WO2019083483A2 - A vaginal implant - Google Patents

A vaginal implant

Info

Publication number
WO2019083483A2
WO2019083483A2 PCT/TR2018/050554 TR2018050554W WO2019083483A2 WO 2019083483 A2 WO2019083483 A2 WO 2019083483A2 TR 2018050554 W TR2018050554 W TR 2018050554W WO 2019083483 A2 WO2019083483 A2 WO 2019083483A2
Authority
WO
WIPO (PCT)
Prior art keywords
vaginal
implant
implant according
excipient
vaginal implant
Prior art date
Application number
PCT/TR2018/050554
Other languages
French (fr)
Other versions
WO2019083483A3 (en
Inventor
Isik OZGUNEY
Suleyha HILMIOGLU POLAT
Dilek YESIM METIN
Osman ZEKIOGLU
Seda RENCBER
Betul Rumeysa TEMEL
Original Assignee
Ege Universitesi
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
Priority claimed from TR2017/15422A external-priority patent/TR201715422A2/en
Application filed by Ege Universitesi filed Critical Ege Universitesi
Publication of WO2019083483A2 publication Critical patent/WO2019083483A2/en
Publication of WO2019083483A3 publication Critical patent/WO2019083483A3/en

Links

Classifications

    • 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
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • 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

Definitions

  • the invention is related to an implant that has been developed in order to be used to treat vaginal fungal infections.
  • Vaginitis is one of the most frequently experienced gynecological diseases. I t is known that 30-50% of Vaginitis cases arise from Candida infections. This disease is experienced by 3 ⁇ 4 of women at least once in their lives and more than once in fifty percent of women.
  • vaginal drug delivery systems that comprise antifungal active pharmaceutical ingredient to be more effective, the drugs need to stay in the infected area for a long period of time.
  • Present vaginal drug carrier systems have several disadvantages such as the drug having low acceptability by users, it may cause leakage, and it cannot be kept in the vagina for a long period of time.
  • the present commercial preparations that are used to treat vaginal fungal infections are examined, it is observed that these drugs are applied once or twice a day and generally the treatment continues for 3 to 14 days.
  • the application of once or twice a day during treatment with present preparations is difficult for the patient and this usually leads to discontinuation of treatment and as a result the risk of the infection to repeat itself arises.
  • vaginal implant subject to the invention provides the below mentioned advantages: - Said vaginal implant overcomes the disadvantages of formulations that need to be used every day and that poses application difficulties for many patients and therefore is open to being commercialized in terms of increasing patient compatibility.
  • the vaginal implant subject to the invention can be used for several different active pharmaceutical ingredient used in the treatment of vaginal candidiasis.
  • vaginal implant subject to the invention does not necessitate several process steps that are used during conventional production methods and said implant can be produced with less process steps using only one or two devices.
  • vaginal implant The application of said vaginal implant is quite easy.
  • the vaginal implants subject to the invention eliminates the application frequency arising from using the present preparations for 3 to 14 days and once or twice a day to be applied into the vagina during the treatment of vaginal fungal infections. By this means, the possibility of discontinuation of the treatment by the patient arising from difficulty of application and as a result the risk of repetition of the infection is prevented.
  • the implant After the developed implant is applied, as it released the drug up to 20 days, the implant does not have to be applied every day.
  • the implants subject to the invention are prepared using biodegradable polymers and they do not need to be removed at the end of the treatment period.
  • biodegradable polymers active pharmaceutical ingredient and optionally at least an excipient are used to obtain vaginal implants with sustained release using hot melt extrusion method, or hot melt extrusion followed with injection molding method in the production method of vaginal implants subject to the invention.
