CA2088927A1 - Preservative system for vitamin e aqueous solution - Google Patents
Preservative system for vitamin e aqueous solutionInfo
- Publication number
- CA2088927A1 CA2088927A1 CA 2088927 CA2088927A CA2088927A1 CA 2088927 A1 CA2088927 A1 CA 2088927A1 CA 2088927 CA2088927 CA 2088927 CA 2088927 A CA2088927 A CA 2088927A CA 2088927 A1 CA2088927 A1 CA 2088927A1
- Authority
- CA
- Canada
- Prior art keywords
- tpgs
- formulation
- range
- citric acid
- sodium citrate
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- 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
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
Abstract
PRESERVATIVE SYSTEM FOR VITAMIN E AQUEOUS SOLUTION
ABSTRACT
The invention relates to pharmaceutical formulations for water soluble Vitamin E.
The. formulations may include methyl parabens, propyl parabens, potassium sorbate, propylene glycol, sodium citrate, citric acid, EDTA and tocopheryl polyethylene glycol succinate (TPGS).
ABSTRACT
The invention relates to pharmaceutical formulations for water soluble Vitamin E.
The. formulations may include methyl parabens, propyl parabens, potassium sorbate, propylene glycol, sodium citrate, citric acid, EDTA and tocopheryl polyethylene glycol succinate (TPGS).
Description
The invention relates to a formulation for a pharmaceutical product. In particular, the invention relates to a preservative system for water soluble Vitamin E.
Vitamin E, has traditionally been known as a fat soluble vitamin which exists in a variety of forms, one of the most active of which is d-alpha-tocopherol. Although the exact biological function of Vitamin E in humans is unknown, it is considered an essential element of human nutrition. Many of its therapeutic actions are related to its antioxidant properties. Vitamin E is naturally present in many foods, particularly in cereals, nuts, and leafy green and yellow vegetables. As it is fat soluble in its traditional form, it is stored in the fat fractions of animal tissues and hence significant sources of Vitamin E also ~-10 include eggs and meat. Absorption of Vitamin E from the gastrointestinal tract depends on the presence of bile. As a result, individuals who, as a result of genetic deficiency, ~ ~-pathological condition or otherwise, cannot absorb fat, are wlable to utilize the traditional fat soluble Vitamin E present in many foods. For example, individuals afflicted with the .
disease cystic fibrosis, are unable to effectively absorb fat from their gastrointestinal tract. - ~ -`
Although Vitamin E is available in a formulation suitable for parenteral administration (i.e.
IM Injection) such products are expensive and not always convenient or easy to administer. ~- -In the 1950's Pastman Kodak Company developed a water soluble form of Vitamin E now known as Tocopheryl Polyethylene Glycol 1000 Succinate, abbreviated TPGS. ;
Reference is made to U.S. Patent No. 2,680,749. Although the aforesaid U.S. patent ;
mentions (column 3, lines S3-55) that water solutions of the tocopheryl derivatives can be used for oral administration, further information is not provided. It was recognized early on, by Eastman and others, that the combination of TPGS and water would provide a ~;
~` 2088g27 medium in which molds and other micro-organisms would readily grow and flourish.
Although Eastman considered the problem of developing a formulation for oral administration which induded TPGS and which had a suitable shelf life, Eastman was unsuccessful in overcoming thc problem. To date, some forty years after the Eastman invention, notwithstanding the significant demand for water soluble Vitamin E ~PGS) amongst cystic fibrosis patients and others who for whatever reason cannot absorb fat, no one has been able to formulate, to the knowledge of the inventors, a product for oral administration, incorporating TPGS, which has an acceptable shelf life. ~;
The inventors have, after a lengthy period of study and experimentation, developed -a pharmaceutical formulation and a preservativc system which incorporates TPGS and has a shclf life SUihblc for its intended use, and which mects the regulatory requirements of the Health Protection Branch, Government of Canada.
Thc present invention provides a pharmaceutical formulation comprising:
water soluble Vitamin E ~PGS) 20% w/v potassium sorbate 0.200% w/v methyl paraben 0.128% w/v prowl paraben 0.032% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v distillcd water to 100 ml wherein the pH is 5Ø
ln a further embodiment the invention provides for a pharmaceutical formulation comprising:
TPGS 20% w/v potassium sorbate 0.20% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v propylene glycol 10.0% w/v :
sodium citrate 0.877% w/v citric acid 0.429% w/v ~ . ,. :.
distilled water to 100 ml wherein the pH is 5Ø ~ ~;
In yet a further embodiment the present invention provides a pharmaceutical - ~
formulation comprising: ; :
TPGS 20% w/v potassium sorbate 0.2% wlv propylene glycol 10% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v ~
distilled water to 100 ml : :
wherein the pH is 5Ø :
The problem facing the inventors was to develop a presenative system and a pharmaceutical formulation for water soluble Vitamin E (TPGS), namely a solution, which :
was shelf stable, which met pharmaceutical formularly standards, Canadian government 3 :
, standards, and resulted in a product that was safe and effective for human consumption.
The preservative system and pharmaceutical formulation had to be designed to be suitable and acceptable for oral ingestion. ~ -e :r=_ ; ' ,..... ..... ... ..
Amongst experiments conducted were the following.
A series of Vitamin E solutions containing 75 units per millilitre were prepared with different preservative systems and evaluated for their antimiaobial preservative effectiveness, using USP XXI procedures. TP(;S available from Eætman wæ used as the 10 Vitamin E source. No æsay was performed to determine the content of the Vitamin E
international units. During preparation of the various solutions the TPGS wæ melted first at 50-C and mainhined at this temperature. A 30 gram amount of TPGS was used in all cases. In a separate beaker the preservatives were dissolved in 120 millilitres of water maintained at 85-C. The TPGS was always poured into the water phæe under constant ~ -stirring. Then the volume wæ made up to 150.00 ml using water, at room temperature.
