CA1300014C - Nasal compositions containing vitamin b - Google Patents
Nasal compositions containing vitamin bInfo
- Publication number
- CA1300014C CA1300014C CA000506799A CA506799A CA1300014C CA 1300014 C CA1300014 C CA 1300014C CA 000506799 A CA000506799 A CA 000506799A CA 506799 A CA506799 A CA 506799A CA 1300014 C CA1300014 C CA 1300014C
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- Prior art keywords
- vitamin
- total weight
- weight based
- composition
- therapeutic composition
- 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.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L9/00—Disinfection, sterilisation or deodorisation of air
- A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
- A61L9/04—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air without heating
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
- A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
-
- 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
- A61K9/0043—Nose
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Otolaryngology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
Therapeutic compositions of a vitamin B12, for nasal administration are provided, which comprise a therapeutically effective amount of a vitamin B12 in an isotomic aqueous buffer at a pH of from about 4 to 6 containing sufficient thickening agent so that the viscosity is from about 2500 to 6500 cps.
Therapeutic compositions of a vitamin B12, for nasal administration are provided, which comprise a therapeutically effective amount of a vitamin B12 in an isotomic aqueous buffer at a pH of from about 4 to 6 containing sufficient thickening agent so that the viscosity is from about 2500 to 6500 cps.
Description
~0~
This invention is concerned with compositions for nasal administration of a vitamin B12 to a human suffering a vitamin s12 deficiency. It is concerned also with such compositions in dosage unit form and with methods of administering such compositions.
Cyanocobalamin is a vitamin B12, and is one of the Bl 2 class of vitamins which includes vitamin Bl 2a (hydroxocobalamin), vitamin B12b (aquacobalamin), vitamin B12C (nitrilocobalamin), coenzyme B12 (5'Odeoxyadenosine cobalamine) and methyl B12 (methyl cobalamine). Cyanocobalamin is the principal member of the class, and the most widely employed in medicine. This invention will be described as it relates to cyanocobalamin, but those skilled in the art will recognize that the invention is aplicable to the class.
Vitamin B12 is an essential compound for normal growth, hematopoiesis, production of all epithelial cells and maintenance of myelin throughout the ncr-v~ou~ system. It was first isolated from liver concentrate by Rickes and his coworkers in 1948 and structurally elucidated by Hodgkin and her coworkers in the late 1950's. It is currently commercially available as a tablet and as an injectable.
~3~
Therapeutically, vitamin B12 is employed in the treatment of a variety of B12 deficiency afflictions, principally anemias such as pernicious and diplyllobothrium latum. Although the minimum daily requirement of vitamin B12 is approximately 0.1 ug, the generally prescribed initial therapeutic dose is 100 to 1000 ug given intramuscularly. Maintenance therapy with vitamin B12 is usually 100 ug intramuscularly, monthly and must be continued for life.
Since pernicious anemia is often a disease of later years when many sufferers have reduced muscle mass or are atrophic, repeated intramuscular injections of vitamin B~2 can be inconvenient, painful and often require doctor's visits. In some cases at least in the early stages, hospitalization is required.
As a result, there is a need for a more convenient, less painful and less expensive method of administering vitamin B12, particularly one that would not require hospitalization or repeated physician contacts.
Unfortunately, up to the present time no efficient method of administering B12 which will achieve therapeutically useful blood levels of the vitamin except parenteral administration has been devised.
In 1953 and 1954 Monto et al in Am. J. Med. Sci., 223, 113 (1953) and Arch. of Int. Med. 93,219 (1954) described administration of B12 by nasal inhalation and instillation. The ~ o~ e vehicles for administration were a~e~e~3 isotonic sodium chloride solution and lactose powder. Although the results were reported as effective, safe and economical, the fact is that parenteral administration remains the only method regarded by the medical community as a safe, reliable and effective method for treating vitamin B12 deficiencies in humans. No composition for nasal inhalation or instillation has become commercially ~3~0~
. .
available for nasal administration to mammals. Neither have there been any further publications describing nasal inhalation or instillation of which applicant is aware.
The difficulty with nasal instillation by nasal dosage as the procedure is described in the cited articles is that most of the B12 passes immediately into the throat. It is not in contact with the nasal mucosa for a sufficient period of time to permit useful and uniform absorption. Most of the B12 so administered is, in fact wasted.