  • natamycin and tioconazole are used as active pharmaceutical ingredient.
  • the biodegradable polymer used in developing of the implants they do not need to be removed by the patient after application and as a result this enables practical usage and efficient treatment.
  • the production method of said vaginal implant comprises the below mentioned process steps: i. First of all the active pharmaceutical ingredient (5-90% ) is mixed with the biodegradable polymer (10-90% )
  • step (iii) Following this the mixture is fed into the hot melt extruder and the extrudates that are obtained are used as implants or the obtained extrudates are injected into a special mold by means of injection molding and are shaped to obtain an implant or the agents that are mixed in step (i) and optionally step (ii) are turned into implants by means of injection molding.
  • the operation temperature of the device is arranged to be between 60-1 10°C for natamycin and 50-90°C for tioconazole.
  • Poly(D,L-lactide-co-glycolide) 50:50 having different molecular weight (7.000-54.000) is used as polymer and optionally mucoadhesive polymers (hydroxypropylmethyl cellulose (HPMC) , carboxymethyl cellulose (CMC) , hydroxylpropyl cellulose (HPC) , chitosan, carbomer 974P, carbomer 971 P, polycarbophil etc.) are used.
  • HPMC hydroxypropylmethyl cellulose
  • CMC carboxymethyl cellulose
  • HPC hydroxylpropyl cellulose
  • HPC hydroxylpropyl cellulose
  • chitosan carbomer 974P
  • carbomer 971 P polycarbophil etc.
  • Natamycin and tioconazole are used separately as active pharmaceutical ingredients. 5-90% (w/w) of active pharmaceutical agents is loaded into the developed vaginal implants.
  • the vaginal implants that are prepared with natamycin comprise 400-600 mg active pharmaceutical ingredients and they provide release between 10-20 days.
  • the vaginal implants prepared with tioconazole comprise 225-1750 mg active pharmaceutical ingredients and they provide release for 3-14 days.
  • the plasticizer agent(s) that can be used optionally according to the invention can be selected from polyethylene glycol (between PEG 200 to PEG 8000) , glycerin, propylene glycol, triethyl citrate, diethyl phthalate, tributyl citrate, dibutyl phthalate, dibutyl acetate and triacetin.
  • the plasticizer(s) that have been selected can be added to the developed vaginal implants at a ratio between 0-20% .
  • excipients(s) that may be used optionally in order to alter the release profile of the implant of the invention are selected from glyceril monostearate, glycose, lactose, sodium chloride, calcium carbonate, magnesium carbonate, magnesium hydroxide, a water soluble polymer, hydroxypropyl cellulose, polyethylene glycol, or a solid lipid such as tripalmitin or tristearin.
  • the selected excipient(s) used to alter the release profile is added to the vaginal implants at the ratio of 0-50% .
  • the vaginal implants subject to the invention carry out sustained or controlled release in order to be used in treating vaginal infections. These implants release active pharmaceutical ingredient up to 20 days following the application of the formulation and during this period of time they biodegrade in the body of the patient.
  • the implants subject to the invention can particularly be used in treating vaginal candidiasis.
  • the vaginal implant that is obtained comprises 5-90% (w/w) of active pharmaceutical ingredient, 10-95% (w/w) of biodegradable polymers, and optionally at least an excipient.
  • excipients are excipients used to alter the release profile and/or mucoadhesive polymers and/or plasticizers, wherein the vaginal implant subject to the invention optionally comprises 0-40% (w/w) of mucoadhesive polymer and/or 0-20% (w/w) of plasticizers and/or 0-50% (w/w) of an excipient used to alter the release profile.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Reproductive Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Gynecology & Obstetrics (AREA)
  • Urology & Nephrology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention is related to an implant that has been developed in order to be used to treat vaginal fungal infections.