Six sample formulations were prepared (A,B,C,D,E,E7. pH adjustments were made on samples B, D and F, using citric æid and sodium citrate. Being an esterfied molecule, TPGS is likely to undergo hydrolysis to some extent. In order to minimize this reaction and improve the overall stability of formulae the buffer (citric acid/sodium citrate) must be 20 dissolved in the initial quantity of water, before the other ingredients. All preservative systems and Ievels used were acceptable to the Health Protection Branch.
Thc following sample for nulations werc preparcd:
SAI~P~ P. A
Distilled Water q.s. to 150.00 ml -:.
Methyl Paraben 0.27 Grams -: :
Propyl Parabcn 0.03 Grams : - :-TPGS 30.00 Grams pH = 4.8 ~ :~
. "
SA~
Same as Sample A, but pH = 3.5 SAMP~ F, C ~ -Distilled Wata q.s. to150.00 ml Methyl Parabcn 0.12 Grams Potassium Sorbate 0.06 Grams -::
TPGS 30.00 Grams ~ ~
pH = 5.5 ~ -Samc as Sample C, but pH = 3.9 Distillcd Watcr q.s. to 150.00 ml ::
Methyl Parabcn 0.12 Grams ~:
Potassium Bcnzonate 0.06 Grams ~:
TPGS 30.00 Grams pH = 5.0 Samc as Sample E, but pH = 3.9 , Thc following organisms were used in evaluating the different sample formulations:
Vitamin E, has traditionally been known as a fat soluble vitamin which exists in a variety of forms, one of the most active of which is d-alpha-tocopherol. Although the exact biological function of Vitamin E in humans is unknown, it is considered an essential element of human nutrition. Many of its therapeutic actions are related to its antioxidant properties. Vitamin E is naturally present in many foods, particularly in cereals, nuts, and leafy green and yellow vegetables. As it is fat soluble in its traditional form, it is stored in the fat fractions of animal tissues and hence significant sources of Vitamin E also ~-10 include eggs and meat. Absorption of Vitamin E from the gastrointestinal tract depends on the presence of bile. As a result, individuals who, as a result of genetic deficiency, ~ ~-pathological condition or otherwise, cannot absorb fat, are wlable to utilize the traditional fat soluble Vitamin E present in many foods. For example, individuals afflicted with the .
disease cystic fibrosis, are unable to effectively absorb fat from their gastrointestinal tract. - ~ -`
Although Vitamin E is available in a formulation suitable for parenteral administration (i.e.
IM Injection) such products are expensive and not always convenient or easy to administer. ~- -In the 1950's Pastman Kodak Company developed a water soluble form of Vitamin E now known as Tocopheryl Polyethylene Glycol 1000 Succinate, abbreviated TPGS. ;
Reference is made to U.S. Patent No. 2,680,749. Although the aforesaid U.S. patent ;
mentions (column 3, lines S3-55) that water solutions of the tocopheryl derivatives can be used for oral administration, further information is not provided. It was recognized early on, by Eastman and others, that the combination of TPGS and water would provide a ~;
~` 2088g27 medium in which molds and other micro-organisms would readily grow and flourish.
Although Eastman considered the problem of developing a formulation for oral administration which induded TPGS and which had a suitable shelf life, Eastman was unsuccessful in overcoming thc problem. To date, some forty years after the Eastman invention, notwithstanding the significant demand for water soluble Vitamin E ~PGS) amongst cystic fibrosis patients and others who for whatever reason cannot absorb fat, no one has been able to formulate, to the knowledge of the inventors, a product for oral administration, incorporating TPGS, which has an acceptable shelf life. ~;
The inventors have, after a lengthy period of study and experimentation, developed -a pharmaceutical formulation and a preservativc system which incorporates TPGS and has a shclf life SUihblc for its intended use, and which mects the regulatory requirements of the Health Protection Branch, Government of Canada.
Thc present invention provides a pharmaceutical formulation comprising:
water soluble Vitamin E ~PGS) 20% w/v potassium sorbate 0.200% w/v methyl paraben 0.128% w/v prowl paraben 0.032% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v distillcd water to 100 ml wherein the pH is 5Ø
ln a further embodiment the invention provides for a pharmaceutical formulation comprising:
TPGS 20% w/v potassium sorbate 0.20% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v propylene glycol 10.0% w/v :
sodium citrate 0.877% w/v citric acid 0.429% w/v ~ . ,. :.
distilled water to 100 ml wherein the pH is 5Ø ~ ~;
In yet a further embodiment the present invention provides a pharmaceutical - ~
formulation comprising: ; :
TPGS 20% w/v potassium sorbate 0.2% wlv propylene glycol 10% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v ~
distilled water to 100 ml : :
wherein the pH is 5Ø :
The problem facing the inventors was to develop a presenative system and a pharmaceutical formulation for water soluble Vitamin E (TPGS), namely a solution, which :
was shelf stable, which met pharmaceutical formularly standards, Canadian government 3 :
, standards, and resulted in a product that was safe and effective for human consumption.
The preservative system and pharmaceutical formulation had to be designed to be suitable and acceptable for oral ingestion. ~ -e :r=_ ; ' ,..... ..... ... ..
Amongst experiments conducted were the following.
A series of Vitamin E solutions containing 75 units per millilitre were prepared with different preservative systems and evaluated for their antimiaobial preservative effectiveness, using USP XXI procedures. TP(;S available from Eætman wæ used as the 10 Vitamin E source. No æsay was performed to determine the content of the Vitamin E
international units. During preparation of the various solutions the TPGS wæ melted first at 50-C and mainhined at this temperature. A 30 gram amount of TPGS was used in all cases. In a separate beaker the preservatives were dissolved in 120 millilitres of water maintained at 85-C. The TPGS was always poured into the water phæe under constant ~ -stirring. Then the volume wæ made up to 150.00 ml using water, at room temperature.
Six sample formulations were prepared (A,B,C,D,E,E7. pH adjustments were made on samples B, D and F, using citric æid and sodium citrate. Being an esterfied molecule, TPGS is likely to undergo hydrolysis to some extent. In order to minimize this reaction and improve the overall stability of formulae the buffer (citric acid/sodium citrate) must be 20 dissolved in the initial quantity of water, before the other ingredients. All preservative systems and Ievels used were acceptable to the Health Protection Branch.