Compositions have now been discovered for the nasal administration of B1 which can be kept in contact with the nasal .~ 7~C ~ SQ 2 mn~os~ for an extended period of time. During the time the compositions are in such contact, the B is uniformly absorbed 12~os~
from the compositions through the nasal ~ and is then uniformly distributed systemically. The use of the compositions, because of the efficiency with which the B12 is absorbed allows the use of much lesser amounts of B1~ than is normally pres~nt in parenteral B12 compositions. Moreover, since the patient can self administer the B12, the need for hospitalization or physician contacts is minimized and may even be eliminated.
This invention provides vitamin B12 containing compositions specifically formulated for nasal administration which will, unlike aqueous isotonic sodium chloride compositions, remain in caS~
contact with the nasal mucesc for a sufficiently long period of time to permit consistent, continuous and uniform absorption of therapeutically effective amounts of a vitamin B12 through the nasal mucous membrane.
~30~
The invention, therefore comprises compositions containing a therapeutically effective amount of a vitamin B12, such compositions being sufficiently viscous to maintain themselves in the nasal passages for a period of time which is long enough so that most of the B12 is absorbed. The compositions are stable, easy to handle, and may be self administered by the patient.
More specifically the compositions of the invention are for nasal administration and contain a-therapeutically effective amount of a vitamin B12 in an isotonic aqueous buffer at a pH of from about 4 to 6. The compositions may be in the form of gels, lotions, ointments, creams and the like and will contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions even up to 10,000 cps may be employed. The preferred compositions have a viscosity of 2500 to 5000 cps, since above that range they become more difficult to administer.
Due to the efficiency with which the B12 is adsorbed from the compositions of this invention, a therapeutically effective amount of B12 for nasal administration will normally be appreciably less than for other methods of administration.
Typically the concentration of B12 in a composition of the invention will be 0.05% to 1% by weight based on the total weight. In dosage unit forms the dosage will normally be from about S0 to 1000 micrograms.
The pH of the compositions of this invention is from about 4 to 6. At this pH, B12 is stable so that the compositions have a shelf life which may be a year or more. Additionally, at this pH, irritation of the nasa~ mucosa is minimal. The pH is ~h y ~ ~ p~O ~
maintained with a ~ acceptable buffer composition suitably an acetate, citrate, phosphate, phthalate, borate, or other buffer.
~L3~ iL4 Acetate and citrate buffers are preferred for convenience and economy.
The isotonicity of the composition is accomplished using sodium chloride, or other pharmaceutically acceptable agent such as dextrose, boric acid, sodium tartrate or other inorganic or organic solute~ Sodium chloride is preferred particularly for buffers containing sodium ions.
Viscosity of the compositions is maintained at the selected level using a therapeutically acceptable thickening agent.
Methyl cellulose is preferred because it is easily and economically available and is easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulo~s~e~,~carbomer, and ~i~ the like. The preferred concentration of the ~ k-ne~ will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity.
Preferred compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of humectants can be employed including, for example sorbito~, propylene glycol or glycerol. As with the thickeners. the concentration will vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the invention.
, An enhanced absorption of B12 across the mucous membrane can be accomplished employing a surfactant. Typically useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydridès such as Tween ~0~ Polyoxyl 40 Stearate~
Polyoxyethylene 50 Stearate and Octoxynol~ The usual concentration is from 1% to 10% based on the total weight.
:~
': ~ t~ad~P~ 5 ~3 i~scf e~
A preservative is generally employed to -incrcsc the shelf life of the compositions. Benzyl alcohol is suitable, although a variety of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative will be from 0.02% to 2% based on the total weight, although there may be appreciable variation depending upon the agent selected.
The therapeutically effective compositions of thi-s invention are prepared by mixing the ingredients following generally accepted procedures. For example~the selected components may be simply mixed in a blender, or other standard machine to produce a concentrated mixture which is then adjusted to the final concentration and viscosity by the addition of water.
A typical composition of this invention contains the following components per 100 ml.
Ben~yl alcohol, NF 1.50ml Sodium chloride, NSP0.82gm Methyl cellulose, USP (400 cps) 2.00gm Acetic acid, NF 0.1Ogm Sodium acetate (anhyd, USP) 0.27gm Sorbitol soln., USP5.00ml Cyanocobalamine, USP0.1Ogm Water, purifiedq.s. 100.00ml The viscosity of the formulation is about 4500 cps. The pH
is about 5.
The following non-limiting examples are given by way of illustration only and are not to be considered limitations of this invention of which many apparent variations are possible without departing from the spirit or scope thereof.