Description

A VAGI NAL I MPLANT
Technical Field
The invention is related to an implant that has been developed in order to be used to treat vaginal fungal infections.
Known State of the Art ( Prior Art) Vaginitis is one of the most frequently experienced gynecological diseases. I t is known that 30-50% of Vaginitis cases arise from Candida infections. This disease is experienced by ¾ of women at least once in their lives and more than once in fifty percent of women.
During Vaginitis treatment, topical antifungal treatment is preferred as antifungal drugs cause toxicity as a result of systemic application. I n order for vaginal drug delivery systems that comprise antifungal active pharmaceutical ingredient to be more effective, the drugs need to stay in the infected area for a long period of time. Present vaginal drug carrier systems have several disadvantages such as the drug having low acceptability by users, it may cause leakage, and it cannot be kept in the vagina for a long period of time. When the present commercial preparations that are used to treat vaginal fungal infections are examined, it is observed that these drugs are applied once or twice a day and generally the treatment continues for 3 to 14 days. However the application of once or twice a day during treatment with present preparations is difficult for the patient and this usually leads to discontinuation of treatment and as a result the risk of the infection to repeat itself arises.
Brief Description of the I nvention and its Aims
The vaginal implant subject to the invention provides the below mentioned advantages: - Said vaginal implant overcomes the disadvantages of formulations that need to be used every day and that poses application difficulties for many patients and therefore is open to being commercialized in terms of increasing patient compatibility.
The vaginal implant subject to the invention can be used for several different active pharmaceutical ingredient used in the treatment of vaginal candidiasis.
The production of the vaginal implant subject to the invention does not necessitate several process steps that are used during conventional production methods and said implant can be produced with less process steps using only one or two devices.
The application of said vaginal implant is quite easy.
The vaginal implants subject to the invention eliminates the application frequency arising from using the present preparations for 3 to 14 days and once or twice a day to be applied into the vagina during the treatment of vaginal fungal infections. By this means, the possibility of discontinuation of the treatment by the patient arising from difficulty of application and as a result the risk of repetition of the infection is prevented.
After the developed implant is applied, as it released the drug up to 20 days, the implant does not have to be applied every day.
The implants subject to the invention are prepared using biodegradable polymers and they do not need to be removed at the end of the treatment period.
Detailed Description of the I nvention
The biodegradable polymers, active pharmaceutical ingredient and optionally at least an excipient are used to obtain vaginal implants with sustained release using hot melt extrusion method, or hot melt extrusion followed with injection molding method in the production method of vaginal implants subject to the invention. Within the scope of the invention natamycin and tioconazole are used as active pharmaceutical ingredient. As the biodegradable polymer used in developing of the implants they do not need to be removed by the patient after application and as a result this enables practical usage and efficient treatment.
The production method of said vaginal implant comprises the below mentioned process steps: i. First of all the active pharmaceutical ingredient (5-90% ) is mixed with the biodegradable polymer (10-90% )
ii. I n order to overcome the difficulties faced in preparing extrusion products and to increase the processability of the polymer optionally a plasticizer and/or an excipient used to change the release profile and/or a muco-adhesive agent to enable the attachment of the implant to the vagina is added to the mixture,
iii. Following this the mixture is fed into the hot melt extruder and the extrudates that are obtained are used as implants or the obtained extrudates are injected into a special mold by means of injection molding and are shaped to obtain an implant or the agents that are mixed in step (i) and optionally step (ii) are turned into implants by means of injection molding.
The operation temperature of the device is arranged to be between 60-1 10°C for natamycin and 50-90°C for tioconazole.
During the preparation of extrudates, Poly(D,L-lactide-co-glycolide) 50:50 having different molecular weight (7.000-54.000) is used as polymer and optionally mucoadhesive polymers (hydroxypropylmethyl cellulose (HPMC) , carboxymethyl cellulose (CMC) , hydroxylpropyl cellulose (HPC) , chitosan, carbomer 974P, carbomer 971 P, polycarbophil etc.) are used.
Natamycin and tioconazole are used separately as active pharmaceutical ingredients. 5-90% (w/w) of active pharmaceutical agents is loaded into the developed vaginal implants. The vaginal implants that are prepared with natamycin comprise 400-600 mg active pharmaceutical ingredients and they provide release between 10-20 days. The vaginal implants prepared with tioconazole comprise 225-1750 mg active pharmaceutical ingredients and they provide release for 3-14 days.
The plasticizer agent(s) that can be used optionally according to the invention can be selected from polyethylene glycol (between PEG 200 to PEG 8000) , glycerin, propylene glycol, triethyl citrate, diethyl phthalate, tributyl citrate, dibutyl phthalate, dibutyl acetate and triacetin. The plasticizer(s) that have been selected can be added to the developed vaginal implants at a ratio between 0-20% .
The excipients(s) that may be used optionally in order to alter the release profile of the implant of the invention are selected from glyceril monostearate, glycose, lactose, sodium chloride, calcium carbonate, magnesium carbonate, magnesium hydroxide, a water soluble polymer, hydroxypropyl cellulose, polyethylene glycol, or a solid lipid such as tripalmitin or tristearin. The selected excipient(s) used to alter the release profile is added to the vaginal implants at the ratio of 0-50% .
The vaginal implants subject to the invention carry out sustained or controlled release in order to be used in treating vaginal infections. These implants release active pharmaceutical ingredient up to 20 days following the application of the formulation and during this period of time they biodegrade in the body of the patient. The implants subject to the invention can particularly be used in treating vaginal candidiasis.
The vaginal implant that is obtained comprises 5-90% (w/w) of active pharmaceutical ingredient, 10-95% (w/w) of biodegradable polymers, and optionally at least an excipient.
These excipients are excipients used to alter the release profile and/or mucoadhesive polymers and/or plasticizers, wherein the vaginal implant subject to the invention optionally comprises 0-40% (w/w) of mucoadhesive polymer and/or 0-20% (w/w) of plasticizers and/or 0-50% (w/w) of an excipient used to alter the release profile.