Thc following sample for nulations werc preparcd:
SAI~P~ P. A
Distilled Water q.s. to 150.00 ml -:.
Methyl Paraben 0.27 Grams -: :
Propyl Parabcn 0.03 Grams : - :-TPGS 30.00 Grams pH = 4.8 ~ :~
. "
SA~
Same as Sample A, but pH = 3.5 SAMP~ F, C ~ -Distilled Wata q.s. to150.00 ml Methyl Parabcn 0.12 Grams Potassium Sorbate 0.06 Grams -::
TPGS 30.00 Grams ~ ~
pH = 5.5 ~ -Samc as Sample C, but pH = 3.9 Distillcd Watcr q.s. to 150.00 ml ::
Methyl Parabcn 0.12 Grams ~:
Potassium Bcnzonate 0.06 Grams ~:
TPGS 30.00 Grams pH = 5.0 Samc as Sample E, but pH = 3.9 , Thc following organisms were used in evaluating the different sample formulations:
2 0 8 8 9 2 7 90900~3 ,'-,..,-1) ~an~i~lki~an~ ATCC 10231 2) ~pcr~su~ ATCC 16404 3) ~cbclichia~Qli ATCC 8739 4) Pseudomona~ ~i~2sa ATCC 9027 S) StapllylQ~gccus ~ ATCC 6538 cedure A 20 millilitre sample of each formulation was transferred to each of the five 10 sterile capped bacteriological tubes of suitable size. Each tube was inoculated with one of thc standardized microbial suspensions of the above organisms using a ratio equivalent to 0.10 millilitre of inoculum to 20 millilitres of product. The concentrations of the organisms in the test preparation were standardized after inoculation to 500,000 per millilitre. The inoculated tubes were incubated at 20 to 25C. Each of the containers was cxamined at 7, 14, 21 and 28 days, subsequent to inoculation. When a formula appeared to fail the requirements of the test, further testing wæ suspended.
The results for all the sample formulas were as follows:
NIJMSE~ OF MICROORGANISMS SURVTVING OURING rSTING PERIOD
Initial Or~anism Concentration 7th Oay 14th Oay 21st Oay ZBth Oay Microorganisms oer Mill iliter - :-C. albicans SOO,OOO 390,000 480,000 A. niae SOO,OOO 180,000 -- -- ~
More than c. coli Soo,OOO3,000,0007,600,000 P. ae~ucinosa SOO,OOO2,275,00014,300,000 ~
More than : :.
S. aureus SOO,OOO2,550,000300,000 -- -- ~ ~
-','.
~further ~esting was suspended.
SAMPL 3 ~ - i NUM8E~ OF MIC.~OORGANISMS SURYIYTNG OURING ,cil;NG ?EP.IOD
Initial Organism Concentrat10n 7th Oay 14~h Oay2!5~ Da~,~ Z8th Oay Microorganisms ~er Milliliter C. ~lbic3ns SOO,OOOSgO,OOO625,000480,300 499,300 A. nio~er SOO,oOO100,000115,300110,300 60,300 E. ccli SOO,OOO88,_009,!00 135 NIL
P. aeruqinosa ;00,000 NIL NIL NIL ,YIL
S. aureus SOO,OOO ;00 NIL NIL NIL
~ ~ NUM~EF~ OF MIC~OORGANI5MS SURVIYING OURING TESTING PERIOD
,.
Initial Orcanism Concentration 7th Oay 14th Day21st Da~/ 28th ~ay Microorcanisms Der Milliliter C. albicans SOO,OOO 67,500 79,000 --~ --A. niger 500,000 170,000 E. coli soo,aoo ~ o,ooo lll, More than P. aeruginosa SOO,OOO 660,0003.000.000 -- --More than S. aureus SOO,OOO 1,6iO,000 300,000 -- --~Further testing suspended.
SAMP~. O
.
NUMBER OF MICROORGANISilS SUR`/I'/I?IG OURING TESIING PERIOD
Orcanism Initial 7th Oay 14th Day 21s; Day 28th Oav Microorcanisms oer Milliliter C. albicans iOO.OOO 68"00 90,00Q 168,000 g1,300 A. niqer 500.000 240,300 85,000 250,000 25;,300 E. coli SOO,OOO 1,050 NIL NI! NIL
P. aeruginosa ;00.300 NIL NIL NIL l`IIL
The results for all the sample formulas were as follows:
NIJMSE~ OF MICROORGANISMS SURVTVING OURING rSTING PERIOD
Initial Or~anism Concentration 7th Oay 14th Oay 21st Oay ZBth Oay Microorganisms oer Mill iliter - :-C. albicans SOO,OOO 390,000 480,000 A. niae SOO,OOO 180,000 -- -- ~
More than c. coli Soo,OOO3,000,0007,600,000 P. ae~ucinosa SOO,OOO2,275,00014,300,000 ~
More than : :.
S. aureus SOO,OOO2,550,000300,000 -- -- ~ ~
-','.
~further ~esting was suspended.
SAMPL 3 ~ - i NUM8E~ OF MIC.~OORGANISMS SURYIYTNG OURING ,cil;NG ?EP.IOD
Initial Organism Concentrat10n 7th Oay 14~h Oay2!5~ Da~,~ Z8th Oay Microorganisms ~er Milliliter C. ~lbic3ns SOO,OOOSgO,OOO625,000480,300 499,300 A. nio~er SOO,oOO100,000115,300110,300 60,300 E. ccli SOO,OOO88,_009,!00 135 NIL
P. aeruqinosa ;00,000 NIL NIL NIL ,YIL
S. aureus SOO,OOO ;00 NIL NIL NIL
~ ~ NUM~EF~ OF MIC~OORGANI5MS SURVIYING OURING TESTING PERIOD
,.