~3~
The following compositions prepared by mixing.
Phenylmereurie Aeetate NF 0.002g Borie Aeid NF 1.740g Methyleellulose ~4000 CPS) USP 2.000g Aeetic Acid NF 0.100g Sodium Aeetate (Anhydrous) USP 0.270g Glyeerin USP 5.000ml Cyanocobalamin USP 0.1QOg Water, Purified USP q.s. 100.000ml B
Benzalkonium Chloride NF 0.020g Potassium Chloride USP 1.080g Hydroxyethyl Cellulose (3500-4000 CPS) NF 1.000g Acetie Acid NF ~nh~r~ o. lOOg Sodium Aeetate (~.n~;~i~ ) USQ 0.270g Propylene Gloeol USP 5.000ml Cyanoeobalamin USP 1.000g Water, Purified USP q.s. 100.000ml C
Thimerosal USP 0.002g Dextrose USP 5.120g Polysorbate 80 USP 10.000g Methyleellulose (4000 CPS) USP 1.33g Acetic Acid NF 0.100g Sodium Aeetate (Anhydrous) USP 0.270g gL30~
Glycerin tlSP 5.000ml --Cyanocobalamin USP 0.500ml Water, Purified q.s.100.000ml Methylparaben NF 0.020g Propylparaben NF 0.010g Sodium Chloride ~SP 0.820g Xanthan Gum NF 2.000g Acetic Acid NF 0.100g Sodium Acetate ~Anhydrous) USP 0.270g Propylene Glycol USP 5.000g Cyanocobalamin USP 0.200g Water, Purified q.s. 100.000ml The vlscosities of the compositions are within the range ., ~ , defined above.
,$
I " ~ .
~ typical composition disclosed above just prior to the examples~,tested in humans in order to determine quantitative increases in B12 Blood Levels following nasal administration.
Three normal volunteers received 0.1cc of the cited composition (100ug B12) inserted nasally with a nasal syringe applicator.
Serial Blood Samples were drawn from the subjects at 0, 0.05, 0.08, 0.16, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.3, 8~0, and 24 hours following dosing and assayed for B12 content by radioimmunoassay.
It was found that in less than 15 minutes after administration the serum level of B12 was significantly elevated and that significantly elevated blood levels were maintained during the full 24 hours of the study period.
~L30~
The actual plasma b]ood levels of B12, in the subjects following its nasal administration in the a~ove cited composition, were:
TIME (hours) P MA LEVELS (Picograms) 0 5~9 0.05 631 0.08: 628 0.16 674 0.25 754 0.5 729 1.0 804 2.0 794 3.0 769 4.0 727 6.0 752 8.0 803 24.0 729 An additional and similar study was performed with three human subjects using the same composition in which 0.2cc was administered intranasally (200ug B12 ) The actual plasma blood levels obtained were:
- TIME (hours~ PLASMA LEVELS (Picoqrams~
0.05 630 0.08 637 0.16 680 0.25 699 0.5 742 1.0 809 2.0 849 130~
4.0 764 6.0 722 8.0 742 24.0 675 A composition of this invention containing the following components per lO0 ml was prepared. This composition is identical with that listed as "typical" at page 6 hereof, except that an amount and type of methyl cellulose identical to that in composition A, Example l has been substituted:
Benzyl Alcohol NF 1.50ml Sodium Chloride USP 0.82g ; Methyl Cellulose (4000 cps.) 1.33g Acetic Acid NF O.lOg Sodium Acetate (Anhydrous) 0.27g Sorbitol Solution USP 5.00ml Cyanocoabalamin USP O.lOg Water, Purified USP q.s. lOO.OOOml This composition was tested in three humans as described in the previous example. The nasal administration of 200ug of Bl2 in 0.2cc gave the following serum Bl2 levels~
-- 1 0 -- , ..
. ~
TIME (hours)PLASMA LEVELS (Picograms) 0.0 731 0.05 734 0.08 725 0.16 845 0.25 837 0.5 940 1.0 975 2.0 1027 3.0 1038 4.0 1002 6.0 969 8.0 945 24.0 925 Again it was found that in approximately 15 minutes after ~ administration the serum level of Bl~ was significantly -~ elevated and that significantly elevated blood levels were maintained during the full 24 hours of the study period.
- lOa -' ~3~0~)~4 The following comparative experiment was con-ducted on forty normal, human, adult volunteers to compare the availability, speed of availability, and duration of availability of B12 administered by various routes.