Claims

CLAI MS
A vaginal implant used in treating vaginal infections, characterized in that it comprises 5-90% (w/w) of an active pharmaceutical ingredient, 10-95% (w/w) of a biodegradable polymer and optionally at least an excipient.
A vaginal implant according to claim 1 , characterized in that the active pharmaceutical ingredient is natamycin.
A vaginal implant according to claim 2, characterized in that it comprises 400-600 mg natamycin.
A vaginal implant according to claim 1 , characterized in that the active pharmaceutical ingredient is tioconazole.
A vaginal implant according to claim 4, characterized in that it comprises 225-1750 mg tioconazole.
A vaginal implant according to claim 1 , characterized in that the biodegradable polymer is Poly(D,L-lactide-co-glycolide) .
A vaginal implant according to claim 1 , characterized in that the excipient is a mucoadhesive polymer and/or plasticizer and/or an excipient used to alter the release profile.
A vaginal implant according to claim 1 , characterized in that it comprises 0-40% (w/w) of mucoadhesive polymer and/or 0-20% (w/w) of plasticizer and/or 0-50% (w/w) of an excipient used in order to alter the release profile.
A vaginal implant according to claim 1 , characterized in that the mucoadhesive polymer is hydroxypropylmethyl cellulose (HPMC) , carboxymethyl cellulose (CMC) , hydroxylpropyl cellulose (HPC) , chitosan, carbomer 974P, carbomer 971 P or polycarbophil.
A vaginal implant according to claim 1 , characterized in that the plasticizer is polyethylene glycol, glycerin, propylene glycol, triethyl citrate, diethyl phthalate, tributyl citrate, dibutyl phthalate, dibutyl acetate or triacetin.
A vaginal implant according to claim 1 , characterized in that, the agent used to alter the release profile is glyceril monostearate, glycose, lactose, sodium chloride, calcium carbonate, magnesium carbonate, magnesium hydroxide, a water soluble polymer, hydroxypropyl cellulose, polyethylene glycol, or a solid lipid such as tripalmitin or tristearin.
A production method of the vaginal implant according to any of the preceding claims, characterized by the following process steps; i. I nitially an active pharmaceutical ingredient which is 5-90% (w/w) is mixed with the biodegradable polymer which is 10-90% (w/w) ,
ii. A plasticizer in order to increase the processability of the polymer and optionally to overcome the difficulties faced in preparing extrudates, and/or an excipient that is used to change the release profile and/or a muco-adhesive agent to enable the attachment of the implant to the vagina is added to the mixture iii. An implant is obtained from this mixture. 3 A method according to claim 12, characterized in that; the mixture of said optional agents mentioned in step (ii) and the agents mentioned in step (i) in the process step (iii) are fed into the hot melt extruder and the extrudates that are obtained are used as an implant.
4 A method according to claim 12, characterized in that the extrudates obtained by feeding the mixture of said optional agents mentioned in step (ii) and the agents mentioned in step (i) in the process step (iii) into the hot melt extruder device are shaped by means of the injection molding method and by using a special mold to prepare the implant. 5. A method according to claim 12, characterized in that the mixture of said optional agents mentioned in step (ii) and the agents mentioned in step (i) in the process step (iii) is turned into an implant by means of an injection molding method. 6. A method according to claim 12, characterized in that the operation temperature of the hot melt extruder for natamycin is adjusted to be between 60-1 10°C.
7. A method according to claim 12, characterized in that the operation temperature of the hot melt extruder for tioconazole is adjusted to be between 50-90°C. 8. Usage of the vaginal implant according to any of the preceding claims in treating vaginal candidiasis.
PCT/TR2018/050554 2017-10-11 2018-10-04 A vaginal implant WO2019083483A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/15422 2017-10-11
TR2017/15422A TR201715422A2 (en) 2017-07-10 2017-10-11 A VAGINAL IMPLANT

Publications (2)

Publication Number Publication Date
WO2019083483A2 true WO2019083483A2 (en) 2019-05-02
WO2019083483A3 WO2019083483A3 (en) 2019-06-13

Family

ID=66246994

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2018/050554 WO2019083483A2 (en) 2017-10-11 2018-10-04 A vaginal implant

Country Status (1)

Country Link
WO (1) WO2019083483A2 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020022048A1 (en) * 2000-05-26 2002-02-21 Bromberg Lev E. Composite wafer for controlled drug delivery
US9642829B2 (en) * 2012-12-04 2017-05-09 The University Of Hong Kong Antifungal compound and uses thereof
US10182985B2 (en) * 2014-06-11 2019-01-22 Massachusetts Institute Of Technology Residence structures and related methods

Also Published As

Publication number Publication date
WO2019083483A3 (en) 2019-06-13

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