a series of precursor lesions. For squamous cell carcinoma (“SCC”), invasive lung cancer develops from first mild, then moderate and severe atypia, then CIS, and then invasive cancer over an average of 10 years. Not much is known about the development of other lung tumor types, but atypical adenomatous hyperplasia of the lung (“AAH”) is considered to be the preinvasive lesion of adenocarcinoma. [011] Non-melanoma skin cancer is the most common type of malignancy.
- SCC squamous cell carcinoma
- AAH atypical adenomatous hyperplasia of the lung
- Keratinocytic non-melanoma skin cancers originate in the epidermis and consist of basal cell carcinoma ("BCC") and squamous cell carcinoma (“SCC"). About 80% of such tumors are BCCs, which appear to originate from basal cells of the epidermis and occasionally those of the infundibular and outer root sheath of the hair follicles. These are slow-growing tumors that are locally invasive but rarely metastasize. SCCs appear to originate in the keratinizing cells of the epidermis. SCCs are generally more aggressive than BCCs and have a much higher potential for metastasis. IEN precursor to
- SCC appears as a proliferation of transformed, neoplastic keratinocytes confined to the epidermis and is characterized by thickened, cornified, scaly lesions that develop on the surface of the skin because of improper maturation of keratinocytes.
- Breast cancer is believed to be the most common cancer in women excluding BCCs and SCCs of skin and the second most common cause of cancer deaths in women.
- Breast IEN which spans the continuum from simple hyperplasia without atypia to CIS, is a recognized risk factor for invasive breast cancer. The predominant phenotype in breast IEN is reportedly a progressive increase in the proportion of cells expressing estrogen receptor ("ER").
- PIN Prostate intraepithelial neoplasia
- PIN lesions are found to be characterized by collections of proliferative prostatic epithelial cells confined within prostatic ducts that exhibit many morphological features of prostate cancer cells. Such features include architectural disorganization, enlarged cell nuclei and nucleoli.
- PDSf lesions are currently classified into two grades, low- grade PIN (formerly PIN 1) and high-grade PIN (HGPIN, formerly PIN 2 and PIN 3). Current use of the term PIN generally refers only to HGPIN.
- HGPIN is a precursor of prostatic adenocarcinoma
- PIN is usually localized in the peripheral zone of the prostate, where 70% of prostatic carcinomas occur.
- Both PIN and carcinoma exhibit enhanced proliferative activity (about 3 fold that of benign tissue), cytokeratin immunoreactivity, lectin binding, and loss of blood group antigen.
- PIN lesions are asymptomatic and cannot be easily diagnosed or detected except through examination of prostate tissue histologically. Available evidence supports the conclusion that presence of PIN on prostate biopsy predicts for an increased risk for prostate cancer and that some PIN give rise to prostate cancers.
- Bladder cancer is believed to be the fourth most common cancer in males in the United States, accounting for 6% (39,200) of new cancer cases and 3% (8,300) of cancer-related deaths in 2001. hi United States females, the incidence is lower with 2% (15,100) of new cases and less than 2% (4,100) of cancer deaths. Of these cancers that are confirmed histologically, the majority is transitional cell carcinoma (“TCC”). Invasive TCC are thought to arise from one of two IEN precursor lesions, papillary TCC and transitional cell carcinoma in situ (“TIS"). Papillary TCC is the most common bladder tumor, characterized by papillae protruding into the bladder lumen and composed of several layers of urothelial cells.
- the urothelial cells exhibit a spectrum of cytological atypia and proliferative activity, with grade 1 lesions showing slight cytological atypia and some mitoses, grade 2 showing moderate cytological atypia and some mitoses, and grade 3 lesions showing marked nuclear atypia and frequent mitoses.
- Lower grade flat lesions in the bladder often termed mild dysplasia and moderate dysplasia are also recognized.
- TCC and TIS can be distinguished from invasive carcinoma in that the latter is characterized by progressive penetration of cancer cells through the lamina limba of the bladder urothelium into the underlying musculature.
- Superficial bladder cancers, i.e., papillary TCC and TIS, and invasive bladder cancers often present with symptoms of hematuria or discomfort.
- Vulval intraepithelial neoplasia (“VIN”) is defined as the pre-invasive phase of carcinoma of the vulva. It affects 20 to 30 per 100,000 women, with women under 41 constituting 40% of the cases. VIN presents as pruritus vulvae or abnormal skin lesion of the vulva. Management options include local excision and careful monitoring or steroidal treatment. Approximately 6% of the lesions become malignant. It is further believed that if VIN is diagnosed, then there is a greater than 10% risk of neoplasia elsewhere, generally in the cervix.
- Pancreatic intraepithelial neoplasia has been classified into three grades. PanIN 2 and PanIN 3 are believed to be precursors to invasive pancreatic carcinoma. Pancreatic neoplasms can be classified phenotypically based on their cellular lineages, such as ductal, acinar and endocrine phenotypes. Most pancreatic neoplasms are of the ductal type and can be classified as ductal adenocarcinomas.
- ductal adenocarcinoma intraductal papillary mucinous neoplasm including colloid carcinoma, mucinous cystic neoplasm, medullary carcinoma, and other rare tumors.
- Ductal adenocarcinomas are believed to have developed from ductal proliferative lesions arising in the pancreatic duct system, as described in Kloppel, G. and Luttges, J. (2004) and Takaori, K. et al. (2004).
- AIN intraepithelial neoplasia
- TIN Testicular intraepithelial neoplasia
- Penile intraepithelial neoplasia may be a precursor to high-grade PenileBSf and anogenital carcinoma, as described in Aynaud, O. and Bergeron, C. (2004).
- Conjunctival-corneal intraepithelial neoplasia (“CCIN”) is described in Dudney, B.W. and Malecha, M.A. (2004).
- Jordan et al. in US 5,008,294 claims the use of certain catecholic butanes for "inhibiting the growth of a tumor which comprises topically administering to the situs of the tumor of a mammal in need of said treatment an effective amount of a composition comprising at least 1 catecholic butanes" of a specified formula.
- Jordan et al. further claims treatment for tumors of the skin, keratosis of the skin, and actinic keratosis.
- NDGA derivatives that were isolated from Larrea tridentate and use thereof for the suppression of Tat transactivation of a lentivirus in a cell.
- Hwu, J.R. et al. (1998) described the synthesis of mono-, di-, tri-, and tetra-O-methylated NDGA and isolation of such in pure forms.
- Huang et al. in US 6,214,874, further claim, among other things, methods for treating HPV-induced tumor comprising application of at least one NDGA derivative of a specified formula. Additionally, in US 6,417,234, Huang et al. describes, among other things, a method of treating tumors using at least one NDGA derivative of a specified formula. In US 6,608,108, Huang et al. claim, among other things, methods of inhibiting survivin production in a eukaryotic cell cycle and methods of stimulating apoptosis in a cell expressing CDC-2 and survivin. [022] There is an urgent medical need to develop compositions, kits and methods for treatment of intraepithelial neoplasia of all epithelial cell types so as to reduce the morbidity and mortality of cancer. SUMMARY OF THE INVENTION
- the invention is directed to a pharmaceutical composition for treatment of intraepithelial neoplasia or dysplasia.