Commercially available oral and sublingual tablets were compared with the compositions Gf this invention which were administered orally. All samples were tested by high performance liquid chromatography for Bl2 per dosage unit was as follows:
Methyl Cellulose 20 gm Sodium Citrate 3.2gm Citric Acid 1.2gm enæa I kon~uv~
A ~a~u~k~nium chloride 50% 0.4ml Cyanocolalami~e 2.5gm Purified Water q.s. to lOOml i tr n s~l The composition used to prepare the 400 mcg ~n~U~#~ dosage unit was identical except that it con-tained 4.0 gm. of cyanocolalamine.
Serial blood samples were from the subjects at 0, 5, 1, 2, 4, 8, 24, 48 and 72 hours following dosing and assayed for B~2 content by radioimmunossay.
The results are shown in Figures 1, 2, 3 and 4 in which concentration in picograms per ml. is plotted against time. The results are also summarized in table 1. In the table, the ~ lnc is the B~2 average concentration of B12 in the volunteer group prior to Bl2 administration.
9 ~- ~30~ L4 C ~
~3~
. u~ a~
n, ~ ~ . ~ ~ r~ 0 v) ~ ~ ~ r C~
~_ ~ ~ o ~ o X u~ o r~ ~ n~
~~1:) ~ 0 ,~
_ O
o m ~ E ~ o o ,,, u~
m~ u~
E E E E
~ u) Ul ~D r r a~ ~ ~ ~ ~ D h ~ C a ~ ~ ~ t~
. - g o~ t~
u~ a~ t~ r~ u ~) ~D ~ r r ~1~ r\ G 8 ~ ~ C
m~
~3 Q OQ~ P
~1 ~ O ~ O ~ U~ ~ O
~ E~ u~ t/) E~
4~ o O ~ o ~ t~ ~
o o o o ~3~
From an analysis of the figures and the tables, the following unexpected advantages for nasal administration of B12 in the compositions of this invention will be apparent:
1. Increased blood levels at lower dosages.
2. Maximum blood levels achieved more rapidly, and at lower dosage levels.
3. High blood levels maintained for entire period of test as indicated by larger areas under the carve.
4. Substantially higher blood levels at lower dosages even two days after administration.
This invention is concerned with compositions for nasal administration of a vitamin B12 to a human suffering a vitamin s12 deficiency. It is concerned also with such compositions in dosage unit form and with methods of administering such compositions.
Cyanocobalamin is a vitamin B12, and is one of the Bl 2 class of vitamins which includes vitamin Bl 2a (hydroxocobalamin), vitamin B12b (aquacobalamin), vitamin B12C (nitrilocobalamin), coenzyme B12 (5'Odeoxyadenosine cobalamine) and methyl B12 (methyl cobalamine). Cyanocobalamin is the principal member of the class, and the most widely employed in medicine. This invention will be described as it relates to cyanocobalamin, but those skilled in the art will recognize that the invention is aplicable to the class.
Vitamin B12 is an essential compound for normal growth, hematopoiesis, production of all epithelial cells and maintenance of myelin throughout the ncr-v~ou~ system. It was first isolated from liver concentrate by Rickes and his coworkers in 1948 and structurally elucidated by Hodgkin and her coworkers in the late 1950's. It is currently commercially available as a tablet and as an injectable.
~3~
Therapeutically, vitamin B12 is employed in the treatment of a variety of B12 deficiency afflictions, principally anemias such as pernicious and diplyllobothrium latum. Although the minimum daily requirement of vitamin B12 is approximately 0.1 ug, the generally prescribed initial therapeutic dose is 100 to 1000 ug given intramuscularly. Maintenance therapy with vitamin B12 is usually 100 ug intramuscularly, monthly and must be continued for life.
Since pernicious anemia is often a disease of later years when many sufferers have reduced muscle mass or are atrophic, repeated intramuscular injections of vitamin B~2 can be inconvenient, painful and often require doctor's visits. In some cases at least in the early stages, hospitalization is required.
As a result, there is a need for a more convenient, less painful and less expensive method of administering vitamin B12, particularly one that would not require hospitalization or repeated physician contacts.
Unfortunately, up to the present time no efficient method of administering B12 which will achieve therapeutically useful blood levels of the vitamin except parenteral administration has been devised.
