WO2014131096A1 - Formulation obtenue par association de l'antiviral aciclovir avec la vitamine b6 et un anti-histaminique pour le traitement de l'herpès et moyen d'application - Google Patents

Formulation obtenue par association de l'antiviral aciclovir avec la vitamine b6 et un anti-histaminique pour le traitement de l'herpès et moyen d'application Download PDF

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Publication number
WO2014131096A1
WO2014131096A1 PCT/BR2014/000038 BR2014000038W WO2014131096A1 WO 2014131096 A1 WO2014131096 A1 WO 2014131096A1 BR 2014000038 W BR2014000038 W BR 2014000038W WO 2014131096 A1 WO2014131096 A1 WO 2014131096A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
formulation
acyclovir
herpes
treatment
Prior art date
Application number
PCT/BR2014/000038
Other languages
English (en)
Portuguese (pt)
Inventor
Eliana MARTINS LIMA
Marize Campos. VALADARES BOZINIS
Original Assignee
Advance Pharma Tecnologia E Inovação Ltda - Me
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Advance Pharma Tecnologia E Inovação Ltda - Me filed Critical Advance Pharma Tecnologia E Inovação Ltda - Me
Publication of WO2014131096A1 publication Critical patent/WO2014131096A1/fr

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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • This patent application is for a bioadhesive topical formulation containing the combination of acyclovir (antiviral), pyridoxine (vitamin B6) and diphenhydramine (antihistamine) drugs, which have been shown through studies and clinical trials, effective in treating herpes.
  • the formulation object of this invention is intended for the treatment of herpes, with application in the medical segment.
  • Herpes simplex is a DNA virus that can establish latent infections for long periods without being noticed by the immune system, developing alternative mechanisms to evade and reduce the impact of patient-specific defense processes. It is an alpha herpes virus with two known genotypes, type 1, more associated with cold sores and type 2, which determines anogenital lesions.
  • HSV-1 and HSV-2 are transmitted by different routes and involve several different areas of the body, which increases herpes epidemiology and clinical manifestations. Animal vectors have not been described and therefore the virus is only transmitted from human to human. The virus is transmitted through personal contact from an infected individual (during productive episodes of the virus) to a susceptible individual.
  • HSV viral infection induces swelling of cells, which lose their plasma membranes and form giant cells with multiple nuclei.
  • cell lysis occurs, a clear fluid containing large amounts of virus appears between the dermis and epidermis layers. In the structure of the dermis an intense inflammatory process occurs.
  • the vesicular fluid becomes pustular (pus formation), with recruitment of inflammatory cells, wound formation and subsequent healing.
  • HSV causes outbreaks that involve painful sores or ulcers that affect the mouth or genitals. Once the body has been infected, the virus remains in the skin and nerve cells in latent form for life. Some factors such as low immunity, stress, cold or exposure to strong ultraviolet rays may cause new lesions to appear.
  • Recurrent herpes produces the following symptoms: pain, burning and itching, usually six hours before the first vesicles appear. These vesicles usually appear on the edge of the lips and persist for 48 hours. It then progresses to the pustular or ulcerative stage, which lasts from 72 to 96 hours. Healing is complete 8 to 10 days after the onset of herpes.
  • Acyclovir is a nucleoside analog that chemically resembles deoxyguanosine, a DNA precursor purine. Deoxyguanosine is normally converted to nucleotide 5-triphosphate, which serves as one of four substrates for DNA polymerase during DNA construction. Acyclovir, in its inactive state, has no antiviral activity. However, it acts as an alternative substrate for the HSV thymidine kinase enzyme, which converts the drug to acyclovir 5-monophosphate.
  • Acyclovir 5-monophosphate is sequentially converted by cellular enzymes to acyclovir 5-triphosphate, which exerts its antiviral activity by two mechanisms: DNA polymerase inhibition and DNA strand termination.
  • the major goal of acyclovir therapy is to prevent viral replication. The early stages of infection, where pain and pruritus are observed, have no specific treatment.
  • aciclovir as the drug used today in the cases of HSV-1 and HSV-2, during the studies, the intravenous, oral and topical administration of aciclovir were effective in reducing the duration of virus binding to the body by 85, 80 and 50% respectively.
  • the present invention consists essentially of a bioadhesive topical formulation containing the combination of acyclovir (antiviral), pyridoxine (vitamin B6) and diphenhydramine (antihistamine).
  • viral HSV infection induces swelling of cells, which lose their plasma membranes and form giant cells with multiple nuclei.
  • cell lysis occurs, a clear fluid containing large amounts of virus appears between the dermis and epidermis layers.
  • an intense inflammatory process occurs, producing symptoms such as pain, itching and burning.
  • healing occurs, the vesicular fluid becomes pustular, with recruitment of inflammatory cells, wound formation and subsequent healing.
  • the inventor aware of the effects of acyclovir on Herpes virus treatments, set out to pursue a more efficient treatment that would provide patients with speed, comfort and effectiveness in resolving herpes lesions.
  • B-complex vitamins were used as analgesic drugs to treat pain associated with their deficiencies. More recently, however, B-vitamins have been shown to be effective in treating pain associated with polyneuropathies, neuralgias, radiculopathies, and neuritis.
  • B-complex vitamins such as pyridoxine (vitamin B6)
  • pyridoxine vitamin B6
  • vitamin B6 has antinociceptive action, as well as anti-inflammatory effects. These effects may be observed after administration of vitamin B6 in painful changes, whether or not related to vitamin deficiency.