- the composition comprises at least one compound that inhibits binding of a transcription factor to a regulatory region of a gene involved in regulation of cell cycle or a gene involved in cell survival and a pharmaceutically acceptable carrier or excipient such as, for example, DMSO, saline, ethanol, phosphate buffered saline, Cremaphor, ethanol, water or mixtures thereof, wherein the composition is formulated for delivery to situs of the intraepithelial neoplasia or dysplasia.
- the transcription factor is SpI or E2Fl.
- the intraepithelial neoplasia or dysplasia is other than actinic keratosis or keratosis of the skin, hi other embodiments, the intraepithelial neoplasia or dysplasia is other than an intraepithelial neoplasia of the skin.
- the intraepithelial neoplasia or dysplasia is mucosal.
- the intraepithelial neoplasia or dysplasia is cervical.
- the intraepithelial neoplasia or dysplasia is prostatic.
- the intraepithelial neoplasia or dysplasia is penile, hi further embodiments, the intraepithelial neoplasia or dysplasia is testicular.
- the intraepithelial neoplasia or dysplasia is vulvar.
- the intraepithelial neoplasia or dysplasia is oral.
- the intraepithelial neoplasia or dysplasia is anal.
- the intraepithelial neoplasia or dysplasia is pancreatic.
- the intraepithelial neoplasia or dysplasia is lung or pulmonary.
- the intraepithelial neoplasia or dysplasia is breast.
- the intraepithelial neoplasia or dysplasia is colon.
- the intraepithelial neoplasia or dysplasia is colorectal.
- the intraepithelial neoplasia or dysplasia is head and neck.
- the intraepithelial neoplasia or dysplasia is esophageal.
- the intraepithelial neoplasia or dysplasia is skin.
- the intraepithelial neoplasia or dysplasia is conjunctival-corneal.
- the intraepithelial neoplasia or dysplasia is bladder.
- the compound in the composition is a catecholic butane having a structural formula of Formula I:
- R 1 and R 2 are independently -H, a lower alkyl, a lower acyl, an alkylene or an amino acid residue or substituted ammo acid residue or salt thereof;
- R 3 , R 4 , R 5 , R 6 , R 1O , Rn, R 12 and R 13 are independently -H or a lower alkyl;
- R 7 , R 8 and Rg are independently -H, -OH, a lower alkoxy, a lower acyloxy, or any two adjacent groups together may be an alkyene dioxy, and optionally, -OR 1; -OR 2 , R 7 , R 8 and R 9 are each an amino acid residue or a substituted amino acid residue or salt thereof.
- the compound is other than NDGA.
- the compound has a structural formula of
- R 1 , R 2 , R 3 and R 4 are not each -OH simultaneously.
- the compound is tetra-O-methyl NDGA
- each OfR 1 , R 2 , R 3 and R 4 independently represent an N,N-dimethyl substituted amino acid residue or a salt thereof.
- the composition comprises a rinse such as an oral rinse, a wash such as a bladder wash, a cream, a lotion, a gel including an adhesive gel, a patch, such as an mucosal patch, a spray such as an oral spray, an ointment, a solid such as a tablet, an aerosol, an inhalant such as a powder or spray, a foam, an enema, a suppository, or a liquid including an injectable liquid or in drops such as topical ocular drops.
- the gene is a gene of CDC (cell division cycle) family such as CDC2 or CDC6, a gene of histone family, a gene of Bub family such as Bubl, a gene of cyclin family such as cyclin A2, a gene of cyclin family such as cyclin C, cyclin El, cyclin F, a gene of E2F family such as E2F1, a gene of topoisomerase family such as TOP2A, a gene of VEGF family, or a gene of BRCA family.
- the cyclin family comprises cyclin-dependent kinase such as cyclin dependent kinase 7, or CDKN3.
- the gene is a proliferating cell nuclear antigen
- the intraepithelial neoplasia or dysplasia is associated with a viral infection, hi certain embodiments, the virus is HPV, HSV, EBV, HBV, JC virus, Varicella-zoster virus, adenovirus, parvovirus, or a lenti-virus.
- the gene involved in survival is survivin.
- the composition is formulated for administration intravenously, or orally, or buccally, or by inhalation, or intranasally, or intraperitoneally, or subcutaneously, or intravaginally, or by implantation such as in a pessary.
- the composition is formulated for administration or onto the surface of the neoplasia or dysplasia, provided that the lesion is other than actinic keratosis.
- the composition is formulated for administration onto the surface of the neoplasia or dysplasia, provided that the lesion is other than premalignant tumors of the skin.
- the compound is for application onto the surface of the neoplasia or dysplasia via delivery by inhalation, by intranasal administration, or as a rinse or a wash, or as a suppository or an enema and the compound is present in the composition at a concentration in a range of about 0.05 wt % to about or less than about 30 wt %, optionally, the concentration of the compound is about or less than about 27.5 wt %, or 25 wt %, or 22.5 wt %, or 20 wt %, or 17.5 wt %, or 15 wt %, or 12.5 wt %, or 10 wt %, or 7.5 wt %, or 5 wt %, or 2.5 wt %, or 1.25 wt %.
- the compound is for administration intravenously, intraperitoneally, or subcutaneously and is present in the composition at a concentration in a range of about 0.1 mg/ml to about or less than about 500 mg/ml, optionally, the concentration is in a range of about 0.5 mg/ml to about or less than 475 mg/ml, or about 1 mg/ml to about or less than 400 mg/ml, or about 2 mg/ml to about or less than 375 mg/ml, or about 5 mg/ml to about or less than 350 mg/ml, or about 7.5 mg/ml to about or less than 325 mg./ml, or about 10 mg/ml to about or less than 300 mg/ml, or about 12.5 mg/ml to about or less than 275 mg/ml, or about 15 mg/ml to about or less than 250 mg/ml, or about 17.5 mg/ml to about or less than 225 mg/ml, or about 20 mg/ml to about or less than
- the compound is for administration orally, for example, as a tablet, and the compound is present in the composition at a concentration of not less than about 98 wt %, or about 95 wt %, or about 90 wt %, or 80 wt %, or 70 wt %, or 60 wt %, or 50 wt %, or 40 wt %, or 30 wt %, or 20 wt %, or 10 wt %, or 5 wt %, or about 2 wt %, or about 1 wt %.
- the invention is directed to a method of treatment of intraepithelial neoplasia in a subject comprising the steps of:
- composition (b) administering the composition to the subject.