In 1953 and 1954 Monto et al in Am. J. Med. Sci., 223, 113 (1953) and Arch. of Int. Med. 93,219 (1954) described administration of B12 by nasal inhalation and instillation. The ~ o~ e vehicles for administration were a~e~e~3 isotonic sodium chloride solution and lactose powder. Although the results were reported as effective, safe and economical, the fact is that parenteral administration remains the only method regarded by the medical community as a safe, reliable and effective method for treating vitamin B12 deficiencies in humans. No composition for nasal inhalation or instillation has become commercially ~3~0~
. .
available for nasal administration to mammals. Neither have there been any further publications describing nasal inhalation or instillation of which applicant is aware.
The difficulty with nasal instillation by nasal dosage as the procedure is described in the cited articles is that most of the B12 passes immediately into the throat. It is not in contact with the nasal mucosa for a sufficient period of time to permit useful and uniform absorption. Most of the B12 so administered is, in fact wasted.
Compositions have now been discovered for the nasal administration of B1 which can be kept in contact with the nasal .~ 7~C ~ SQ 2 mn~os~ for an extended period of time. During the time the compositions are in such contact, the B is uniformly absorbed 12~os~
from the compositions through the nasal ~ and is then uniformly distributed systemically. The use of the compositions, because of the efficiency with which the B12 is absorbed allows the use of much lesser amounts of B1~ than is normally pres~nt in parenteral B12 compositions. Moreover, since the patient can self administer the B12, the need for hospitalization or physician contacts is minimized and may even be eliminated.
This invention provides vitamin B12 containing compositions specifically formulated for nasal administration which will, unlike aqueous isotonic sodium chloride compositions, remain in caS~
contact with the nasal mucesc for a sufficiently long period of time to permit consistent, continuous and uniform absorption of therapeutically effective amounts of a vitamin B12 through the nasal mucous membrane.
~30~
The invention, therefore comprises compositions containing a therapeutically effective amount of a vitamin B12, such compositions being sufficiently viscous to maintain themselves in the nasal passages for a period of time which is long enough so that most of the B12 is absorbed. The compositions are stable, easy to handle, and may be self administered by the patient.
More specifically the compositions of the invention are for nasal administration and contain a-therapeutically effective amount of a vitamin B12 in an isotonic aqueous buffer at a pH of from about 4 to 6. The compositions may be in the form of gels, lotions, ointments, creams and the like and will contain a sufficient amount of a thickening agent so that the viscosity is from about 2500 to 6500 cps, although more viscous compositions even up to 10,000 cps may be employed. The preferred compositions have a viscosity of 2500 to 5000 cps, since above that range they become more difficult to administer.
Due to the efficiency with which the B12 is adsorbed from the compositions of this invention, a therapeutically effective amount of B12 for nasal administration will normally be appreciably less than for other methods of administration.
Typically the concentration of B12 in a composition of the invention will be 0.05% to 1% by weight based on the total weight. In dosage unit forms the dosage will normally be from about S0 to 1000 micrograms.
The pH of the compositions of this invention is from about 4 to 6. At this pH, B12 is stable so that the compositions have a shelf life which may be a year or more. Additionally, at this pH, irritation of the nasa~ mucosa is minimal. The pH is ~h y ~ ~ p~O ~
maintained with a ~ acceptable buffer composition suitably an acetate, citrate, phosphate, phthalate, borate, or other buffer.
~L3~ iL4 Acetate and citrate buffers are preferred for convenience and economy.
The isotonicity of the composition is accomplished using sodium chloride, or other pharmaceutically acceptable agent such as dextrose, boric acid, sodium tartrate or other inorganic or organic solute~ Sodium chloride is preferred particularly for buffers containing sodium ions.
Viscosity of the compositions is maintained at the selected level using a therapeutically acceptable thickening agent.
Methyl cellulose is preferred because it is easily and economically available and is easy to work with. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulo~s~e~,~carbomer, and ~i~ the like. The preferred concentration of the ~ k-ne~ will depend upon the agent selected. The important point is to use an amount which will achieve the selected viscosity.
Preferred compositions within the scope of this invention will contain a humectant to inhibit drying of the mucous membrane and to prevent irritation. Any of a variety of humectants can be employed including, for example sorbito~, propylene glycol or glycerol. As with the thickeners. the concentration will vary with the selected agent, although the presence or absence of these agents, or their concentration is not an essential feature of the invention.
, An enhanced absorption of B12 across the mucous membrane can be accomplished employing a surfactant. Typically useful surfactants for these therapeutic compositions include polyoxyethylene derivatives of fatty acid partial esters of sorbitol anhydridès such as Tween ~0~ Polyoxyl 40 Stearate~
Polyoxyethylene 50 Stearate and Octoxynol~ The usual concentration is from 1% to 10% based on the total weight.