Initial Orcanism Concentration 7th Oay 14th Day21st Da~/ 28th ~ay Microorcanisms Der Milliliter C. albicans SOO,OOO 67,500 79,000 --~ --A. niger 500,000 170,000 E. coli soo,aoo ~ o,ooo lll, More than P. aeruginosa SOO,OOO 660,0003.000.000 -- --More than S. aureus SOO,OOO 1,6iO,000 300,000 -- --~Further testing suspended.
SAMP~. O
.
NUMBER OF MICROORGANISilS SUR`/I'/I?IG OURING TESIING PERIOD
Orcanism Initial 7th Oay 14th Day 21s; Day 28th Oav Microorcanisms oer Milliliter C. albicans iOO.OOO 68"00 90,00Q 168,000 g1,300 A. niqer 500.000 240,300 85,000 250,000 25;,300 E. coli SOO,OOO 1,050 NIL NI! NIL
P. aeruginosa ;00.300 NIL NIL NIL l`IIL
5. aureus i. !,100 NIL NIL NîIL
NUM8E?~ OF ~ICROORGANISMS SURVI~ING OURING TESTING PERIoD
Initial Orcanism Concentration 7th Oay 14th Oay 21s; Oay 28th Oay Microo anisms per Milliliter ~ ::
rg . ~:
C. albicans SOO,OOO 260,000 585,000 A. niaer SOO,OOO 85,000 --E. coli SOO,OOO 775,000 300,000 -- - -~
P. aerua,inosaSOO,OOO 340,000 1,20a,0aO - -- -- ' S. aureus SOO.OOO 45.000 30.000 ~~
~fur-her testing suspented. ~.
SAMPLE F
NUMOE~ OF MIC~OORGANISMS SURYI'IING 3URING rES~ING JE?.IOO
Organism ~oncentration 7th Oay 14th Oay 21s. Oay 28th Oay Microorganisms oer ~illilitar C. albicans 500,000 ~3,iOO 59.000 --*
L niger SOO,OOO 155,000 -- -! coli 500,000 107,;00 4,200 . aeruainosa iOO.000 ;.~ I,7l0,0ao -- --~: :
S. aureus S~O.OOO i50 NIL -- -- ~
9 . .
. ~.
. .
Sample formulations A, C, E and F were not acceptable because the concentrations of the identified organisms &iled to keep below the acceptable levels suggested in the USP ~1.
In sample formula B, the concentrations of viable bacteria OE~ ~nli). although not reduced to more than 99.9% of the initial concentration by the fourteenth day, resulted in no count being detected by the twenty-eighth day. ~ the same formula ~
&iled to remain at or below the initial level during the first fourteen days, but it stayed generally at the initial level by the twenty-eighth day. The results suggested there was a delayed preservative effectiveness as a result of formula B.
Sample formula D also met the requirements of the USP X~CI, NT Microbial Presenativc Effectiveness tcst.
Subsequent experimentation with modified formulations using different preservative systems, preservative potentiators and buffers resulted in the identification of the following thrcc preferred embodiments.
- ~edients (% w/v) Formu1a 1 Fontlula 2 E~a~
T.P.G.S. 20.000 20.000 20.000 Potassium Sorbate, N.F. 0.200 0.200 0.200 Methyl Pasaben, N.F. 0.128 0.128 -----Propyl Paraben, N.F. 0.032 0.032 ----- - -Prowlene Glycol, U.S.P. ----- 10.000 10.000 Sodium Citrate, U.S.P. 0.877 0.877 0.877 Citric Acid, U.S.P. 0.429 0.429 0.429 Purified Water, U.S.P 100.000 100.000 100.000 ~ -,;:'~;
Thc pH of fonnulas 1, 2 and 3 was adjusted to 5Ø
:, ' ''`
-`` 2088927 90900_3 The aforesaid formulas 1, 2 and 3 were subjected to a prcsenative challengc tcstaccording to Ciba-Geigy's mcthod IA-140/1.
The presenative challenge test results for each of fonnulations 1, 2 and 3 is set out below.
_ , .
?-ocu~ ~ la 1 ~ ¦ s.~w ¦ t.~-S--os~ ¦ C.~ 5 ~ r ¦~ ~L aECJ~ ¦ ~Ct~L Iorc~ I ~cJ~ o~c: L
¦ L4,aoo,aoa ¦ 26,000,000 l L.000,000 ¦ 70,000 ¦ Loo~a 1 ¦ 600,000 ¦ 2,000 ¦ ~l ¦ 300 000 ¦ (~
14 ¦ q,aoo ¦ ~ 20,aoo ¦ L0 2~ 1 1 oo I ~
Thc initial suspcnsions containcd approx. 106 CFU/ml ..
P~- ¦Fos::;ula 2 :: ~
~0~ S. ~ U5 I t.~ sS_o~ I C. ~ '5 ~ ~ ~
I ~1 OFC~ aFCJIII~ ~C~;
NUM8E?~ OF ~ICROORGANISMS SURVI~ING OURING TESTING PERIoD
Initial Orcanism Concentration 7th Oay 14th Oay 21s; Oay 28th Oay Microo anisms per Milliliter ~ ::
rg . ~:
C. albicans SOO,OOO 260,000 585,000 A. niaer SOO,OOO 85,000 --E. coli SOO,OOO 775,000 300,000 -- - -~
P. aerua,inosaSOO,OOO 340,000 1,20a,0aO - -- -- ' S. aureus SOO.OOO 45.000 30.000 ~~
~fur-her testing suspented. ~.
SAMPLE F
NUMOE~ OF MIC~OORGANISMS SURYI'IING 3URING rES~ING JE?.IOO
Organism ~oncentration 7th Oay 14th Oay 21s. Oay 28th Oay Microorganisms oer ~illilitar C. albicans 500,000 ~3,iOO 59.000 --*
L niger SOO,OOO 155,000 -- -! coli 500,000 107,;00 4,200 . aeruainosa iOO.000 ;.~ I,7l0,0ao -- --~: :
S. aureus S~O.OOO i50 NIL -- -- ~
9 . .
. ~.
. .
Sample formulations A, C, E and F were not acceptable because the concentrations of the identified organisms &iled to keep below the acceptable levels suggested in the USP ~1.