- the subject is in need of treatment.
- the composition is administered orally, buccally, topically, intravenously, subcutaneously, intraperitoneally, intranasally, or by inhalation.
- the composition is administered as a solid such as a tablet or a powder, a patch such as a mucosal patch, a rinse such as an oral rinse, a wash such as a bladder wash, a spray such as an oral spray, a cream, a lotion, an ointment, a gel including an adhesive gel, an inhalant such as a powder or a spray, a foam, an enema, a suppository, or a liquid such as an ingestible or injectable liquid, or drops such as ocular drops.
- the step of administering the composition to the subject comprises administering the compound to the subject at a dose in the range of about 0.5 mg/kg to about or less than about 300 mg/kg, or about 1 mg/kg to about or less than about 275 mg/kg, or about 5 mg/kg to about or less than 250 mg/kg, or about 7.5 mg/kg to about or less than 225 mg/kg, or about 10 mg/kg to about or less than 200 mg/kg, or about 25 mg/kg to about or less than 175 mg/kg, or about 50 mg/kg to about or less than 150 mg/kg, or about 75 mg/kg to about or less than 125 mg/kg, or about 90 mg/kg to about or less than 100 mg/kg.
- the step of administering the composition to the subject comprises administering the compound to the subject at a dose in the range of about 0.5 mg/cm 2 on the basis of the size of the neoplasia, to about or less than about 300 mg/cm 2 , or about 1 mg/cm 2 to about or less than about 275 mg/cm 2 , or about 5 mg/cm 2 to about or less than 250 mg/cm 2 , or about 7.5 mg/cm 2 to about or less than 225 mg/cm 2 , or about 10 mg/cm 2 to about or less than 200 mg/cm 2 , or about 25 mg/cm 2 to about or less than 175 mg/cm 2 , or about 50 mg/cm 2 to about or less than 150 mg/cm 2 , or about 75 mg/cm 2 to about or less than 125 mg/cm 2 , or about 90 mg/cm 2 to about or less than 100 mg/cm 2 .
- the composition is formulated as a nanoparticle composition, a liposomal composition, a micellar composition, an emulsion, [070]
- the invention is directed to a kit for treatment of intraepithelial neoplasia comprising any one of the compositions described above, instructions for use of the composition and, optionally, an applicator for administration of the composition.
- FIG. 1 shows the serum levels of M 4 N formulations (20% M 4 N) following intravaginal administration in Rabbits on study day 1.
- FIG. 2 shows the serum levels OfM 4 N formulations (20% M 4 N) following intravaginal administration in Rabbits on study day 5.
- the present invention provides for compositions, kits and methods for treatment of intraepithelial neoplasia or dysplasia.
- the invention can be more clearly understood in light of the following definitions:
- active pharmaceutical ingredient or “API” as used herein means the catecholic butane or NDGA derivative present in the pharmaceutical compositions being claimed herein,
- Alkylene dioxy refers to methylene or substituted methylene dioxy or ethylene or substituted ethylene dioxy.
- amino acid residue or substituted amino acid residue or salt thereof in reference to one of the -R groups in Formula I or Formula II is an amino acid residue or a substituted amino acid residue or salt of an amino acid residue or salt of a substituted amino acid residue including but not limited to: alanine, arginine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, 5-hydroxylysine, 4-hydroxyproline, thyroxine, 3-methylhistidine, ⁇ -
- the "buffer” suitable for use herein includes any buffer conventional in the art, such as, for example, Tris, phosphate, imidazole, and bicarbonate.
- R 1 and R 2 are independently -H, a lower alkyl, a lower acyl, an alkylene or an amino acid residue or substituted amino acid residue or salt thereof; R 3 , R 4 , R 5 , R 6 ,
- R 10 , R u , R12 and R 13 are independently -H or a lower alkyl; and R 7 , R 8 and R 9 are independently — H, -OH, a lower alkoxy, a lower acyloxy, or any two adjacent groups together may be an alkyene dioxy.
- -OR 11 -OR 2 , R 7 , R 8 and R 9 are each an amino acid residue or a substituted amino acid residue or salt thereof.
- a "gene” as used herein means an open reading frame encoding a protein or polypeptide, for example, an rnRNA, a cDNA, or genomic DNA that may or may not include intervening introns or adjacent 5' or 3' untranslated regions involved in the regulation of expression.
- a gene involved in regulation of cell cycle means a gene that encodes a protein the presence of which is necessary for a cell to progress through its cell cycle.
- An example of such a gene is CDC2.
- a gene involved in cell survival means a gene that encodes a protein the presence of which is necessary for the cell to maintain its viability.
- a survival factor e.g., survivin
- a gene involved in DNA repair e.g., DNA repair, or human telomerase reverse transcriptase.
- “Lower acyl” means C 1 - C 6 acyl, optionally, C 1 - C 3 acyl.
- “Lower alkyl” means C 1 - C 6 alkyl, optionally, C 1 - C 3 alkyl.
- NDGA nordihydroguaiaretic acid
- NDGA derivative as used herein means a derivative of NDGA in which one or more of the -OH groups are substituted, as in Formula II:
- R 1 , R 2 , R 3 and R 4 are independently -OH, a lower alkoxy, a lower acyloxy, or an amino acid residue or substituted amino acid residue or salt thereof but are not each -OH simultaneously; and R 5 , R 6 are independently -H or an alkyl such as a lower alkyl.
- the term includes, for example, a compound in which R 1 , R 2 , R3 and R 4 are each -OCH 3 , or
- R 5 , R 6 are each -H or each a lower alkyl. In one embodiment of the invention, R 5 , R 6 are each -CH 3 Or-CH 2 CH 3 .
- a "regulatory region of a gene” as used herein means a region upstream of the translational start of a gene that includes a binding site for one or more transcription factors, a promoter, an enhancer, or the like.
- a “substantially purified” compound in reference to the catecholic butanes or NDGA derivatives for administration herein is one that is substantially free of compounds that are not the catecholic butane or NDGA derivatives of the present invention (hereafter, "non-NDGA materials"). By substantially free is meant at least 50%, preferably at least 70%, more preferably at least 80%, even more preferably at least 90% free and still more preferably at least 95% free of non-NDGA materials.
- treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
- the effect may be prophylactic in terms of completely or partially preventing a condition or disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a condition or disease and/or adverse affect attributable to the condition or disease.
- Treatment covers any treatment of a condition or disease in a mammal, particularly in a human, and includes: (a) preventing the condition or disease from occurring in a subject which may be predisposed to the condition or disease but has not yet been diagnosed as having it; (b) inhibiting the condition or disease, such as, arresting its development; and (c) relieving, alleviating or ameliorating the condition or disease, such as, for example, causing regression of the condition or disease.
- a “pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any conventional type.
- a “pharmaceutically acceptable carrier” is non-toxic to recipients at the dosages and concentrations employed, and is compatible with other ingredients of the formulation.