:~
': ~ t~ad~P~ 5 ~3 i~scf e~
A preservative is generally employed to -incrcsc the shelf life of the compositions. Benzyl alcohol is suitable, although a variety of preservatives including, for example, Parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative will be from 0.02% to 2% based on the total weight, although there may be appreciable variation depending upon the agent selected.
The therapeutically effective compositions of thi-s invention are prepared by mixing the ingredients following generally accepted procedures. For example~the selected components may be simply mixed in a blender, or other standard machine to produce a concentrated mixture which is then adjusted to the final concentration and viscosity by the addition of water.
A typical composition of this invention contains the following components per 100 ml.
Ben~yl alcohol, NF 1.50ml Sodium chloride, NSP0.82gm Methyl cellulose, USP (400 cps) 2.00gm Acetic acid, NF 0.1Ogm Sodium acetate (anhyd, USP) 0.27gm Sorbitol soln., USP5.00ml Cyanocobalamine, USP0.1Ogm Water, purifiedq.s. 100.00ml The viscosity of the formulation is about 4500 cps. The pH
is about 5.
The following non-limiting examples are given by way of illustration only and are not to be considered limitations of this invention of which many apparent variations are possible without departing from the spirit or scope thereof.
~3~
The following compositions prepared by mixing.
Phenylmereurie Aeetate NF 0.002g Borie Aeid NF 1.740g Methyleellulose ~4000 CPS) USP 2.000g Aeetic Acid NF 0.100g Sodium Aeetate (Anhydrous) USP 0.270g Glyeerin USP 5.000ml Cyanocobalamin USP 0.1QOg Water, Purified USP q.s. 100.000ml B
Benzalkonium Chloride NF 0.020g Potassium Chloride USP 1.080g Hydroxyethyl Cellulose (3500-4000 CPS) NF 1.000g Acetie Acid NF ~nh~r~ o. lOOg Sodium Aeetate (~.n~;~i~ ) USQ 0.270g Propylene Gloeol USP 5.000ml Cyanoeobalamin USP 1.000g Water, Purified USP q.s. 100.000ml C
Thimerosal USP 0.002g Dextrose USP 5.120g Polysorbate 80 USP 10.000g Methyleellulose (4000 CPS) USP 1.33g Acetic Acid NF 0.100g Sodium Aeetate (Anhydrous) USP 0.270g gL30~
Glycerin tlSP 5.000ml --Cyanocobalamin USP 0.500ml Water, Purified q.s.100.000ml Methylparaben NF 0.020g Propylparaben NF 0.010g Sodium Chloride ~SP 0.820g Xanthan Gum NF 2.000g Acetic Acid NF 0.100g Sodium Acetate ~Anhydrous) USP 0.270g Propylene Glycol USP 5.000g Cyanocobalamin USP 0.200g Water, Purified q.s. 100.000ml The vlscosities of the compositions are within the range ., ~ , defined above.
,$
I " ~ .
~ typical composition disclosed above just prior to the examples~,tested in humans in order to determine quantitative increases in B12 Blood Levels following nasal administration.
Three normal volunteers received 0.1cc of the cited composition (100ug B12) inserted nasally with a nasal syringe applicator.
Serial Blood Samples were drawn from the subjects at 0, 0.05, 0.08, 0.16, 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.3, 8~0, and 24 hours following dosing and assayed for B12 content by radioimmunoassay.
It was found that in less than 15 minutes after administration the serum level of B12 was significantly elevated and that significantly elevated blood levels were maintained during the full 24 hours of the study period.