In sample formula B, the concentrations of viable bacteria OE~ ~nli). although not reduced to more than 99.9% of the initial concentration by the fourteenth day, resulted in no count being detected by the twenty-eighth day. ~ the same formula ~
&iled to remain at or below the initial level during the first fourteen days, but it stayed generally at the initial level by the twenty-eighth day. The results suggested there was a delayed preservative effectiveness as a result of formula B.
Sample formula D also met the requirements of the USP X~CI, NT Microbial Presenativc Effectiveness tcst.
Subsequent experimentation with modified formulations using different preservative systems, preservative potentiators and buffers resulted in the identification of the following thrcc preferred embodiments.
- ~edients (% w/v) Formu1a 1 Fontlula 2 E~a~
T.P.G.S. 20.000 20.000 20.000 Potassium Sorbate, N.F. 0.200 0.200 0.200 Methyl Pasaben, N.F. 0.128 0.128 -----Propyl Paraben, N.F. 0.032 0.032 ----- - -Prowlene Glycol, U.S.P. ----- 10.000 10.000 Sodium Citrate, U.S.P. 0.877 0.877 0.877 Citric Acid, U.S.P. 0.429 0.429 0.429 Purified Water, U.S.P 100.000 100.000 100.000 ~ -,;:'~;
Thc pH of fonnulas 1, 2 and 3 was adjusted to 5Ø
:, ' ''`
-`` 2088927 90900_3 The aforesaid formulas 1, 2 and 3 were subjected to a prcsenative challengc tcstaccording to Ciba-Geigy's mcthod IA-140/1.
The presenative challenge test results for each of fonnulations 1, 2 and 3 is set out below.
_ , .
?-ocu~ ~ la 1 ~ ¦ s.~w ¦ t.~-S--os~ ¦ C.~ 5 ~ r ¦~ ~L aECJ~ ¦ ~Ct~L Iorc~ I ~cJ~ o~c: L
¦ L4,aoo,aoa ¦ 26,000,000 l L.000,000 ¦ 70,000 ¦ Loo~a 1 ¦ 600,000 ¦ 2,000 ¦ ~l ¦ 300 000 ¦ (~
14 ¦ q,aoo ¦ ~ 20,aoo ¦ L0 2~ 1 1 oo I ~
Thc initial suspcnsions containcd approx. 106 CFU/ml ..
P~- ¦Fos::;ula 2 :: ~
~0~ S. ~ U5 I t.~ sS_o~ I C. ~ '5 ~ ~ ~
I ~1 OFC~ aFCJIII~ ~C~;
6,1~00,000 12,000,000 l400.000 1 700,00 1IO.~C0 .;~ :
20,aoo ¦3, 000 ¦~ ' ¦ 240~aoo ¦~ L , 14 ¦ L00 ¦ ~ o~aoo ¦ lo 2~ L ~ o,aaa ~o ¦ ~ L ~ ¦ 1. 200 ~
~2 1 ~ 1 I .
The initial suspcnsions contained approx. 106 CE~U/ml , . ..... -. . .. . . . . . . . ... ..
-~" 2088927 90900~3 eroduct ¦ Fors~ula 3 ~o~or~ E.col~ ¦ S.~u~u~ ¦ P.~cru~ J.~7 r _~ ~eJ~ I O~Cr~l ¦ OFCJ31 ¦ ~FCt~l I Wc~
1 4~000,000 1 3.000.000 1~.,000.000 1 10,000 1 10.000 7 1 400.000 1 20,000 1~1 1340.000 ~1.
14 ¦ ~ ~ ! ~ L ¦20,000 ¦1o 2 1 ~ .0~0 1 100 28 ~ 8,000 1 100 Thc initial suspcnsions containcd appro~c. 106 CFU/ml In thc tablc bclow, a phosphatc buffer/peptonc solution was uscd as a dilucnt in a challcnge tcst. The resultiDg figures werc rcgardcd as "positive control" results.
.
.. ...
~otuc~ Jl~o~ In~-r ~ eo~ .. ~
~ :'''::
ISlea~_ ~.col~S.~u~ P.~ r~gY~o~-C.~l~ic~ Ac.~ig r ~ ~rc~ wcr~ I~rc~ ~rcJ~ ~IFC~ .,,,'`~
O ~,0,000,000 2,000,000 ! 2.000.000 1 700,000 1 20.000 7 28.000.000 I0,000,000 30.000.000 ¦ ~,2 00,0 ao ¦ 10,000 :
1~ 30000000 300,000.000 ! L30000000 1 2,000,000 1 30.000 2~. 300,000,000 3~0.000.000 1 ) 300.000.000 1 200.000.000 1 300,000 I . :
28 ~300,000,000 )300.000,000 I )300.~00.000 1 200,~00,000 1 1.000.000 ~
42 _ l I _ _ I I ~ :
Thc initial suspcnsions containcd approx. 106 CFU/ml , :
-~ "~:
, ,~
Experiments were also conducted with respcct to Edetate Disodium (EDTA).
EDTA was found to be useful in the formula of the invention when used in combination with parabens and/or sorbates. In palticular, a formula containing 10% w/v propylene glycol and buffered to pH 4 and 5, with EDTA 0.05% w/v combined with parabens orpotassium sorbate rcspectively, eradicated the initial bacterial population virtually totally by the second day and no growth was observed on day seven. In a further trial, buffered to pH 4, where propylene glycol was abseint and EDTA was combined with potassiumsorbate alone, gave similar rcsults.
With respcct to the ingrcdients uscd in the formulations of the invention, the inventors make the following comments.
Potassium sorbatc is a prcscrvative having anti-bacterial and anti-fungal properties. Potassium sorbate is active in thc acidic zone, up to pH 6.5.
Propyl paraben and methyl parabcn are csters each of which exhibit prcservative propeltics, comparablc to those exhibited by potassium sorbatc. The parabens arc sctive within a pH rangc of 4-8. Thcir loss in potcncy in ccrtain cascs, mandatcs thc addition of -otha moleculcs having prcservative activity. In thc present casc, thc spectrum of activity of the paraben esters is increased by thc addition of thc potassium sorbate. Thc potassium sorbah is particularly activc against molds and yeasts and will compensate any potcntial deactivationof the parabens.