- the carrier for a formulation containing the present catecholic butane or NDGA derivatives preferably does not include oxidizing agents and other compounds that are known to be deleterious to such.
- Suitable carriers include, but are not limited to, water, dextrose, glycerol, saline, ethanol, buffer, dimethyl sulfoxide, Cremaphor EL, phosphate buffered saline and combinations thereof.
- the carrier may contain additional agents such as wetting or emulsifying agents, or pH buffering agents. Other materials such as anti-oxidants, humectants, viscosity stabilizers, and similar agents may be added as necessary.
- Pharmaceutically acceptable salts herein include the acid addition salts
- salts formed with the free carboxyl groups may also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, and histidine.
- pharmaceutically acceptable excipient includes vehicles, adjuvants, or diluents or other auxiliary substances, such as those conventional in the art, which are readily available to the public.
- pharmaceutically acceptable auxiliary substances include pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like.
- subject refers to an animal being treated with the present compositions, including, but not limited to, simians, humans, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.
- patient refers to an animal being treated with the present compositions, including, but not limited to, simians, humans, felines, canines, equines, bovines, porcines, ovines, caprines, mammalian farm animals, mammalian sport animals, and mammalian pets.
- the catecholic butanes of the present invention can be prepared by any method know in the art.
- such compounds can be made as described in US 5,008,294.
- the NDGA derivatives and formulations thereof can be made by any process conventional in the art.
- the NDGA derivatives can be made as described in, US 5,008,294 (Jordan et al, issued Apr 16, 1991); US 6,291,524 (Huang et al., issued Sep 18, 2001); Hwu, J.R. et al. (1998); or McDonald, R. W. et al. (2001).
- an NDGA derivative, tetra-O-methyl NDGA, also known as meso-l,4-bis(3,4-dimethoxyphenyl)-2,3- dimethylbutane, or M 4 N is made as follows: a solution is made containing NDGA and potassium hydroxide in methanol in a reaction flask. Dimethyl sulfate is then added to the reaction flask and the reaction is allowed to proceed. The reaction is finally quenched with water, causing the product to precipitate. The precipitate is isolated by filtration and dried in a vacuum oven. The compound is then dissolved in a solution of methylene chloride and toluene and subsequently purified through an alumina column.
- the solvents are removed by rotary evaporation and the solid is resuspended in isopropanol and isolated by filtration.
- the filter cake is dried in a vacuum oven.
- the resulting tetra-O-methyl NDGA (M 4 N) is crystallized by refiuxing the filter cake in isopropanol and re-isolating the crystals by filtration.
- certain NDGA derivatives of the present invention such as G 4 N, also known as meso-l,4-bis[3,4- (dimethylaminoacetoxy)phenyl] -(2R,3 S)-dimethylbutane or tetra-dimethylglycinyl NDGA, or a hydrochloride salt thereof and similar compounds having amino acid substituents, can also be prepared according to conventional methods, as described in, for example, US 6,417,234.
- the present invention further provides compositions, including pharmaceutical compositions, comprising the catecholic butanes, including the NDGA derivatives, as active pharmaceutical ingredients ("API"), and pharmaceutically acceptable carriers or excipients.
- the API of the present invention can be incorporated into a variety of formulations for therapeutic administration, such as, for example, those described in PCT/US2004/016117, including nanoparticle formulations, micellar formulations, liposomal formulations, water-soluble formulations, or lipid-based formulations.
- the catecholic butanes of the present invention can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers, excipients or diluents, and may be formulated into solid, semi-solid, liquid, or gaseous forms, such as foams, sprays, film, pessaries, tablets, pills, capsules, sustained release formulations, powders, washes, liposomes, nanoparticles, granules, gels, creams, ointments, solutions, emulsions, suspensions, suppositories, injections, inhalants and aerosols.
- Pharmaceutically acceptable carriers or excipients suitable for use herein are described in a variety of publications.
- compositions herein are formulated in accordance to the mode of potential administration and the disease indication to be treated.
- the composition may be a converted to a powder or spray in aerosol form, as conventional in the art, for such purposes.
- Other formulations, such as for oral or parenteral delivery, are also used as conventional in the art. Examples of the different formulations for treatment of different intraepithelial neoplasia via different routes of administration are set forth in Table 1.
- Oral and intravenous administration may be used for treatment of any of the intraepithelial neoplasia for early stage IEN (not clinically noticeable, but present) as well as for multiple lesions, or lesions not easily accessible to topical application, inhaled therapy, bladder instillation, rectal, intravaginal or other local therapy.
- compositions in liquid form may include a buffer, which is selected according to the desired use of the catecholic butanes or NDGA derivatives, and may also include other substances appropriate for the intended use. Those skilled in the art can readily select an appropriate buffer, a wide variety of which are known in the art, suitable for an intended use.
- the composition can comprise a pharmaceutically acceptable excipient, a variety of which are known in the art.
- the compositions of the instant invention will contain from less than about 0.5 % up to about 99 % of the active pharmaceutical ingredient or API, that is, the catecholic butanes, including the NDGA derivatives herein; optionally, the instant invention will contain about 2% to about 90% of the active ingredient.
- the present pharmaceutical composition includes the active ingredient or
- API being present in the composition at a concentration in a range, for example, where the compound is for application onto the surface of the neoplasia or for delivery by inhalation, by intranasal administration, or as a rinse or a wash, or as a suppository or an enema, of about 0.5 wt % to about or less than about 50 wt %, or less than 40 wt %, or less than 30 wt %, optionally, the concentration of the compound is about or less than about 27.5 wt %, or 25 wt %, or 22.5 wt %, or 20 wt %, or 17.5 wt %, or 15 wt %, or 12.5 wt %, or 10 wt %, or 7.5 wt %, or 5 wt %, or 2 wt %, or 1.25 wt %.
- the API is present in the composition at a concentration in a range of about 0.1 mg/ml to about or less than about 500 mg/ml, optionally, the concentration is in a range of about 0.5 mg/ml to about or less than 475 mg/ml, or about 1 mg/ml to about or less than 400 mg/ml, or about 2 mg/ml to about or less than 375 mg/ml, or about 5 mg/ml to about or less than 350 mg/ml, or about 7.5 mg/ml to about or less than 325 mg./ml, or about 10 mg/ml to about or less than 300 mg/ml, or about 12.5 mg/ml to about or less than 275 mg/ml, or about 15 mg/ml to about or less than 250 mg/ml, or about 17.5 mg/ml to about or less than 225 mg/ml, or about 20 mg/ml to about or
- the API is present in the composition at a concentration of not less than about 98 wt %, or about 95 wt %, or about 90 wt %, or 80 wt %, or 70 wt %, or 60 wt %, or 50 wt %, or 40 wt %, or 30 wt %, or 20 wt %, or 10 wt %, or 5 wt %, or about 2 wt %, or about 1 wt %.