~L30~
The actual plasma b]ood levels of B12, in the subjects following its nasal administration in the a~ove cited composition, were:
TIME (hours) P MA LEVELS (Picograms) 0 5~9 0.05 631 0.08: 628 0.16 674 0.25 754 0.5 729 1.0 804 2.0 794 3.0 769 4.0 727 6.0 752 8.0 803 24.0 729 An additional and similar study was performed with three human subjects using the same composition in which 0.2cc was administered intranasally (200ug B12 ) The actual plasma blood levels obtained were:
- TIME (hours~ PLASMA LEVELS (Picoqrams~
0.05 630 0.08 637 0.16 680 0.25 699 0.5 742 1.0 809 2.0 849 130~
4.0 764 6.0 722 8.0 742 24.0 675 A composition of this invention containing the following components per lO0 ml was prepared. This composition is identical with that listed as "typical" at page 6 hereof, except that an amount and type of methyl cellulose identical to that in composition A, Example l has been substituted:
Benzyl Alcohol NF 1.50ml Sodium Chloride USP 0.82g ; Methyl Cellulose (4000 cps.) 1.33g Acetic Acid NF O.lOg Sodium Acetate (Anhydrous) 0.27g Sorbitol Solution USP 5.00ml Cyanocoabalamin USP O.lOg Water, Purified USP q.s. lOO.OOOml This composition was tested in three humans as described in the previous example. The nasal administration of 200ug of Bl2 in 0.2cc gave the following serum Bl2 levels~
-- 1 0 -- , ..
. ~
TIME (hours)PLASMA LEVELS (Picograms) 0.0 731 0.05 734 0.08 725 0.16 845 0.25 837 0.5 940 1.0 975 2.0 1027 3.0 1038 4.0 1002 6.0 969 8.0 945 24.0 925 Again it was found that in approximately 15 minutes after ~ administration the serum level of Bl~ was significantly -~ elevated and that significantly elevated blood levels were maintained during the full 24 hours of the study period.
- lOa -' ~3~0~)~4 The following comparative experiment was con-ducted on forty normal, human, adult volunteers to compare the availability, speed of availability, and duration of availability of B12 administered by various routes.
Commercially available oral and sublingual tablets were compared with the compositions Gf this invention which were administered orally. All samples were tested by high performance liquid chromatography for Bl2 per dosage unit was as follows:
Methyl Cellulose 20 gm Sodium Citrate 3.2gm Citric Acid 1.2gm enæa I kon~uv~
A ~a~u~k~nium chloride 50% 0.4ml Cyanocolalami~e 2.5gm Purified Water q.s. to lOOml i tr n s~l The composition used to prepare the 400 mcg ~n~U~#~ dosage unit was identical except that it con-tained 4.0 gm. of cyanocolalamine.
Serial blood samples were from the subjects at 0, 5, 1, 2, 4, 8, 24, 48 and 72 hours following dosing and assayed for B~2 content by radioimmunossay.
The results are shown in Figures 1, 2, 3 and 4 in which concentration in picograms per ml. is plotted against time. The results are also summarized in table 1. In the table, the ~ lnc is the B~2 average concentration of B12 in the volunteer group prior to Bl2 administration.
9 ~- ~30~ L4 C ~
~3~
. u~ a~
n, ~ ~ . ~ ~ r~ 0 v) ~ ~ ~ r C~
~_ ~ ~ o ~ o X u~ o r~ ~ n~
~~1:) ~ 0 ,~
_ O
o m ~ E ~ o o ,,, u~
m~ u~
E E E E
~ u) Ul ~D r r a~ ~ ~ ~ ~ D h ~ C a ~ ~ ~ t~
. - g o~ t~
u~ a~ t~ r~ u ~) ~D ~ r r ~1~ r\ G 8 ~ ~ C
m~
~3 Q OQ~ P
~1 ~ O ~ O ~ U~ ~ O
~ E~ u~ t/) E~
4~ o O ~ o ~ t~ ~
o o o o ~3~
From an analysis of the figures and the tables, the following unexpected advantages for nasal administration of B12 in the compositions of this invention will be apparent:
1. Increased blood levels at lower dosages.
2. Maximum blood levels achieved more rapidly, and at lower dosage levels.
3. High blood levels maintained for entire period of test as indicated by larger areas under the carve.
4. Substantially higher blood levels at lower dosages even two days after administration.
Claims (24)
1. A therapeutic composition for nasal administration comprising a therapeutically effective amount of a vitamin B12 in an isotonic aqueous buffer at a pH of from about 4 to 6 containing sufficient thickening agent so that the viscosity is from about 2500 to 6500 cps.
2. A therapeutic composition of Claim 1 wherein the vitamin B12 is cyanocobalamin.
3. A composition as in Claim 1 or 2 additionally containing from about 1% to 10% by weight based on the total weight of a humectant.
4. A composition as in Claim 1 or 2 additionally containing from about 0.2% to 2% by weight based on the total weight of a surfactant.
5. A composition as in Claim 1 or 2 additionally containing from about 1% to 10% by weight based on the total weight of a humectant and from about 0.2% to 2% by weight based on the total weight of a surfactant.
6. A therapeutic composition as in Claim 1 wherein the thickening agent is methyl cellulose.
7. A therapeutic composition of Claim 6 wherein the vitamin B12 is cyanocobalamin.
8. A therapeutic composition of Claim 6 or 7 additionally containing from about 1% to 10% by weight based on the total weight of a humectant and from about 0.2% to 2% by weight based on the total weight of a surfactant.
9. A therapeutic composition for nasal administration in dosage unit form containing from 50 to 1000 micrograms of a vitamin B12 in an isotonic aqueous buffer at a pH of from about 4 to 6 containing sufficient thickening agent so that the viscosity is from about 2500 to 6500 cps.
10. A therapeutic composition as in Claim 9 wherein the vitamin B12 is cyanocobalamin.
11. A therapeutic composition as in Claim 9 or 10 additionally containing from about 1% to 10% by weight based on the total weight of a humectant.
12. A therapeutic composition as in Claim 9 or 10 additionally containing from about 0.2% to 2% by weight based on the total weight of a surfactant.
13. A therapeutic composition as in Claim 9 or 10 additionally containing from about 1% to 10% by weight based on the total weight of a surfactant.
14. A therapeutic composition as in Claim 9 wherein the thickening agent is methyl cellulose.
15. A therapeutic composition as in Claim 14 wherein the vitamin B12 is a cyanocobalamin.
16. A therapeutic composition as in Claim 14 or 15 additionally containing from about 1% to 10% by weight based on the total weight of a humectant and from about 0.2% to 2% by weight based on the total weight of a surfactant.
17. Use of a nasally administerable therapeutic composition comprising a therapeutically effective amount of a vitamin B12 in an isotonic aqueous buffer at a pH of from about 4 to 6 containing sufficient thickening agent so that the viscosity is from about 2500 - 6500 cps, for treating a human for vitamin B12 deficiency.
18. Use as defined in claim 17 wherein the vitamin B12 is cyanocobalamin.
19. Use as defined in claim 17 or claim 18 wherein the composition additionally contains from about 1% to 10% by weight based on the total weight of a humectant.
20. Use as defined in claim 17 or claim 18 wherein the composition additionally contains from about 0.2% to 2% by weight based on the total weight of a surfactant.
21. Use as defined in claim 17 or claim 18 wherein the composition additionally contains from about 1% to 10% by weight based on the total weight of a humectant and from about 0.2% to 2% by weight based on the total weight of a surfactant.
22. Use as defined in claim 17 wherein the thickening agent is methyl cellulose.
23. Use as defined in claim 22 wherein the vitamin B12 is cyanocobalamin.
24. Use as defined in claim 22 or claim 23 wherein the composition additionally contains from about 1% to 10% by weight based on the total weight of a humectant and from about 0.2% to 2% by weight based on the total weight of a surfactant.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72384485A | 1985-04-16 | 1985-04-16 | |
| US723,844 | 1985-04-16 | ||
| US06/848,690 US4724231A (en) | 1985-04-16 | 1986-04-08 | Nasel compositions containing vitamin B12 |
| US848,690 | 1986-04-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1300014C true CA1300014C (en) | 1992-05-05 |
Family
ID=27110879
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000506799A Expired - Fee Related CA1300014C (en) | 1985-04-16 | 1986-04-16 | Nasal compositions containing vitamin b |
Country Status (5)
| Country | Link |
|---|---|
| KR (1) | KR870700363A (en) |
| CA (1) | CA1300014C (en) |
| DE (1) | DE3672430D1 (en) |
| DK (1) | DK603886A (en) |
| NO (1) | NO174182C (en) |
-
1986
- 1986-04-15 DE DE8686902732T patent/DE3672430D1/en not_active Expired - Lifetime
- 1986-04-16 CA CA000506799A patent/CA1300014C/en not_active Expired - Fee Related
- 1986-12-11 NO NO865010A patent/NO174182C/en not_active IP Right Cessation
- 1986-12-15 DK DK603886A patent/DK603886A/en not_active Application Discontinuation
- 1986-12-15 KR KR860700891A patent/KR870700363A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| DE3672430D1 (en) | 1990-08-09 |
| NO865010L (en) | 1986-12-11 |
| NO174182B (en) | 1993-12-20 |
| DK603886D0 (en) | 1986-12-15 |
| NO174182C (en) | 1994-03-30 |
| KR870700363A (en) | 1987-12-28 |
| DK603886A (en) | 1986-12-15 |
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