  • vitamin B6 has an analgesic effect in the second phase of the inflammatory process and this effect seems to be related to opioid receptor activation.
  • Histamine is a substance present in many tissues and produces pharmacological effects even in small doses. Histamine's main actions are muscle contraction, capillary dilation, and gastric secretion of hydrochloric acid. When a skin prick occurs, a triple response is produced, generating a lesion clinically identical to urticaria. Thus, when histamine enters the general circulation, it produces symptoms whose intensity depends on the dose. We highlight the tightening of the skin, tachycardia, headache and hypotension. When histamine is released locally it produces symptoms such as edema, itching, urticaria and bronchoconstriction. Diphenhydramine can be used as an antihistamine with sedative effect in oral form, and can also be applied to the skin with anesthetic and anti-itching effect.
  • Diphenhydramine a histamine receptor antagonist
  • Diphenhydramine a histamine receptor antagonist
  • It is usually administered orally, but intramuscular or intravascular preparations may be administered after severe allergic reactions and topical application is widely used in local allergic reactions.
  • the topical formulation containing 2% diphenhydramine is also used to reduce itching after insect bites, mild cases of sunburn or contact with poisonous plants.
  • the invention presents a novel formulation with the aim of obtaining three distinct effects: decreased viral replication (acyclovir), pain (pyridoxine) and pruritus (diphenhydramine), and this association is nonexistent in the state of the art. and from reasoned studies, it was concluded that the combination of the three drugs would not have undesirable effects on the patient, in the qualitative manner defined in the invention, with markedly superior therapeutic effect compared to conventional treatments.
  • the new formulation (acyclovir + vitamin B6 + diphenhydramine) and the commercially available acyclovir formulation due to the decreased size of crystals of this drug.
  • the bioadhesiveness enables the need for many applications throughout the day to be reduced, with greater permanence of the drug at the application site.
  • the new formulation can also be adapted to various skin tones and can also be applied by the iontophoresis technique, with the intention of further reducing herpes treatment time.
  • THE FORMULATION OBTAINED BY THE ACICLOVIR ANTIVIRAL ASSOCIATION WITH VITAMIN B6 AND ANTIHYSTAMIN FOR HERPES TREATMENT AND APPLICATION is a topical formulation with bioadhesive characteristics containing the association of drugs ( acyclovir), pyridoxine (vitamin B6) and diphenhydramine (antihistamine) for the treatment of herpes.
  • the combination of the mentioned drugs allows decreased viral replication (acyclovir), pain (pyridoxine) and pruritus (diphenhydramine). Additionally, the formulation is bioadhesive, allowing for greater retention of drugs on the skin and may decrease the need for many applications throughout the day. Another advantage of this new formulation is its adaptation to various skin tones.
  • topical formulation object of this invention, obeys the following qualitative and quantitative definition, establishing its concentration in mass or volume:
  • the first step - the reduction crystal aciciovir by microfluidization process a mixture of aciciovir, d-panthenol, hydroxypropylmethylcellulose and water is passed into the microfluidizer (20,000 psi, 30K) aciciovir until the crystals remain with an average size between 0.5 at 15 micrometers (optical light microscopy / DLS - Dynamic Light Scattering I - Laser Diffraction).
  • the presence of submicron size crystal populations (on the nano scale) ensures a larger surface area and, consequently, a higher permeation of the drug.
  • Fig. 1 Magnified view of aciciovir crystals before the microfluidization process
  • Fig. 2 Magnified view of aciciovir crystals after microfluidization process.
  • 2nd step - addition of the other components of the formulation a simple mixture of the other compounds of the formulation is made with the product obtained in step 1, in the determined proportions, which mixture can be performed manually, mechanically or in other forms, without any parameters. specific temperature, time or pressure.
  • the accelerated stability test of the formulation was performed for 6 months and showed no change in color, pH, viscosity or phase separation.
  • the final product is in the form of a semi-solid topical preparation that can be adapted to various skin tones and can be prepared with or without the inclusion of dyes.
  • the iontophoresis technique can be used to apply this new formulation, acting as a physical promoter of drug permeation.
  • the present invention is an important advance in proposing better treatment and relief alternatives for Herpes patients, offering them better conditions to live with the disease that, although inactive most of the time, always presents itself, particularly in times of low immunity, stress and others.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une formulation obtenue par association de l'antiviral aciclovir avec la vitamine B6 et un anti-histaminique pour le traitement de l'herpès, ainsi qu'un moyen d'application, comprenant une formulation à usage topique, à caractéristiques bioadhésives et adaptable aux divers teints de peau, contenant l'association des médicaments aciclovir (antiviral), pyridoxine (vitamine B6) et diphénhydramine (anti-histaminique), qui se sont montrés efficaces, dans des études et des tests cliniques, pour le traitement de l'herpès.
PCT/BR2014/000038 2013-02-27 2014-02-10 Formulation obtenue par association de l'antiviral aciclovir avec la vitamine b6 et un anti-histaminique pour le traitement de l'herpès et moyen d'application WO2014131096A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR102013004649 2013-02-27
BRBR1020130046493 2013-02-27