- the present composition is formulated as a jelly and includes, one or more of glacial acetic acid, oxyquinoline sulfate, ricinoleic acid, glycerin, tragacanth, acacia, propyl paraben, potassium hydroxide, stannous chloride, potassium bitartarate, and water, and optionally egg albumin or fragrance or perfume,
- the jelly includes, for example, any of the foregoing or one or more of lactic acid, methyl paraben, povidone, propylene glycol, sodium carboxymethyl cellulose, sorbic acid and sorbitol solution.
- the jelly includes, for example, any of the foregoing or one or more of boric acid and cellulose gum.
- the jelly includes, for example, any of the foregoing or one or more of Cremaphor and hydroxyethyl cellulose.
- the composition is formulated as a bioadhesive gel.
- a bioadhesive gel includes one or more of water, glycerin, mineral oil, Polycarobphil, hydro genated palm oil glyceride, Carbomer 934P, methyl paraben, sorbic acid and NaOH.
- the present composition is formulated as a gel and includes one or more of Carbopol 974P, or one or more of C31G, type A gelatin, purified corn starch, hydroxypropylmethyl cellulose, glycerin/glycerine and water, hi one aspect of the invention, the gel includes any of the foregoing or one or more of cellulose gum, lactic acid, methyl paraben, povidone, propylene glycol, sorbic acid and sorbitol solution. In another aspect of the invention, the gel includes any of the foregoing or one or more of mineral oil, Polycarobphil, Carbomer 934P, hydrogenated palm oil glyceride and sodium hydroxide.
- the gel includes any of the foregoing or one or more of EDTA and propyl paraben. In yet another aspect of the invention, the gel includes any of the foregoing or one or more of colloidal silicon dioxide and triacetin.
- the present composition is formulated as a cream and the cream includes, for example, one or more of urea, sodium propionate, methionine, cysteine and inositol, hi another embodiment, the cream includes any of the foregoing or one or more of lactose, propylene glycol, stearic acid, diglycol stearate, methyl paraben, propyl paraben, trolamine and lactic acid.
- the cream includes any of the foregoing or one or more of benzyl alcohol, cetyl alcohol, 1-octyl dodecanol, polysorbate 60, sorbitan monostearate and spermaceti.
- the cream includes any of the foregoing or one or more of cetostearyl alcohol, cetyl palmitate and mineral oil.
- the cream includes any of the foregoing or one or more of sodium phosphate, monobasic adipic acid, colloidal silicon dioxide, magnesium stearate, maize starch, polysorbate 80, and sodium bicarbonate.
- the cream includes any of the foregoing or one or more of aloe barbadensis gel, aluminium sulfate, calcium acetate, cetearyl alcohol, corn oil, glycerine, isopropyl palmitate, light mineral oil, maltodextrin, potato dextrin, water, sodium cetearyl sulfate, sodium lauryl sulfate, vitamin A palmitate, vitamin D, vitamin E, white petrolatum, and white wax.
- the cream includes any of the foregoing or one or more of benzoic acid, butylated hydroxyl anisole, fragrance, palm oil and Peg stearate.
- the cream includes any of the foregoing or one or more of stearyl alcohol, white ceresin wax, glyceryl stearate or monostearate, and hydroxypropylmethyl cellulose
- the cream includes any of the foregoing or one or more of propylene glycol 100 stearate, cetyl esters wax, Peglicol 5 oleate, Pegoxol stearate, propylene glycol 400 stearate, cetyl stearyl alcohol, peanut oil, glycerin, glutamic acid, citric acid, sodium hydroxide, propylene glycol monostearate, methyl stearate, SLS, cholesterol, diethylaminoethyl stearamide, lanolin, lecithin, phosphoric acid, isopropyl myristate, and propyl glycol.
- the composition is formulated as a suppository and the suppository contains, for example, one or more of propylene glycol 400 and 3350, polysorbate 80, glycerin, lactic acid, cover made of gelatin, water, methyl paraben, propyl paraben, and color.
- the suppository includes any of the foregoing or one or more of C31G, and propylene glycol 1450 or 8000.
- the suppository includes any of the foregoing or one or more of sodium bicarbonate, sodium citrate, and tartaric acid or glycerides of fatty acids, or butylated hydroxyl anisole, palm kernel oil and coconut oil.
- the composition is formulated as a tablet and the tablet contains, for example, one or more of adipic acid, colloidal silicon dioxide, lactose, magnesium stearate, maize starch, Polysorbate 80, sodium bicarbonate, and stearic acid.
- the tablet comprises any of the foregoing or one or more of microcrystalline cellulose, hydroxypropylmethyl cellulose, lactic acid and crospovidone.
- the tablet contains any of the foregoing or one or more of potato starch, gelatin, and talc.
- the composition is formulated as a douche and the douche contains, for example, one or more of sodium citrate, citric acid, vinegar, 0-9, diazolidinyl urea, cetylpyridinium chloride, EDTA,
- the composition is provided on a film and the film contains, for example, one or more of glycerine and polyvinyl alcohol.
- the catecholic butanes, including the NDGA derivatives of the subject invention find use as therapeutic agents in situations where one wishes to provide a treatment to a subject who has intraepithelial neoplasia or dysplasia.
- a variety of animal hosts are treatable according to the subject methods, including human and non-human animals.
- hosts are "mammals” or “mammalian,” where these terms are used broadly to describe organisms which are within the class mammalia, including the orders carnivore (e.g., dogs and cats), rodentia (e.g., guinea pigs, and rats), and other mammals, including cattle, goats, horses, sheep, rabbits, pigs, and primates (e.g., humans, chimpanzees, and monkeys). In many embodiments, the hosts will be humans. Animal models are of interest for experimental investigations, such as providing a model for treatment of human disease. Further, the present invention is applicable to veterinary care as well.
- an effective amount of the present composition is administered to the host, where an "effective amount" means a dosage sufficient to produce a desired result, hi some embodiments, the desired result is at least an inhibition of progression of the neoplasia or dysplasia.
- the appropriate dose to be administered depends on the subject to be treated, such as the general health of the subject, the age of the subject, the state of the disease or condition, the weight of the subject, the size of the tumor, for example. Generally, between about 0.1 mg and about 500 mg or less may be administered to a child and between about 0.1 mg and about 5 grams or less may be administered to an adult.
- the active agent can be administered in a single or, more typically, multiple doses.
- Preferred dosages for a given agent are readily determinable by those of skill in the art by a variety of means. Other effective dosages can be readily determined by one of ordinary skill in the art through routine trials establishing dose response curves. The amount of agent will, of course, vary depending upon the particular agent used.