EDTA is an antioxidant and antibactcrial synergist, having also intrinsic antimicrobial activity. Whcn used in combination with parabcns and/or sorbates, EDTA
will providc a broad spectrum prcservative cf&ct including toxic activity against Gram Ncgativc bactcria like Pseudomas sp. EDTA may bc uscd in thc formula of thc invcntion, , ~", ~ ;, - ."
~ 2088927 in the range of 0.025-0.100%.
The citric acid and sodium citrate are uscd in combination as a buffer. Citric acid is also a sequestering/anti-oxidant agent and hencc can further improve the overall stability of the Vitamin E solutions. The concentration of citric acid and sodium citrate uscd can bc varicd to some extent, æ long as the resulting pH of the formulation is within the rangc 4-6. Thc propylcne glycol is uscful in the fonnuiation of the invention as a solvcnt and prcscrvativc. ~t is a water miscible co-solvent and an inhibitor of fcrmcntation, and has its own toxic acthity against bacteria and fungi. Furthermore, propylcnc glycol can potcntiate thc anti-microbial cffccts of other prcscrvatives. Propylene glycol also acts as a vitamin stabilizcr.
Thc water acts as a solubilizing and diluting vchicle.
In formulas 1 and 2, wc havc a complex prcscrvativc system, where the spectrum ~;
of activity of parabcn cslcls is increascd by thc addition of thc potassium sorbatc. In ~ -formula 2, potcntiation of action results duc to the other anti-microbials, whercas in formula 3, good rcsults are obtaincd cvcn whcn the parabens are excluded. An acpcrimcntal formulation, containing only 0.2% potassium sorbate, without parabcns and `
propylene gtycol, failcd to pass the preservative challcnge tcst. The prefcrred pH is pH 5, using the citrie aeid/sodium citratc buffcr systcm, as this pH appcars to optimize thc ~
--activity of both parabens and thc sorbate.
From thc microbiological assays, it may be noted that at 28 days formula 1 was ~ -better tban fomnula 2, which in tum was better than fomnula 3. At 42 days, fonnulas 1, 2 and 3 were equally good. There appcars to be a delayed prcscrvative action from :~
propylcne glycol in rcspect of fomnulas 2 and 3.
~:` 2088927 The following ingredients may be used in the invention in the following concentration ranges:
potassium sorbate 0.08-0.20% w/v methyl paraben 0.00-0.20% w/v (0.00-0.14% preferrcd) propyl paraben 0.00-0.20% w/v (0.00-0.05% preferred) EDTA 0.025-0.100% w/v propylene glycol 0-2S.0% w/v (depending on the amount of the parabens present, 0.00-10.00% is the preferred range) sodium citrate 0.65-1.25% w/v (0.85-0.93% preferred) citric acid 0.06-1.50% w/v (0.10-1.20% preferred) (sodium citrate/citric acid in combination sufficient to stabilize and buffer the pH
witbin the range 4-O
TPGS up to 20.0% w/v.
In view of the disclosure herein, those sldlled in the art will recognize tbat furtber and other embodiments of the present invention may be utilized without departing from tbc spirit and substance of the invention.
20,aoo ¦3, 000 ¦~ ' ¦ 240~aoo ¦~ L , 14 ¦ L00 ¦ ~ o~aoo ¦ lo 2~ L ~ o,aaa ~o ¦ ~ L ~ ¦ 1. 200 ~
~2 1 ~ 1 I .
The initial suspcnsions contained approx. 106 CE~U/ml , . ..... -. . .. . . . . . . . ... ..
-~" 2088927 90900~3 eroduct ¦ Fors~ula 3 ~o~or~ E.col~ ¦ S.~u~u~ ¦ P.~cru~ J.~7 r _~ ~eJ~ I O~Cr~l ¦ OFCJ31 ¦ ~FCt~l I Wc~
1 4~000,000 1 3.000.000 1~.,000.000 1 10,000 1 10.000 7 1 400.000 1 20,000 1~1 1340.000 ~1.
14 ¦ ~ ~ ! ~ L ¦20,000 ¦1o 2 1 ~ .0~0 1 100 28 ~ 8,000 1 100 Thc initial suspcnsions containcd appro~c. 106 CFU/ml In thc tablc bclow, a phosphatc buffer/peptonc solution was uscd as a dilucnt in a challcnge tcst. The resultiDg figures werc rcgardcd as "positive control" results.
.
.. ...
~otuc~ Jl~o~ In~-r ~ eo~ .. ~
~ :'''::
ISlea~_ ~.col~S.~u~ P.~ r~gY~o~-C.~l~ic~ Ac.~ig r ~ ~rc~ wcr~ I~rc~ ~rcJ~ ~IFC~ .,,,'`~
O ~,0,000,000 2,000,000 ! 2.000.000 1 700,000 1 20.000 7 28.000.000 I0,000,000 30.000.000 ¦ ~,2 00,0 ao ¦ 10,000 :
1~ 30000000 300,000.000 ! L30000000 1 2,000,000 1 30.000 2~. 300,000,000 3~0.000.000 1 ) 300.000.000 1 200.000.000 1 300,000 I . :
28 ~300,000,000 )300.000,000 I )300.~00.000 1 200,~00,000 1 1.000.000 ~
42 _ l I _ _ I I ~ :
Thc initial suspcnsions containcd approx. 106 CFU/ml , :
-~ "~:
, ,~
Experiments were also conducted with respcct to Edetate Disodium (EDTA).
EDTA was found to be useful in the formula of the invention when used in combination with parabens and/or sorbates. In palticular, a formula containing 10% w/v propylene glycol and buffered to pH 4 and 5, with EDTA 0.05% w/v combined with parabens orpotassium sorbate rcspectively, eradicated the initial bacterial population virtually totally by the second day and no growth was observed on day seven. In a further trial, buffered to pH 4, where propylene glycol was abseint and EDTA was combined with potassiumsorbate alone, gave similar rcsults.