Publications (1)

Publication Number Publication Date
WO2014131096A1 true WO2014131096A1 (fr) 2014-09-04

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PCT/BR2014/000038 WO2014131096A1 (fr) 2013-02-27 2014-02-10 Formulation obtenue par association de l'antiviral aciclovir avec la vitamine b6 et un anti-histaminique pour le traitement de l'herpès et moyen d'application

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017029298A1 (fr) * 2015-08-17 2017-02-23 Sanovel Ilac Sanayi Ve Ticaret A.S. Composition antivirale topique

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1320909C (fr) * 1985-03-25 1993-08-03 John A. Busciglio Composition topique pour le traitement de lesions cutaneo-muqueuses
US20030152640A1 (en) * 2001-09-14 2003-08-14 Dolak Terence M. Method and composition for treating viral outbreaks
JP2004196786A (ja) * 2002-12-03 2004-07-15 Taisho Pharmaceut Co Ltd 難溶性抗ウイルス成分含有水溶性外用剤組成物
WO2007070569A2 (fr) * 2005-12-13 2007-06-21 Lowder Tom R Composition et regime de traitement des lesions herpetiques epidermiques causees par le virus herpetique, le zona et l'herpes genital
DE102007054985A1 (de) * 2007-11-17 2009-05-20 Gerhard Dr. Sauermann Topische Produkte zur Reduzierung der Häufigkeit von Rezidiven bei Lippenherpes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA1320909C (fr) * 1985-03-25 1993-08-03 John A. Busciglio Composition topique pour le traitement de lesions cutaneo-muqueuses
US20030152640A1 (en) * 2001-09-14 2003-08-14 Dolak Terence M. Method and composition for treating viral outbreaks
JP2004196786A (ja) * 2002-12-03 2004-07-15 Taisho Pharmaceut Co Ltd 難溶性抗ウイルス成分含有水溶性外用剤組成物
WO2007070569A2 (fr) * 2005-12-13 2007-06-21 Lowder Tom R Composition et regime de traitement des lesions herpetiques epidermiques causees par le virus herpetique, le zona et l'herpes genital
DE102007054985A1 (de) * 2007-11-17 2009-05-20 Gerhard Dr. Sauermann Topische Produkte zur Reduzierung der Häufigkeit von Rezidiven bei Lippenherpes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ANDREW X. CHEN ET AL.: "Solubility Enhancement of Nucleosides and Structurally Related Compounds by Complex Formation", PHARMACEUTICAL RESEARCH, vol. 11, no. 3, 1994, XP002915350, DOI: doi:10.1023/A:1018913104383 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017029298A1 (fr) * 2015-08-17 2017-02-23 Sanovel Ilac Sanayi Ve Ticaret A.S. Composition antivirale topique

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