- the composition is administered to the subject with the API being at a dose in the range of about 0.5 mg/kg to about or less than about 300 mg/kg, or about 1 mg/kg to about or less than about 275 mg/kg, or about 5 mg/kg to about or less than 250 mg/kg, or about 7.5 mg/kg to about or less than 225 mg/kg, or about 10 mg/kg to about or less than 200 mg/kg, or about 25 mg/kg to about or less than 175 mg/kg, or about 50 mg/kg to about or less than 150 mg/kg, or about 75 mg/kg to about or less than 125 mg/kg, or about 90 mg/kg to about or less than 100 mg/kg.
- the composition is administered to the subject with the API being at a dose in the range of about 0.5 mg/cm 2 on the basis of the size of the neoplasia, to about or less than about 300 mg/cm 2 , or about 1 mg/cm 2 to about or less than about 275 mg/cm 2 , or about 5 mg/cm 2 to about or less than 250 mg/cm 2 , or about 7.5 mg/cm 2 to about or less than 225 mg/cm 2 , or about 10 mg/cm 2 to about or less than 200 mg/cm 2 , or about 25 mg/cm 2 to about or less than 175 mg/cm 2 , or about 50 mg/cm 2 to about or less than 150 mg/cm 2 , or about 75 mg/cm 2 to about or less than 125 mg/cm 2 , or about 90 mg/cm 2 to about or less than 100 mg/cm 2 .
- the frequency of administration of the active agent will be determined by the care giver based on age, weight, disease status, health status and patient responsiveness.
- the agents may be administered one or more times daily, weekly, monthly or as appropriate as conventionally determined.
- the agents may be administered intermittently, such as for a period of days, weeks or months, then not again until some time has passed, such as 3 or 6 months, and then administered again for a period of days, weeks, or months.
- Administration of the active agents can be achieved in various ways, such as by oral, buccal, rectal, intranasal, intravenous, subcutaneous, intraperitoneal, intra-arterial, intra-tracheal, intraventricular, intracranial, interstitial, transdermal, etc., or by inhalation or implantation such as in pessaries and suppositories.
- nanoparticle, micelle and liposomal preparations containing the present API can be prepared as described in PCT/US2004/016117 and administered systemically, including parenterally and intranasally, as well as interstitially, orally, topically, transdermally, via inhalation or implantation, such as for drug targeting, enhancement of drug bioavailability and protection of drug bioactivity and stability.
- Nanoparticle bound drugs herein are expected to achieve prolonged drug retention in tumors.
- the active agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active agents or therapeutics including other small molecules, antibodies or protein therapeutics.
- pharmaceutically active agents or therapeutics including other small molecules, antibodies or protein therapeutics.
- the active agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, com starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.
- the preparations can be made in a manner conventional in the art, such as described in, for example, Epstein, J.B. et al. (2002) and Pitten, F. et al. (2003).
- the carrier or excipient may contain minor amounts of auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents or emulsifying agents.
- auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents or emulsifying agents.
- Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Co. Rawlins EA, (1997).
- the composition or formulation to be administered will, in any event, contain a quantity of the API adequate to achieve the desired state in the subject being treated.
- the active agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or non-aqueous solvent, such as vegetable or other similar oils, including corn oil, castor oil, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.
- the active agents can be utilized in aerosol formulation to be administered via inhalation.
- the compounds of the present invention can be formulated into pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like.
- the active agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases.
- bases such as emulsifying bases or water-soluble bases.
- the compounds of the present invention can be administered rectally via a suppository.
- the suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.
- Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the API.
- unit dosage forms for injection or intravenous administration may comprise the API in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.
- unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of API of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
- the specifications for the novel unit dosage forms of the present invention depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host.
- Kits with multiple or unit doses of the active agent are included in the present invention.
- kits in addition to the containers containing the multiple or unit doses of the compositions containing the NDGA derivatives will be an informational package insert with instructions describing the use and attendant benefits of the drugs in treating pathological condition of interest.
- an applicator for administration of the present composition is included in each kit.
- compositions and formulations described herein are useful for the treatment of intraepithelial neoplasia or dysplasia, such as, for example, mucosal, cervical, prostatic, penile, testicular, vulvar, oral, anal, pancreatic, lung, breast, colon, colorectal, head and neck, esophageal, conjunctival-corneal, or bladder intraepithelial neoplasia or dysplasia, with our without association with viral infections, such as HIV, HPV, HSV, HBV, HCV, EBV, JC virus, Varicell-zoster virus, adenovirus, parvovirus or lentivirus.
- the Examples set forth below are exemplary in nature and are not to be interpreted as limiting the present invention.
- inflammation of the urinary bladder was noted, and in one M 4 N-treated rabbit, heterophil infiltrates were seen in the vaginal mucosa. It is unknown if these findings were drug related, or related to the dosing procedure. There were no other treatment related histologic or gross organ changes, and findings of lower absolute basophil counts, and ALT values in the M 4 N-treated group were considered incidental.
- M 4 N minimal absorption OfM 4 N occurred after administration, with serum levels inconsistent, and generally less than lOng/mL at peak concentration. It was concluded that administration of M 4 N in white petrolatum for 14 days as an intravaginal application produced incidental minimal or mild edema in both control and M 4 N-treated rabbits, and minimal erythema in M 4 N-treated rabbits. There were single instances of inflammation in the urinary bladder and heterophilic infiltrates transmigrating the vaginal mucosa into the lumen in treated rabbits which are most likely related to dosing procedure.
- Inhibition of Sp-I binding activity can be determined by any conventional method, for example, in a gel mobility shift assay as described in U.S. 6,608,108. Briefly, different concentrations of the present compounds, such as M 4 N in DMSO or G 4 N (tetra-O-N,N-dimethylglycinyl NDGA) in PBS can be incubated with 32 P-labeled DNA in a binding buffer for 30 min at 25°C. DNA binding domain of recombinant SpI protein (SpI - 167D) can be next added and incubated for additional 30 min in the presence of a large excess of BSA protein. The gels can be 5% non-denaturing polyacrylamide gel with each lane being loaded with 5 ⁇ l of each reaction volume.
- M 4 N in DMSO or G 4 N tetra-O-N,N-dimethylglycinyl NDGA
- DNA binding domain of recombinant SpI protein SpI - 167D
- a 2 g mixture OfM 4 N at a concentration of about 200 mg/g in 85% olive oil and 15% beeswax was made as follows. About 1.7 ml of olive oil was added to a glass beaker containing a stir bar. The beaker was placed on a magnetic plate and the stir bar was set to stir at medium speed. About 400 mg OfM 4 N was slowly added to the olive oil in the center of the beaker with the aid of a spatula to prevent M 4 N from sticking to the beaker wall. The M 4 N/olive oil mixture was stirred for about 2 hr or until all M 4 N had dissolved or was uniformly suspended without any clump being present.
- the M 4 N/olive oil mixture was optionally heated at about 60° C for about 30 min. (or longer if a larger volume of solution was desired, for example, 1 hr at 60° C for 100 ml of the M 4 N/olive oil mixture), or longer as need to ensure complete dissolution of M 4 N.
- the M 4 N/olive oil mixture was observed for presence of any undissolved M 4 N by holding the beaker against a white followed by a dark background, looking for presence of particulates. If crystals formed, the M 4 N /olive oil solution could be heated again at 60° C for about 1 hr, with stirring, on a hot magnetic plate until all M 4 N was dissolved back in solution.
- the stir bar was removed from the beaker and the M 4 N/olive oil/beeswax mixture was allowed to cool down.
- the final M 4 N/olive oil/beeswax mixture was stored at room temperature and was kept protected from light. This process may be scaled up or down to obtain the requisite volume or concentration OfM 4 N. This process formed a yellow cream with a melting point of 40 0 C.
- Formulations containing M 4 N in other water-insoluble lipids may be similarly made, such as, for example, by substituting olive oil in the process described above with mineral oil, corn oil, sesame oil, soybean oil, peppermint oil, lecithin, or other solubilizing agents, and combinations thereof, and substituting beeswax with paraffin, PEG 3350, or other stiffening agents, and combinations thereof.
- a 2 g mixture OfM 4 N at a concentration of about 200 mg/g (w/w) in 70% olive oil, 15% beeswax and 15% lecithin was made as follows. About 1.4 ml of olive oil was added to a glass beaker containing a stir bar. The beaker was placed on a magnetic plate and the stir bar was set to stir at medium speed. About 400 mg of M 4 N was slowly added to the olive oil in the center of the beaker with the aid of a spatula to prevent M 4 N from sticking to the beaker wall. The M 4 N/olive oil mixture was stirred for about 2 hr or until all M 4 N had dissolved or was uniformly suspended without any clump being present.
- the M 4 N/olive oil mixture was optionally heated at about 60° C for about 30 min. (or longer if a larger volume of solution was desired, for example, 1 hr at 60° C for 100 ml of the M 4 N/olive oil mixture), or longer as need to ensure complete dissolution of M 4 N.
- the M 4 N/olive oil mixture was observed for presence of any undissolved M 4 N by holding the beaker against a white followed by a dark background, looking for presence of particulates. If crystals formed, the M 4 N /olive oil solution could be heated again at 60° C for about 1 hr, with stirring, on a hot magnetic plate until all M 4 N was dissolved back in solution.
- the stir bar was removed from the beaker and the M 4 N/olive oil/beeswax/lecithin mixture was allowed to cool down.
- the final M 4 N/olive oil/beeswax/lecithin mixture was stored at room temperature and was kept protected from light. This process may be scaled up or down to obtain the requisite volume or concentration OfM 4 N. This process formed a yellow cream with a melting point of about 37°C.
- Formulations containing M 4 N in other water-insoluble lipids may be similarly made, such as, for example, by substituting olive oil in the process described above with mineral oil, corn oil, sesame oil, soybean oil, peppermint oil, or other solubilizing agents, and combinations thereof, substituting beeswax with paraffin, PEG 3350, or other stiffening agents, and combinations thereof, and substituting lecithin with Tween 80, TPGS, Tween 20, PEG 300, PEG 400, PEG 400 monolaurate, glycerol, polyvinyl pyrrolidone, propylene glycol, or other solubilizing agents, and combinations thereof.
- Formulations containing M 4 N in other water-insoluble lipids combined with non-ionic, ionic or amphipathic surfactants or water-soluble organic solvents may be similarly made, such as, for example, by substituting olive oil in the process described above with corn oil, sesame oil, soybean oil, peppermint oil, or mineral oil, substituting lecithin with Tween 80, TPGS, Tween 20, PEG 300, PEG 400, PEG 400 monolaurate, glycerol, polyvinyl pyrrolidone, propylene glycol, or other solubilizing agents, and combinations thereof, and substituting white beeswax with paraffin, PEG 3350, or other stiffening agents, and combinations thereof.
- a 2 g mixture of M 4 N at a concentration of about 200 mg/g (w/w) in 40% PEG 400, 40% Tween 80 and 20 % PEG3350 was made as follows. About 0.8 ml of PEG 400 and about 0.8 ml of Tween 80 were added to a glass beaker containing a stir bar. The beaker was placed on a magnetic plate and the stir bar was set to stir at medium speed. About 400 mg of M 4 N was slowly added to the PEG400/Tween80 mixture in the center of the beaker with the aid of a spatula to prevent M 4 N from sticking to the beaker wall.
- the M 4 N/PEG400/Tween80 mixture was stirred for about 2 hr or until all M 4 N had dissolved or was uniformly suspended without any clump being present.
- the M 4 N/ PEG400/Tween80 mixture was optionally heated at about 60° C for about 30 min. (or longer if a larger volume of solution was desired, for example, 1 hr at 60° C for 100 ml of the M 4 N/PEG400/Tween80 mixture), or longer as need to ensure complete dissolution of M 4 N.
- the M 4 N/PEG400/Tween80 mixture was observed for presence of any undissolved M 4 N by holding the beaker against a white followed by a dark background, looking for presence of particulates.
- the M 4 N/PEG400/Tween80 solution could be heated again at 60° C for about 1 hr, with stirring, on a hot magnetic plate until all M 4 N was dissolved back in solution.
- About 400 mg of PEG 3350 was added to a glass beaker containing a stir bar. The beaker was also placed on a magnetic plate and the stir bar was set to stir at medium speed.
- the PEG3350 was heated at about 50°C for about 30 min. (or longer if a larger quantity was desired), or until all the PEG 3350 was melted.
- the M 4 N/PEG400/Tween80 solution was then added to about 400 mg of melted PEG335O and stirred and heated at about 55°C for about 30 min or until all the M 4 N/PEG400/Tween80/PEG3350 mixture had dissolved or was uniformly mixed.
- the stir bar was removed from the beaker and the M 4 N/PEG400/Tween80/PEG3350 mixture was allowed to cool down.
- the final M 4 N/PEG400/Tween80/PEG3350 mixture was stored at room temperature and was kept protected from light. This process may be scaled up or down to obtain the requisite volume or concentration of M 4 N. This process formed a smooth white cream with a melting point of about 38.5°C.
- Formulations containing M 4 N in other water-soluble organic solvents or surfactants may be similarly made, such as, for example, by substituting PEG 400 and/or Tween 80 in the process described above with Tween 20, Tween 80, TPGS, lecithin, PEG 300, PEG 400, PEG 400 monolaurate, glycerol, polyvinyl pyrrolidone, propylene glycol, or other solubilizing agents, and combinations thereof, substituting PEG 3350 with paraffin, beeswax or other stiffening agents, and combinations thereof.