With respcct to the ingrcdients uscd in the formulations of the invention, the inventors make the following comments.
Potassium sorbatc is a prcscrvative having anti-bacterial and anti-fungal properties. Potassium sorbate is active in thc acidic zone, up to pH 6.5.
Propyl paraben and methyl parabcn are csters each of which exhibit prcservative propeltics, comparablc to those exhibited by potassium sorbatc. The parabens arc sctive within a pH rangc of 4-8. Thcir loss in potcncy in ccrtain cascs, mandatcs thc addition of -otha moleculcs having prcservative activity. In thc present casc, thc spectrum of activity of the paraben esters is increased by thc addition of thc potassium sorbate. Thc potassium sorbah is particularly activc against molds and yeasts and will compensate any potcntial deactivationof the parabens.
EDTA is an antioxidant and antibactcrial synergist, having also intrinsic antimicrobial activity. Whcn used in combination with parabcns and/or sorbates, EDTA
will providc a broad spectrum prcservative cf&ct including toxic activity against Gram Ncgativc bactcria like Pseudomas sp. EDTA may bc uscd in thc formula of thc invcntion, , ~", ~ ;, - ."
~ 2088927 in the range of 0.025-0.100%.
The citric acid and sodium citrate are uscd in combination as a buffer. Citric acid is also a sequestering/anti-oxidant agent and hencc can further improve the overall stability of the Vitamin E solutions. The concentration of citric acid and sodium citrate uscd can bc varicd to some extent, æ long as the resulting pH of the formulation is within the rangc 4-6. Thc propylcne glycol is uscful in the fonnuiation of the invention as a solvcnt and prcscrvativc. ~t is a water miscible co-solvent and an inhibitor of fcrmcntation, and has its own toxic acthity against bacteria and fungi. Furthermore, propylcnc glycol can potcntiate thc anti-microbial cffccts of other prcscrvatives. Propylene glycol also acts as a vitamin stabilizcr.
Thc water acts as a solubilizing and diluting vchicle.
In formulas 1 and 2, wc havc a complex prcscrvativc system, where the spectrum ~;
of activity of parabcn cslcls is increascd by thc addition of thc potassium sorbatc. In ~ -formula 2, potcntiation of action results duc to the other anti-microbials, whercas in formula 3, good rcsults are obtaincd cvcn whcn the parabens are excluded. An acpcrimcntal formulation, containing only 0.2% potassium sorbate, without parabcns and `
propylene gtycol, failcd to pass the preservative challcnge tcst. The prefcrred pH is pH 5, using the citrie aeid/sodium citratc buffcr systcm, as this pH appcars to optimize thc ~
--activity of both parabens and thc sorbate.
From thc microbiological assays, it may be noted that at 28 days formula 1 was ~ -better tban fomnula 2, which in tum was better than fomnula 3. At 42 days, fonnulas 1, 2 and 3 were equally good. There appcars to be a delayed prcscrvative action from :~
propylcne glycol in rcspect of fomnulas 2 and 3.
~:` 2088927 The following ingredients may be used in the invention in the following concentration ranges:
potassium sorbate 0.08-0.20% w/v methyl paraben 0.00-0.20% w/v (0.00-0.14% preferrcd) propyl paraben 0.00-0.20% w/v (0.00-0.05% preferred) EDTA 0.025-0.100% w/v propylene glycol 0-2S.0% w/v (depending on the amount of the parabens present, 0.00-10.00% is the preferred range) sodium citrate 0.65-1.25% w/v (0.85-0.93% preferred) citric acid 0.06-1.50% w/v (0.10-1.20% preferred) (sodium citrate/citric acid in combination sufficient to stabilize and buffer the pH
witbin the range 4-O
TPGS up to 20.0% w/v.
In view of the disclosure herein, those sldlled in the art will recognize tbat furtber and other embodiments of the present invention may be utilized without departing from tbc spirit and substance of the invention.
Claims (18)
1. A shelf stable pharmaceutical formulation for TPGS comprising:
potassium sorbate 0.08-0.200% w/v propylene glycol 0.0-25.000% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6, utilizing sodium citrate and citric acid as a buffer system.
potassium sorbate 0.08-0.200% w/v propylene glycol 0.0-25.000% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6, utilizing sodium citrate and citric acid as a buffer system.
2. The formulation of claim 1, including methyl paraben in the range of 0.00-0.20% w/v and propyl paraben in the range of 0.00-0.20% w/v.
3. The formulation of claim 2 wherein sodium citrate is in the range of 0.65-1.25% w/v and citric acid is in the range of 0.06-1.50% w/v.