- a 2 g mixture OfM 4 N at a concentration of about 200 mg/g (w/w) in 45% Tween 80, 40% PEG 400, 7.5% beeswax and 7.5 % PEG3350 was made as follows. About 0.9 ml of Tween 80 and about 0.8 ml of PEG 400 were added to a glass beaker containing a stir bar. The beaker was placed on a magnetic plate and the stir bar was set to stir at medium speed. About 400 mg OfM 4 N was slowly added to the Tween80/PEG400 mixture in the center of the beaker with the aid of a spatula to prevent M 4 N from sticking to the beaker wall.
- the M 4 N/Tween80/PEG400 mixture was stirred for about 2 hr or until all M 4 N had dissolved or was uniformly suspended without any clump being present.
- the M 4 N/Tween80/PEG400 mixture was optionally heated at about 60° C for about 30 min. (or longer if a larger volume of solution was desired, for example, 1 hr at 60° C for 100 ml of the M 4 N/Tween80/PEG400 mixture), or longer as need to ensure complete dissolution of M 4 N.
- the M 4 N/Tween80/PEG400 mixture was observed for presence of any undissolved M 4 N by holding the beaker against a white followed by a dark background, looking for presence of particulates.
- the M 4 N/Tween80/PEG400 solution could be heated again at 60° C for about 1 hr, with stirring, on a hot magnetic plate until all M 4 N was dissolved back in solution.
- About 150 mg of white beeswax and about 150 mg of PEG 3350 were added to a glass beaker containing a stir bar. The beaker was also placed on a magnetic plate and the stir bar was set to stir at medium speed.
- the beeswax/PEG3350 mixture was heated at about 50°C for about 30 min. (or longer if a larger quantity was desired), or until all the beeswax and PEG 3350 were melted.
- the M 4 N/Tween80/PEG400 solution was then added to about 600 mg of melted beeswax/PEG3350 mixture and stirred and heated at about 50°C for about 30 min or until all the
- M 4 N/Tween80/PEG400/beeswax/PEG3350 mixture was allowed to cool down.
- the final M 4 N/Tween80/PEG400/beeswax/PEG3350 mixture was stored at room temperature and was kept protected from light. This process may be scaled up or down to obtain the requisite volume or concentration OfM 4 N. This process formed a smooth white cream with a melting point of about 37.5°C.
- Formulations containing M 4 N in other water-soluble organic solvents or surfactants may be similarly made, such as, for example, by substituting PEG 400 and/or Tween 80 in the process described above with Tween 20, Tween 80, TPGS, lecithin, PEG 300, PEG 400, PEG 400 monolaurate, glycerol, polyvinyl pyrrolidone, propylene glycol, or other solubilizing agents, and combinations thereof, substituting beeswax and/or PEG 3350 with paraffin, PEG 3350, beeswax or other stiffening agents, and combinations thereof.
- EXAMPLE 6 CLINICAL CERVICAL APPLICATION OF M4N.
- M4N Tetra-O-Methyl Nordihyrdroguaiaretic Acid
- CIN Cervical Intraepithelial Neoplasia
- Cervical biopsies were taken at Day 1 and follow up biopsies were taken at Day 71.
- Serum levels were below limit of quantification after administration of the 1% formulation.
- PEG 400 PEG 3350 5 10.07 ⁇ 2.67 32.73 ⁇ 3.12 33.94 ⁇ 4.93 35.85 ⁇ 8.52 24.90 ⁇ 5.81 14.47 ⁇ 3
- Intraepithelial Neoplasia An Important Target for Accelerated New Agent
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US11/572,349 US8440648B2 (en) | 2004-07-20 | 2005-07-19 | Methods and compositions for treatment of intraepithelial neoplasia |
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US58941804P | 2004-07-20 | 2004-07-20 | |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1848418A2 (fr) * | 2004-10-06 | 2007-10-31 | Johns Hopkins University | Utilisation de derives d'acide nordihydroguaiaretique pour traiter des cancers et des infections virales et microbiennes qui resistent aux medicaments |
EP2349340A2 (fr) * | 2008-10-15 | 2011-08-03 | Erimos Pharmaceuticals LLC | Formulations aqueuses stables de medicaments insolubles ou peu solubles dans l'eau |
Citations (3)
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US5008294A (en) * | 1985-02-11 | 1991-04-16 | Chemex Pharmaceuticals, Inc. | Methods of treating tumors with compositions of catecholic butanes |
US5541232A (en) * | 1993-06-23 | 1996-07-30 | Chemex Pharmaceuticals, Inc. | Treatment of multidrug resistant diseases |
US6417234B1 (en) * | 1999-10-15 | 2002-07-09 | Johns Hopkins University | Nordihydroguaiaretic derivatives for use in treatment of tumors |
-
2005
- 2005-07-19 WO PCT/US2005/025639 patent/WO2006014669A2/fr active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5008294A (en) * | 1985-02-11 | 1991-04-16 | Chemex Pharmaceuticals, Inc. | Methods of treating tumors with compositions of catecholic butanes |
US5541232A (en) * | 1993-06-23 | 1996-07-30 | Chemex Pharmaceuticals, Inc. | Treatment of multidrug resistant diseases |
US6417234B1 (en) * | 1999-10-15 | 2002-07-09 | Johns Hopkins University | Nordihydroguaiaretic derivatives for use in treatment of tumors |
Non-Patent Citations (2)
Title |
---|
HELLER ET AL.: 'Tetra-O-methyl Nordihydroguaiaretic Acid Induces G2 Arrest in Mammalian Cells and Exhibits Tumoricidal Activity in Vivo' CANCER RESEARCH vol. 61, 15 July 2001, pages 5499 - 5504, XP002322391 * |
PARK S. ET AL.: 'Inhibition of fos-jun-DNA complex formation by dihydroguaiaretic acid and in vitro cytotoxic effects on cancer cells' CANCER LETTERS vol. 127, 1998, pages 23 - 28, XP003003599 * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1848418A2 (fr) * | 2004-10-06 | 2007-10-31 | Johns Hopkins University | Utilisation de derives d'acide nordihydroguaiaretique pour traiter des cancers et des infections virales et microbiennes qui resistent aux medicaments |
EP1848418A4 (fr) * | 2004-10-06 | 2010-09-08 | Univ Johns Hopkins | Utilisation de derives d'acide nordihydroguaiaretique pour traiter des cancers et des infections virales et microbiennes qui resistent aux medicaments |
EP2349340A2 (fr) * | 2008-10-15 | 2011-08-03 | Erimos Pharmaceuticals LLC | Formulations aqueuses stables de medicaments insolubles ou peu solubles dans l'eau |
EP2349340A4 (fr) * | 2008-10-15 | 2012-10-17 | Erimos Pharmaceuticals Llc | Formulations aqueuses stables de medicaments insolubles ou peu solubles dans l'eau |
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WO2006014669A3 (fr) | 2006-11-02 |
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