4. The formulation of claim 1, 2 or 3 including EDTA in the range of 0.025-0.100% w/v.
5. The formulation of claim 1, 2 or 3 wherein methyl paraben is present in the range of 0.00-0.14% w/v.
6. The formulation of claim 1, 2 or 3 wherein propyl paraben is present in the range of 0.00-0.05% w/v.
7. The formulation of claim 1, 2 or 3 wherein propylene glycol is present in the range of 0.00-25.00% w/v.
8. The formulation of claim 1, 2 or 3 wherein sodium citrate is present in the range of 0.85-0.93% w/v.
9. The formulation of claim 1, 2 or 3 wherein citric acid is present in the range of 0.10-1.20% w/v.
10. The formulation of claim 1 wherein propylene glycol is present in the amount of 10.00% w/v.
11. The formulation of claim 1 including methyl paraben up to 0.128% w/v and propyl paraben up to 0.032% w/v.
12. The formulation of claim 1, 2 or 3 wherein the pH is 5.
13. A shelf stable pharmaceutical formulation for TPGS comprising:
methyl paraben 0.00-0.20% w/v propyl paraben 0.00-0.20% w/v potassium sorbate 0.08-0.20% w/v propylene glycol 0.00-25.00% w/v sodium citrate 0.85-1.25% w/v citric acid 0.10-1.50% w/v TPGS up to 20%
water
methyl paraben 0.00-0.20% w/v propyl paraben 0.00-0.20% w/v potassium sorbate 0.08-0.20% w/v propylene glycol 0.00-25.00% w/v sodium citrate 0.85-1.25% w/v citric acid 0.10-1.50% w/v TPGS up to 20%
water
14. A shelf stable pharmaceutical formulation for TPGS comprising:
methyl paraben 0.00-0.14% w/v propyl paraben 0.00-0.05% w/v potassium sorbate 0.08-0.20% w/v propylene glycol 0.00-10.00% w/v sodium citrate 0.65-0.93% w/v citric acid 0.06-1.20% w/v TPGS up to 20%
water
methyl paraben 0.00-0.14% w/v propyl paraben 0.00-0.05% w/v potassium sorbate 0.08-0.20% w/v propylene glycol 0.00-10.00% w/v sodium citrate 0.65-0.93% w/v citric acid 0.06-1.20% w/v TPGS up to 20%
water
15. The formulation of claim 13 or 14 including EDTA in the range of 0.025%-0.100% w/v.
16. A shelf stable pharmaceutical formulation for TPGS comprising:
potassium sorbate 0.200% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
potassium sorbate 0.200% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
17. A shelf stable pharmaceutical formulation for TPGS comprising:
potassium sorbate 0.200% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v propylene glycol 10.000% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
potassium sorbate 0.200% w/v methyl paraben 0.128% w/v propyl paraben 0.032% w/v propylene glycol 10.000% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
18. A shelf stable pharmaceutical formulation for TPGS comprising:
potassium sorbate 0.200% w/v propylene glycol 10.00% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
potassium sorbate 0.200% w/v propylene glycol 10.00% w/v sodium citrate 0.877% w/v citric acid 0.429% w/v TPGS up to 20.00% w/v water wherein the pH is in the range of 4-6.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2088927 CA2088927A1 (en) | 1993-02-11 | 1993-02-11 | Preservative system for vitamin e aqueous solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA 2088927 CA2088927A1 (en) | 1993-02-11 | 1993-02-11 | Preservative system for vitamin e aqueous solution |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2088927A1 true CA2088927A1 (en) | 1994-08-12 |
Family
ID=4151108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2088927 Abandoned CA2088927A1 (en) | 1993-02-11 | 1993-02-11 | Preservative system for vitamin e aqueous solution |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2088927A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5886030A (en) * | 1994-05-06 | 1999-03-23 | Alcon Laboratories, Inc. | Use of vitamin E tocopheryl derivatives in ophthalmic compositions |
| WO2004095952A1 (en) * | 2003-04-29 | 2004-11-11 | Eastman Chemical Company | Beverages containing water-soluble vitamin e |
| EP2722035B1 (en) | 2009-06-19 | 2016-04-27 | Alcon Research, Ltd. | Aqueous pharmaceutical compositions containing borate-polyol complexes |
-
1993
- 1993-02-11 CA CA 2088927 patent/CA2088927A1/en not_active Abandoned
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5886030A (en) * | 1994-05-06 | 1999-03-23 | Alcon Laboratories, Inc. | Use of vitamin E tocopheryl derivatives in ophthalmic compositions |
| WO2004095952A1 (en) * | 2003-04-29 | 2004-11-11 | Eastman Chemical Company | Beverages containing water-soluble vitamin e |
| EP2722035B1 (en) | 2009-06-19 | 2016-04-27 | Alcon Research, Ltd. | Aqueous pharmaceutical compositions containing borate-polyol complexes |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hamilton-Miller | Antimicrobial properties of tea (Camellia sinensis L.) | |
| BERGSSON et al. | Killing of Gram‐positive cocci by fatty acids and monoglycerides Note | |
| Conrad et al. | Extract of Pelargonium sidoides (EPs® 7630) improves phagocytosis, oxidative burst, and intracellular killing of human peripheral blood phagocytes in vitro | |
| KR100722502B1 (en) | Topical suspension formulations containing ciprofloxacin and dexamethasone | |
| Chambers et al. | The osmoprotective properties of urine for bacteria: the protective effect of betaine and human urine against low pH and high concentrations of electrolytes, sugars, and urea | |
| FI114852B (en) | Acidified nitrate for use as an antimicrobial agent | |
| JPH09501702A (en) | Enhanced antibiotic composition | |
| JP2002528405A (en) | Propofol composition | |
| Wang et al. | In vitro antibacterial activity and mechanism of monocaprylin against Escherichia coli and Staphylococcus aureus | |
| Adebolu et al. | Effect of garlic (Allium sativum) on Salmonella typhi infection, gastrointestinal flora and hematological parameters of albino rats | |
| Oksuz et al. | Effect of propolis in the treatment of experimental Staphylococcus aureus keratitis in rabbits | |
| CN100509027C (en) | Non-toxic mucosal disinfectant containing isopropyl alcohol, sesame oil, aloe, and lemon oil | |
| CN111281814A (en) | Compound preservative composition and preparation method and application thereof | |
| CN112245438A (en) | Antibacterial composition, compound marbofloxacin spray thereof and preparation method | |
| EP1863470B1 (en) | A method for preventing and/or treating vaginal and vulval infections | |
| EP0264658A1 (en) | Liquid sterilizing composition | |
| CA2088927A1 (en) | Preservative system for vitamin e aqueous solution | |
| US9492489B2 (en) | Uses of hibiscus, in particular pharmaceutical uses | |
| JPH03106820A (en) | Agent for preventing infection with mycoplasma | |
| EP2575809B1 (en) | Compositions for treating helicobacter pylori infection | |
| Banik et al. | Determination of biological properties of Alocasia Macrorrhizos: A medicinal plant | |
| CN111328811B (en) | Low-concentration alcohol sterilization disinfectant and application thereof | |
| CN113980889A (en) | Medicinal preparation for resisting intracellular mycoplasma infection and application thereof | |
| KANNAN et al. | Treatment of experimental enzootic pneumonia of the pig by norfloxacin or its 6-chloro analogue | |
| US4459307A (en) | Antibacterial drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |