WO2008115605A1 - Clear bismuth treatments and methods for making - Google Patents

Clear bismuth treatments and methods for making Download PDF

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Publication number
WO2008115605A1
WO2008115605A1 PCT/US2008/003902 US2008003902W WO2008115605A1 WO 2008115605 A1 WO2008115605 A1 WO 2008115605A1 US 2008003902 W US2008003902 W US 2008003902W WO 2008115605 A1 WO2008115605 A1 WO 2008115605A1
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Prior art keywords
sodium tartrate
bismuth
solution
bismuth sodium
precipitate
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PCT/US2008/003902
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French (fr)
Inventor
Richard L. Watson
Rich Ronald
Daniel Earl
John Blount
Candice B. Luder
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Ibix
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Publication of WO2008115605A1 publication Critical patent/WO2008115605A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/245—Bismuth; Compounds thereof
    • 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
    • A61K9/08—Solutions

Definitions

  • Applicants' invention relates to methods of treating colic in equines, parvovirus in canines, and gastrointestinal infections in felines using a bismuth sodium tartrate solution.
  • the present invention relates to the preparation of colloidal solutions. More particularly, the invention relates to a method for the preparation of bismuth-containing solutions, most notably of a semitransparent colloidal solution of bismuth sodium tartrate with an extended, stable shelf life.
  • Colic in horses in horses is defined as abdominal pain, but it is a clinical sign or symptom rather than a diagnosis.
  • the term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. There are a variety of different causes of colic, some of which require surgical intervention and can prove fatal. Colic surgery is usually an expensive procedure as it is major abdominal surgery. Among domesticated horses, colic is a major cause of premature death. Therefore, a treatment is highly desirable. Thus, there is a need for a component and method for better treating equines that have contracted colic.
  • Parvovirus is a viral disease of, and carried by, dogs.
  • Adult dogs may be infected carriers without showing any clinical signs. Parvovirus may survive 9 months or longer in the environment when shed in a dog's fecal material. Once contracted, parvo generally takes 7-10 days from the time of exposure prior to the onset of observable symptoms and before a test for parvo will show positive. Parvo is highly contagious to unprotected dogs and can be introduced to a dog through a number of means of contact.
  • the intestinal lining has the biggest concentration of rapidly dividing cells in a canine's body, and these cells are extremely suitable to the parvovirus. The virus attacks and kills these cells, causing diarrhea (often bloody), depression and suppression of white blood cells.
  • Canines infected with parvo often die of dehydration. Therefore, treatment generally consists of IV or sub-cutaneous fluids and antibodies. However, traditionally there has been no cure for parvo. Veterinarians can only treat the symptoms, and try to keep the dog alive by preventing dehydration and loss of proteins. As there is no cure for any virus, treatment for parvo is mostly that of supporting the different systems in the body during the course of the disease. This includes giving fluids, regulating electrolyte levels, controlling body temperature and giving blood transfusions when necessary. Thus, there is a need for a component and method for better treating canines infected with the parvovirus.
  • Gastrointestinal infections are all too common occurrences in felines.
  • a cat that exhibits symptoms of gastrointestinal distress, such as vomiting or diarrhea, is both worrisome and an inconvenience for the pet owner.
  • Treatment for gastrointestinal infections is often ignored, and only attended to if the animal becomes quite ill.
  • elixir of bismuth is produced by diluting a quantity of glycerite of bismuth and adding further quantities of glycerin and aromatic elixirs as preservative agents.
  • the glycerite of bismuth as produced according to the 1936 National Formulary, generally comprises a milky colloidal solution of bismuth sodium tartrate. .
  • a method whereby bismuth sodium tartrate may be produced in a semitransparent colloidal solution, with an extended shelf life, has also previously been developed.
  • the present invention a method for preparation of a semitransparent colloidal solution of bismuth sodium tartrate— generally comprises the steps of producing an aqueous solution of bismuth sodium tartrate; extracting a magma (i.e., precipitate) of bismuth sodium tartrate from the aqueous solution at a pH of approximately 2.2; and then dissolving the magma into a salting-in mixture to form the semitransparent colloidal solution of bismuth sodium tartrate. It is important for certain aspects of the present invention that the magma be extracted at a pH of at least 2.2 but not more than 2.3.
  • the magma is extracted by washing with a wash liquor comprising an addition of distilled water; allowing the magma to settle out of the wash liquor; measuring the pH of the wash liquor after the magma has settled; and then decanting the wash liquor from the magma. This process is then repeated as necessary to arrive at a magma within the critical pH range, whereafter the magma is air dried in preparation for salting-in.
  • the salting-in solution is prepared by heating a quantity of distilled water; dissolving a quantity of sodium bicarbonate into the heated quantity of distilled water; and then mixing a quantity of tartaric acid with the solution of sodium bicarbonate and heated distilled water. In this manner, freezing of the salting-in solution is prevented, thereby ensuring a proper mixture.
  • the preferred method of the present invention further comprises the step of pasteurizing the semitransparent colloidal solution of bismuth sodium tartrate in order to eliminate the need for aromatic elixirs without compromise of product purity.
  • the pasteurizing step comprises raising the semitransparent colloidal solution of bismuth sodium tartrate to a temperature of approximately 54.5. degree. C; holding the solution at the pasteurization temperature for at least five but not more than eight minutes; and then returning the solution to ambient temperature.
  • the preferred method further includes adding preservative to the semitransparent colloidal solution of bismuth sodium tartrate.
  • the resulting semitransparent solution may then be tested for strength utilizing spectral methods.
  • this may comprise the steps of measuring a quantity of light transmitted through a sample of the semitransparent colloidal solution of bismuth sodium tartrate; converting the measured quantity of light to an indicium of the density of active ingredient present within the solution; and then calculating the per unit quantity of bismuth sodium tartrate present.
  • the resulting semitransparent solution may be tested for strength utilizing spectral methods such as atomic absorption spectroscopy. This may comprise the steps of atomizing the sample of the bismuth sodium tartrate solution, passing light of the frequency of bismuth through the resulting vapor; converting the measured quantity of light detected and absorbed after going through the vapor to an indicium of the density of active ingredient present within the solution; and then calculating the per unit quantity of bismuth sodium tartrate present.
  • spectral methods such as atomic absorption spectroscopy. This may comprise the steps of atomizing the sample of the bismuth sodium tartrate solution, passing light of the frequency of bismuth through the resulting vapor; converting the measured quantity of light detected and absorbed after going through the vapor to an indicium of the density of active ingredient present within the solution; and then calculating the per unit quantity of bismuth sodium tartrate present.
  • the preferred method of the present invention also comprises diluting the base solution to an elixir strength according to the tested strength of the base. It is critical, however, that the dilute elixir be buffered to a critical pH range in order to sustain prolonged shelf life without degradation of the semitransparent nature of the product.
  • sodium bicarbonate is added as need to the end product to achieve a final pH of about 7.2 to 7.3.
  • the resulting semitransparent solution may be used for the treatment of horses inflicted with colic, for the treatment of dogs infected with parvovirus, and for the treatment of cats with gastrointestinal infections. It should be noted that a semitransparent solution is not necessary.
  • the treatment is effected by the bismuth sodium tartrate solution, regardless of the preparatory method of the solution.
  • a milky solution prepared by traditional means may also be used.
  • the semitransparent bismuth sodium tartrate solution may be more easily administered to the equine, the canine and the feline.
  • FIGURE 1 shows, in flowchart, the first phase of manufacture according to the preferred method of the present invention of a semitransparent colloidal solution of bismuth sodium tartrate;
  • FIGURE 2 shows, in flowchart, the second phase of manufacture according to the preferred method of the present invention of a semitransparent colloidal solution of bismuth sodium tartrate;
  • FIGURE 3 shows, in flowchart, details of the production of an aqueous solution of bismuth sodium tartrate as implemented according to the steps of FIGURE 1;
  • FIGURE 4 shows, in flowchart, details of a step in the production of the aqueous solution described in FIGURE 3;
  • FIGURE 5 shows, in flowchart, details of the magma extraction process as implemented according to the steps of FIGURE 1;
  • FIGURE 6 shows, in flowchart, a preferred method for production of a salting-in solution utilized according to the steps of FIGURE 1;
  • FIGURE 7 shows, in flowchart, details of a pasteurization process as implemented according to the steps of FIGURE 1;
  • FIGURE 8 shows, in flowchart, details of one spectral strength test as implemented according to the step 17 of RGURE 1;
  • FIGURE 9 shows, in flowchart, details of the preferred spectral strength test as implemented according to the step 17 of FIGURE 1.
  • FIGURE 10 shows a particularly preferred variation of a method of making the glycerite of bismuth in schematic form.
  • a semitransparent colloidal solution of bismuth sodium tartrate is preferably formed in two distinct manufacturing processes— a process 10 for the preparation of a base comprising a glycerite of, as particularly shown in FIGURE 1, and, thereafter, a process 11 for the dilution of the base to an elixir of bismuth, as particularly shown in FIGURE 2.
  • a glycerite of bismuth is generally prepared by producing an aqueous solution of bismuth sodium tartrate, 12, extracting a magma of bismuth sodium tartrate from the aqueous solution, 13, and then dissolving the magma into a salting-in mixture, 14, to initially form the semitransparent colloidal solution of bismuth sodium tartrate.
  • the resultant base is then preferably pasteurized, 15, for reasons that will be better understood further herein, after which a preservative of at least glycerin may be added, 16.
  • the solution obtained according to the method 10 described herein is semitransparent, spectral techniques may be readily employed to safely test the base for strength, 17 after which it may be placed in bulk storage until such time as an elixir strength may be desired.
  • the base formula is diluted to elixir strength, 18, according to the tested strength of active ingredient, and then prepared for consumer packaging, 19, 20, and 21.
  • the process 10 for the preparation of the base comprising the glycerite of bismuth includes by weight:
  • the process 11 for the dilution of the base to the elixir of bismuth includes by weight:
  • the preferred method 12 for producing the aqueous solution of bismuth sodium tartrate from bismuth subnitrate— a known starting material for the active ingredient— is detailed.
  • the first step 22 8.16 kg of bismuth subnitrate is broken into solution in order that further chemical reactions may be effected.
  • this may be accomplished by mixing 7.24 liters of nitric acid with 11.35 liters of distilled water, 23, and dissolving the bismuth subnitrate therein, 24.
  • magma of bismuth sodium tartrate must be washed in order to raise its pH to a level safe for handling and fit for consumption
  • Applicant has discovered that extraction of the magma at a pH greater than 2.3 will result in eventual breakdown of the magma—clouding the semitransparent colloidal solution and in turn preventing the application of certain spectral techniques for strength testing, such as that described in FIGURE 8, and generally resulting in a less attractive product for human consumption.
  • FIGURE 5 the preferred method 13 for extracting the magma at the desired pH is detailed.
  • distilled water is added to the aqueous solution of bismuth sodium tartrate after which the solution is agitated to wash the magma, 29.
  • the magma is then allowed to settle, 30, at which time the pH of the wash liquor is tested, 31.
  • the wash liquor is then decanted from the magma, 32, and, so long as the pH remains below about 2.2, this process is repeated for the further elimination of the strong acid remaining therein.
  • the magma is over-washed, as indicated by a measured pH greater than 2.3, the batch must be aborted, 33, and the entire manufacturing process restarted.
  • the second wash/decant process is followed by adding and blending distilled water to the magma again; pouring this mixture onto a filter; and allowing it to drain from the magma.
  • Those of ordinary skill in the art will recognize many possible alternative techniques for removing the wash liquor from the magma. Such techniques may include placing the filter under vacuum and vacuuming all water from the magma. In any case, all such substantially equivalent methods for removing the wash liquor from the magma should be considered within the scope of the present invention.
  • the salting-in solution comprises a mixture of sodium bicarbonate USP and tartaric acid NF. Because the chemical reaction of sodium bicarbonate with tartaric acid causes a dramatic temperature drop, Applicant has found it desirable to preheat a sodium bicarbonate solution prior to the introduction thereto of the tartaric acid. In this manner, freezing of the solution is prevented and a complete and proper chemical reaction is ensured. In particular, Applicant has found success in raising 11.35 liters of distilled water to approximately 38degrees C in a fifteen-gallon stainless steel tank, 35.
  • the base solution may be pasteurized.
  • Applicant has introduced a pasteurization step 15 in the production process 10 of the base solution.
  • the preferred method for pasteurization 15 of the semitransparent colloidal solution comprises raising the temperature of the solution to approximately 54.5 degrees C, 38, holding the solution at the pasteurization temperature for at least five but not more than eight minutes, 39, and thereafter cooling the solution to ambient temperature, 40. After the solution is cooled, in one embodiment, 10.6 % by wt. of glycerin is added as a preservative, 16.
  • the preservative step 16 further comprises adding at least one additional preservative agent to the glycerite of bismuth.
  • Applicant has found success in evenly blending 4 % by wt. of potassium sorbate into the glycerite of bismuth.
  • the at least one additional preservative agent is added to the glycerite of bismuth during the dilution step 18 (process 11) instead of during the preservative step 16 (process 10).
  • all such substantially equivalent methods comprising addition of at least one additional preservative agent to the glycerite of bismuth should be considered within the scope of the present invention.
  • One particular benefit of producing bismuth sodium tartrate in a semitransparent colloidal solution is that such a solution is particularly adapted for strength testing by certain spectral methods.
  • One embodiment of the method 17 is described with reverence to FIGURE 8, although the preferred embodiment of the method 17 is described with reference to FIGURE 9.
  • such a spectral method may comprise the preparation of a dilute sample, 41, through which a light transmission is measured, 42.
  • the measured light transmission can then be converted to a density value based upon calibration tables for the particular spectral instrument being used, 43.
  • the resulting density value may then be used to calculate the strength of the active ingredient, 44— in the present case bismuth sodium tartrate, which strength may be used in the second phase, 11, of manufacture to effect an accurate dilution of the glycerite of bismuth to an elixir of bismuth.
  • the method 17 may comprise atomizing the sample of the base solution, 45; exciting the bismuth atoms by shining light at the wavelength for bismuth through the resulting vapor, 46; measuring the quantity of light detected and absorbed after going through the vapor, 47; and converting the measured quantity of light to an indicium of the density of active ingredient present within the solution, 48.
  • the resulting density value may then be used to calculate the strength of the active ingredient, 49— in the present case bismuth sodium tartrate, which strength may be used in the second phase, 11, of manufacture to effect an accurate dilution of the glycerite of bismuth to an elixir of bismuth.
  • FIGURE 10 a particularly preferred variation of a method of making glycerites of bismuth for use in the various larger embodiments of the present invention is shown in schematic form.
  • the method of FIGURE 10 comprises various compounding steps within tanks 70 and 80, the results of which are then combined in tank 90 to produce a glycerite of bismuth at output step 95.
  • Tank 70 is preferably a large compounding tank in which water, nitric acid and bismuth subnitrate are compounded, as indicated at imputes 71, 72, and 73, respectively.
  • the water added at input 71 is preferably 27.3 pound of deionized (D.I.) water.
  • D.I. deionized
  • the water is input at input 71, and 25 pounds of nitratic acid (70%) are slowly added in order to produce an acid/water mixture.
  • Twenty pounds of bismuth subnitrate are then added at input 73 and dissolved while blending until the material is fully dissolved. After blending, the resulting mixture is allowed to set for approximately 15 minutes with no agitation. The resulting mixture is then transferred into a transfer container to be later added into tank 90 as output 74 from tank 70.
  • the compounding to take place within tank 80 includes the dissolving of water at input 81 with tartaric acid at input 82 and, later, sodium bicarbonate at input 83 to produce a salting-in solution as output 91 from tank 80.
  • the particularly preferred processes for salting-in solution involves dissolving 15 pounds of tartaric acid in 63.7 pound of D.I. water, blending until completely dissolved.
  • the pre-blend output 74 from tank 70 is then added to the dilute tartaric acid in tank 80, and the resulting mixture is then stirred until a precipitate forms.
  • the sodium bicarbonate of input 83 is then added once the precipitate has formed in tank 80. Most preferably, the sodium bicarbonate is added slowly, in small portions with slow agitation, until 24 pounds has been added, taking care to avoid loss by effervescence.
  • the pH of the resulting mixture is then subjected to a washing process until pH of 2.3 is obtained.
  • the preferred washing process for adjusting the pH of the magma mixture involves repeated cycles of adding water and decanting off excess liquid. More particularly, it is preferred that each washing cycle involves the addition of thirty five pounds of D.I. water to the mixture, then allowing a magma to settle for 20 minutes before decanting. After decanting is accomplished by sucking any clear liquid (i.e., excluding the magma, which settles to the bottom) from the top of tank 80 using a pump or other means as appropriate. The process of adding 35 pounds of water to the mixture and allowing the magma to settle again for another 20 minutes is then repeated until the clear fluid being decanted has reached a pH of 2.3, after which another 35 pounds of D.I. water is added to the tank and blended on low agitation to produce the preferred magma mixture in a slurry.
  • each washing cycle involves the addition of thirty five pounds of D.I. water to the mixture, then allowing a magma to settle for 20 minutes before decanting. After decanting is accomplished by sucking
  • the magma slurry is then filtered and dried to produce a filter cake.
  • the filtering process can be performed using any desired technique, but preferred methods can involve slowly pouring the magma slurry through a Buchner funnel fitted with a filter much like a coffee filter (such as 25 cm filter paper available from Eaton, #615). This process may also be augmented with either positive or negative pressure to draw the slurry through the filter and thereafter dry the filter cake with ambient air. It is typical that this process is a time consuming process that is performed by adding small quantities to the Buchner funnel, waiting and continuing in a batch-like manner due to the amount of time required.
  • Alternative filtering techniques maybe achieved through use of centrifuges or other flow-through filters as will be evident to those of ordinary skill in the art.
  • the filter cake is then dissolved into a heated aqueous solution of sodium bicarbonate 87 and tartaric acid 88. More particularly, preferred techniques involve heating 79 pounds of USP water 86 in a jacketed stainless steel tank 85, slowly dissolving 17 pounds of sodium bicarbonate 87 to the heated water under slow agitation until a clear liquid forms, and then adding 15 pounds of tartaric acid 88 under slow agitation until the resulting solution no longer effervesces.
  • the filter cake produced in Buchner funnel 75 is added to produce a clear magma solution, which is then heated in jacketed tank 85 to 130 degrees Fahrenheit while slowly agitating, then covering the tank and allowing it to cool.
  • the buffered product then serves as a base glycerite of bismuth that can be tested using atomic absorption or other suitable techniques. Principal objectives of such testing are to determine the resulting bismuth content and/or other information to calculate the appropriate dilution required in order to obtain the desired amount of active ingredients in a finished product.
  • the glycerite of bismuth be diluted to elixir strength when finally packaged for distribution to consumers.
  • the dilution is effected, as known to those of ordinary skill in the art, in order to obtain the specified dosage of active ingredient by volume according to the tested strength of the base, 18.
  • Applicant has found success in diluting the glycerite of bismuth using a 1:8 ratio, wherein 47.31 liters of glycerite of bismuth is uniformly blended with 47.31 liters of glycerin and USP distilled water to 100 gallons.
  • the base solution is not placed in bulk storage for 48 hours or more prior to dilution to elixir strength, 0.5% by wt. of potassium sorbate is added to the glycerite of bismuth during the dilution step 18 (instead of during the preservative step 16). Coloring and/or flavoring agents may then be added as desired, 19.
  • the solution is then filtered in accordance with good manufacturing practices to ensure elimination of any foreign object as may have been introduced in the manufacture or storage of the base solution, 20.
  • Treatment of the affected equine, canine, or feline is effected by administration of the bismuth sodium tartrate solution.
  • Administration may be oral, via injection, or via other known means. While doseages may be adjusted, it has been found that a range of 0.5 mL to 4 ml_ per 10 pounds of horse, dog, or cat is effective.
  • the frequency of the administrations can also be varied per the severity of the infection and sickness of the animal, as well as the response to treatment.
  • the solution of this invention is effective as a method of treating the colic affected equine, of treating the parvo infected canine and treating the gastrointestinally infected feline.
  • references to "minor species” are understood to generally refer to any species other than other than dogs, cats, horses, cattle, swine, chickens and turkeys, including those that are kept as household pets, those kept for display and educational purposes in zoos and public aquariums, and those that are raised commercially as food or for recreational fishing, including but not limited to, sheep, goats, game birds, emu, ranched deer, elk, rabbits, hamsters, ferrets, and cavies (e.g. guinea pigs), lizards, tortoises, caged birds, and free- ranging wildlife.
  • the at least one preservative agent (FIGURE 1) useful in embodiments of the present invention may vary widely, including, but not limited to, potassium sorbate, sodium benzoate 7 and salicylic acid.
  • exemplary preservative agents such as potassium sorbate
  • some preservative agents may be desirable for use in formulations for human consumption, while being unacceptable for animal consumption, and vice versa.
  • sodium benzoate may be useful as a preservative agent in formulations for human consumption, yet contraindicated for use in formulations for certain animals, such as felines.
  • preservative agents may be desirable and/or undesirable in formulations for human and/or animal consumption and employ them accordingly without undue experimentation.
  • the products of the present invention may be utilized for the treatment of a variety of conditions in humans. Applicant has found success in treating various maladies of the gastrointestinal tract, including upset stomach, acid indigestion, and heartburn, using an over the counter dosage of 7.5 ml, twice in a 24 hour period for adults, and .5 ml, twice in a 24 hour period for children, each with a strength of 16.25 mg/ml bismuth sodium tartrate.
  • the prescriptive strength for adults may be a multiple of the over the counter strength for adults, and the prescriptive dosage for children may be based on body mass.
  • bismuth sodium tartrate may be beneficial for treating indigestion, nausea and diarrhea, as well as oral ulcers, including but not limited to oral ulcerative mucositis caused by the toxicity of drug and radiation therapy for cancer, cold sores on the lips and face caused by herpes simplex, and aphthous ulcers.
  • bismuth subsalicylate is useful in treating gastric disorders such as colitis, diarrhea, and peptic ulcers.
  • Bismuth compounds are used in burn bandage dressings, antiseptic powders, salves and ointments, and in the treatment of venereal diseases.
  • Bismuth-compound pre-treatment reduces the renal and lethal toxicity of several forms of chemotherapy and may help combat AIDS.
  • bismuth compounds alleviate diaper rash.
  • Bismuth-based antiseptic powders, ointments and burn bandages help heal wounds and remove warts. Will, Rich gave me this info as possible ideas to further coverage. I am not sure how to use it, or if it can be used as novel. Possibly in the alternative embodiments 3 paragraphs down? Doubt it, so didn't do it.
  • the products of the present invention may also be utilized for the treatment of a variety of conditions in major and minor species of animals.
  • animals including, but not limited to, dogs, cats, horses, and ferrets
  • Applicant has found success in providing diarrhea relief using a preferred over the counter dosage of 1 cc per 10 lbs. of animal weight, and a preferred prescriptive dosage of 1 cc per 20 lbs. of animal weight.
  • Anecdotal evidence suggests bismuth sodium tartrate may be beneficial in treating parvovirus.
  • Bismuth sodium tartrate may reduce the death rate in parvovirus by limiting the effect of parvovirus on the intestines.
  • bismuth sodium tartrate may effectively eliminate the symptoms of vomiting, diarrhea and electrolyte imbalance brought on by parvovirus.
  • compositions for administration of bismuth sodium tartrate are contemplated, including but not limited to those suitable for oral, rectal, topical, buccal, and transdermal administration.
  • the formulations are prepared by uniformly admixing the active ingredient with liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture.
  • the carrier must, of course, be acceptable in the sense of being compatible with the bismuth sodium tartrate and any other ingredients in the formulation and must not be harmful to the patient.
  • the carrier is preferably formulated with the active ingredient as a unit-dose formulation, for example, a tablet, which may contain from 0.1% to 99% by weight of the active ingredient.
  • Formulations suitable for oral administration include, but are not limited to, solution, powder or granules, and in discrete units, including but not limited to, capsules, cachets, lozenges, tablets, and dissolvable strips, each containing a predetermined amount of the active ingredient.
  • Formulations suitable for buccal administration are preferably presented as unit dose lozenges.
  • Formulations suitable for rectal administration are preferably presented as unit dose suppositories.
  • Formulations suitable for topical application to the skin include, but are not limited to, ointment, cream, lotion, paste, gel, spray, aerosol, or oil.
  • Carriers, which may be used include, but are not limited to, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
  • Formulations suitable for transdermal administration may also be presented as medicated bandages or discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • one or more active ingredient, active compound, therapeutic agent, prophylactic agent, or drug may be combined with the bismuth sodium tartrate solution, including but not limited to, chemical elements, elemental molecules, complex molecules, antimicrobial agents, H2 blockers, and proton pump inhibitors.
  • Antimicrobial agents include, but are not limited to, antibacterial agents, such as antibiotic and bacteriostatic agents, antiviral agents and antifungal agents.
  • Prophylactic agents include, but are not limited to, anti- inflammatory agents, such as aspirin, acetaminophen or ibuprofen, salicylic acid, salicyloyl salicylic acid, and salicylamide.
  • companion therapy medications administered two or more times every 24 hours may effectively treat Helicobacter pylori infections, thereby eliminating the negative symptoms associated with conditions including, but not limited to, Gastro Esophageal Reflux Disorder (GERD), hiatal hernias, upset stomach, and heartburn.
  • Such companion therapy medications include, but are not limited to, an antibiotic such as penicillin or clarithromycin, and a proton pump inhibitor such as omeprazole or an H2 blocker, and a formulation comprising bismuth sodium tartrate solution.
  • One alternative embodiment described herein includes consolidation of the companion therapy medications including the formulation comprising bismuth, thereby reducing to one, the number of medications administered two or more times every 24 hours.
  • strength of the single medication may be formulated for administration of the preferred daily dosage in a single dose per 24 hours.
  • Another alternative embodiment contemplated herein includes consolidation of the antibiotic, proton pump inhibitor or H2 blocker, and the formulation comprising bismuth, into the single medication administered two or more times every 24 hours.
  • Yet another alternative embodiment includes consolidation of the antibiotic, proton pump inhibitor or H2 blocker, and the bismuth formulation, into the single medication formulated for administration of the preferred daily dosage in a single dose per 24 hours.
  • one of several spectral methods 17 may be employed in determining the density value of the active ingredient in the base solution, including but not limited to, the light transmission method described in FIGURE 8, atomic absorption spectroscopy using flame ionization, as described in FIGURE 9, atomic emission spectroscopy, plasma emission spectroscopy, ultraviolet spectroscopy, and infrared spectroscopy.
  • At least one embodiment of the bismuth sodium tartrate described herein may be formed in one single manufacturing process comprising the steps described with reference to FIGURES 1 and 2.

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Abstract

Applicants' invention relates to methods of making and using a bismuth sodium tartrate solution for treating parvovirus, colic and other gastro-intestinal disorders, involving the preparation of a clear pharmaceutical bismuth solution through careful processing and the use of a salting-in process to obtain the resulting solution, starting with an aqueous solution of bismuth sodium tartrate, extracting a highly acidic precipitate of bismuth sodium tartrate from the aqueous solution, dissolving the precipitate into a salting-in mixture to form a transparent or semitransparent colloidal solution of bismuth sodium tartrate; adding a preservative and diluting it appropriately to produce a safe and effective, orally-administered liquid bismuth pharmaceutical that is clear in appearance and texture.

Description

CLEAR BISMUTH TREATMENTS AND METHODS FOR MAKING
RELATED APPLICATION [0001] The subject matter of the present application is related to, and this application claims priority to U.S. Patent Numbers 6,482,865, 6,699,912, and 6,743,827, dated November 19, 2002, March 2, 2004, and June 1, 2004, respectively, as well as to U.S. Patent Application, Serial Number 10/832,084 filed on April 26, 2004. The disclosures of each of said patents and said application are incorporated herein by reference, as though set forth in their entirety. Despite such a priority claim, subsequent related filings may omit or disclaim such priority if and as appropriate, depending largely on the scope of the subject matter claimed therein.
FIELD OF THE INVENTION [0002] Applicants' invention relates to methods of treating colic in equines, parvovirus in canines, and gastrointestinal infections in felines using a bismuth sodium tartrate solution.
[0003] The present invention relates to the preparation of colloidal solutions. More particularly, the invention relates to a method for the preparation of bismuth-containing solutions, most notably of a semitransparent colloidal solution of bismuth sodium tartrate with an extended, stable shelf life.
BACKGROUND OF THE INVENTION [0004] Colic in horses in horses is defined as abdominal pain, but it is a clinical sign or symptom rather than a diagnosis. The term colic can encompass all forms of gastrointestinal conditions which cause pain as well as other causes of abdominal pain not involving the gastrointestinal tract. There are a variety of different causes of colic, some of which require surgical intervention and can prove fatal. Colic surgery is usually an expensive procedure as it is major abdominal surgery. Among domesticated horses, colic is a major cause of premature death. Therefore, a treatment is highly desirable. Thus, there is a need for a component and method for better treating equines that have contracted colic.
[0005] Parvovirus is a viral disease of, and carried by, dogs. Adult dogs may be infected carriers without showing any clinical signs. Parvovirus may survive 9 months or longer in the environment when shed in a dog's fecal material. Once contracted, parvo generally takes 7-10 days from the time of exposure prior to the onset of observable symptoms and before a test for parvo will show positive. Parvo is highly contagious to unprotected dogs and can be introduced to a dog through a number of means of contact. The intestinal lining has the biggest concentration of rapidly dividing cells in a canine's body, and these cells are extremely suitable to the parvovirus. The virus attacks and kills these cells, causing diarrhea (often bloody), depression and suppression of white blood cells. Canines infected with parvo often die of dehydration. Therefore, treatment generally consists of IV or sub-cutaneous fluids and antibodies. However, traditionally there has been no cure for parvo. Veterinarians can only treat the symptoms, and try to keep the dog alive by preventing dehydration and loss of proteins. As there is no cure for any virus, treatment for parvo is mostly that of supporting the different systems in the body during the course of the disease. This includes giving fluids, regulating electrolyte levels, controlling body temperature and giving blood transfusions when necessary. Thus, there is a need for a component and method for better treating canines infected with the parvovirus.
[0006] Gastrointestinal infections are all too common occurrences in felines. A cat that exhibits symptoms of gastrointestinal distress, such as vomiting or diarrhea, is both worrisome and an inconvenience for the pet owner. Treatment for gastrointestinal infections is often ignored, and only attended to if the animal becomes quite ill.
[0007] Elixir of bismuth has been known at least since the 1936
National Formulary for treatment of various maladies of the human gastrointestinal tract, including acid indigestion. According to the 1936 National Formulary, elixir of bismuth is produced by diluting a quantity of glycerite of bismuth and adding further quantities of glycerin and aromatic elixirs as preservative agents. The glycerite of bismuth, as produced according to the 1936 National Formulary, generally comprises a milky colloidal solution of bismuth sodium tartrate. . A method whereby bismuth sodium tartrate may be produced in a semitransparent colloidal solution, with an extended shelf life, has also previously been developed.
[0008] However, use of any type of bismuth sodium tartrate solution for treatment of colic in equines, parvovirus in canines, or gastrointestinal infections in felines has not been suggested, and this is a new application for preparing solutions to treat such ailments.
[0009] Unfortunately, the National Formulary has failed to provide an accurate method for testing the strength of the glycerite of bismuth and has also failed to suggest methodologies for elimination of aromatic elixirs. As a result, the elixir of bismuth has to date been difficult and unnecessarily expensive to produce in desired strength.
[0010] It is therefore an overriding object of the present invention to improve over the methods of the prior art by presenting a method whereby bismuth sodium tartrate may be produced in a semitransparent colloidal solution, which solution may be accurately and safely tested for strength of active ingredient. It is a further object of the present invention to present such a method wherein the resulting elixir may be expected to have an extended shelf life. Finally, it is yet another object of the present invention to present such a method wherein regulated ingredients, such as aromatic elixirs, may be eliminated from the formula without compromise of product integrity.
SUMMARY OF THE INVENTION
[0011] In accordance with the foregoing objects, the present invention— a method for preparation of a semitransparent colloidal solution of bismuth sodium tartrate— generally comprises the steps of producing an aqueous solution of bismuth sodium tartrate; extracting a magma (i.e., precipitate) of bismuth sodium tartrate from the aqueous solution at a pH of approximately 2.2; and then dissolving the magma into a salting-in mixture to form the semitransparent colloidal solution of bismuth sodium tartrate. It is important for certain aspects of the present invention that the magma be extracted at a pH of at least 2.2 but not more than 2.3. As a result, in the preferred method of the present invention, the magma is extracted by washing with a wash liquor comprising an addition of distilled water; allowing the magma to settle out of the wash liquor; measuring the pH of the wash liquor after the magma has settled; and then decanting the wash liquor from the magma. This process is then repeated as necessary to arrive at a magma within the critical pH range, whereafter the magma is air dried in preparation for salting-in.
[0012] In the preferred method of the present invention, the salting-in solution is prepared by heating a quantity of distilled water; dissolving a quantity of sodium bicarbonate into the heated quantity of distilled water; and then mixing a quantity of tartaric acid with the solution of sodium bicarbonate and heated distilled water. In this manner, freezing of the salting-in solution is prevented, thereby ensuring a proper mixture.
[0013] The preferred method of the present invention further comprises the step of pasteurizing the semitransparent colloidal solution of bismuth sodium tartrate in order to eliminate the need for aromatic elixirs without compromise of product purity. In order to prevent damage to the active ingredient, however, the pasteurizing step comprises raising the semitransparent colloidal solution of bismuth sodium tartrate to a temperature of approximately 54.5. degree. C; holding the solution at the pasteurization temperature for at least five but not more than eight minutes; and then returning the solution to ambient temperature. Following pasteurization, the preferred method further includes adding preservative to the semitransparent colloidal solution of bismuth sodium tartrate. [0014] The resulting semitransparent solution may then be tested for strength utilizing spectral methods. In at least one implementation of the present invention, this may comprise the steps of measuring a quantity of light transmitted through a sample of the semitransparent colloidal solution of bismuth sodium tartrate; converting the measured quantity of light to an indicium of the density of active ingredient present within the solution; and then calculating the per unit quantity of bismuth sodium tartrate present.
[0015] In a preferred implementation, the resulting semitransparent solution may be tested for strength utilizing spectral methods such as atomic absorption spectroscopy. This may comprise the steps of atomizing the sample of the bismuth sodium tartrate solution, passing light of the frequency of bismuth through the resulting vapor; converting the measured quantity of light detected and absorbed after going through the vapor to an indicium of the density of active ingredient present within the solution; and then calculating the per unit quantity of bismuth sodium tartrate present.
[0016] The preferred method of the present invention also comprises diluting the base solution to an elixir strength according to the tested strength of the base. It is critical, however, that the dilute elixir be buffered to a critical pH range in order to sustain prolonged shelf life without degradation of the semitransparent nature of the product. In particular, sodium bicarbonate is added as need to the end product to achieve a final pH of about 7.2 to 7.3.
[0017] The resulting semitransparent solution may be used for the treatment of horses inflicted with colic, for the treatment of dogs infected with parvovirus, and for the treatment of cats with gastrointestinal infections. It should be noted that a semitransparent solution is not necessary. The treatment is effected by the bismuth sodium tartrate solution, regardless of the preparatory method of the solution. A milky solution prepared by traditional means may also be used. However, the semitransparent bismuth sodium tartrate solution may be more easily administered to the equine, the canine and the feline.
[0018] The inventors have discovered that by making and orally administering solutions of this invention to patients, one can effectively treat a horse for colic, a dog infected with parvovirus, and a feline with a gastrointestinal infection, and that this invention helps minimize dehydration due to gastrointestinal disorders, including gastrointestinal disorders secondary to malaria.
[0019] Finally, many other features, objects and advantages of the present invention will be apparent to those of ordinary skill in the relevant arts, especially in light of the foregoing discussions and the following drawings, exemplary detailed description and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS [0020] Although the scope of the present invention is much broader than any particular embodiment, a detailed description of the preferred embodiment follows together with illustrative figures, wherein like reference numerals refer to like components, and wherein:
[0021] FIGURE 1 shows, in flowchart, the first phase of manufacture according to the preferred method of the present invention of a semitransparent colloidal solution of bismuth sodium tartrate;
[0022] FIGURE 2 shows, in flowchart, the second phase of manufacture according to the preferred method of the present invention of a semitransparent colloidal solution of bismuth sodium tartrate;
[0023] FIGURE 3 shows, in flowchart, details of the production of an aqueous solution of bismuth sodium tartrate as implemented according to the steps of FIGURE 1; [0024] FIGURE 4 shows, in flowchart, details of a step in the production of the aqueous solution described in FIGURE 3;
[0025] FIGURE 5 shows, in flowchart, details of the magma extraction process as implemented according to the steps of FIGURE 1;
[0026] FIGURE 6 shows, in flowchart, a preferred method for production of a salting-in solution utilized according to the steps of FIGURE 1;
[0027] FIGURE 7 shows, in flowchart, details of a pasteurization process as implemented according to the steps of FIGURE 1;
[0028] FIGURE 8 shows, in flowchart, details of one spectral strength test as implemented according to the step 17 of RGURE 1; and
[0029] FIGURE 9 shows, in flowchart, details of the preferred spectral strength test as implemented according to the step 17 of FIGURE 1.
[0030] FIGURE 10 shows a particularly preferred variation of a method of making the glycerite of bismuth in schematic form.
[0031] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0032] Although those of ordinary skill in the art will readily recognize many alternative embodiments, especially in light of the illustrations provided herein, this detailed description is exemplary of the preferred embodiment of the present invention, the scope of which is limited only by the claims appended hereto.
[0033] As shown in the accompanying FIGURES, a semitransparent colloidal solution of bismuth sodium tartrate is preferably formed in two distinct manufacturing processes— a process 10 for the preparation of a base comprising a glycerite of, as particularly shown in FIGURE 1, and, thereafter, a process 11 for the dilution of the base to an elixir of bismuth, as particularly shown in FIGURE 2. In the first phase 10 of manufacture, a glycerite of bismuth is generally prepared by producing an aqueous solution of bismuth sodium tartrate, 12, extracting a magma of bismuth sodium tartrate from the aqueous solution, 13, and then dissolving the magma into a salting-in mixture, 14, to initially form the semitransparent colloidal solution of bismuth sodium tartrate. The resultant base is then preferably pasteurized, 15, for reasons that will be better understood further herein, after which a preservative of at least glycerin may be added, 16. Because the solution obtained according to the method 10 described herein is semitransparent, spectral techniques may be readily employed to safely test the base for strength, 17 after which it may be placed in bulk storage until such time as an elixir strength may be desired. In the second phase 11 of manufacture, the base formula is diluted to elixir strength, 18, according to the tested strength of active ingredient, and then prepared for consumer packaging, 19, 20, and 21.
[0034] The process 10 for the preparation of the base comprising the glycerite of bismuth includes by weight:
[0035] (a) 5.0% of nitric acid; [0036] (b) 63.7 % of distilled water;
[0037] (c) 4.0 % of bismuth subnitrate;
[0038] (d) 5.2 % of tartaric acid;
[0039] (e) 7.5 % of sodium bicarbonate;
[0040] (f) 10.6 % of glycerin; and
[0041] (g) 4.0 % of potassium sorbate (if potassium sorbate is added in step 16 of process 10, rather than step 18 in process 11).
[0042] The process 11 for the dilution of the base to the elixir of bismuth includes by weight:
[0043] (a) 12.50 % of glycerin;
[0044] (b) 72.57 % of distilled water;
[0045] (c) 0.50 % of potassium sorbate (if potassium sorbate is added in step 18 of process 11, rather than step 16 in process 10)
[0046] (d) 0.01 % of coloring agent;
[0047] (e) 0.12 % of flavoring agent; and
[0048] (f) 1.80 % of sodium bicarbonate.
[0049] Although those of ordinary skill in the art will recognize the adjustments necessary to produce other quantities of solutions, especially in light of this exemplary description, the following description specifies the quantities necessary for production of approximately 12 gallons of a base of glycerite of bismuth with a strength of 130 mg/ml bismuth sodium tartrate. As will be apparent to those of ordinary skill in the art, this quantity is sufficient to yield approximately 100 gallons elixir of bismuth with a strength of 16.25 mg/ml bismuth sodium tartrate. Although those of ordinary skill in the art will also recognize that the relative quantities of active and/or reactive ingredients are critical to the successful conduct of the present invention, the absolute values are of course typically not critical.
[0050] Referring now to FIGURE 3, the preferred method 12 for producing the aqueous solution of bismuth sodium tartrate from bismuth subnitrate— a known starting material for the active ingredient— is detailed. In the first step 22, 8.16 kg of bismuth subnitrate is broken into solution in order that further chemical reactions may be effected. As known to those of ordinary skill in the art, and as detailed in FIGURE 4, this may be accomplished by mixing 7.24 liters of nitric acid with 11.35 liters of distilled water, 23, and dissolving the bismuth subnitrate therein, 24. After a standing period of approximately 15 minutes to allow operation of the acidic solution on the bismuth subnitrate, 25, a further quantity of 26.5 liters of distilled water is added to dilute the volatile solution to a more safely manageable mixture, 26. At this point, the solution is agitated to ensure complete breakdown of the bismuth subnitrate, 26. Referring now again to FIGURE 3, the broken down solution of bismuth subnitrate is then reacted with 6.13 kg of tartaric acid NF to form bismuth tartrate, 27. Finally, 9.75 kg of sodium bicarbonate USP is added, in small quantities to prevent violent reaction, to the solution of bismuth tartrate to form the desired aqueous solution of bismuth sodium tartrate, 28. Although the foregoing method is the recognized standard procedure for preparation of bismuth sodium tartrate in an aqueous solution, those of ordinary skill in the art will recognize many possible alternatives. For example, it may be possible to break down the bismuth subnitrate with acids other than the very powerful nitric acid. In any case, all such substantially equivalent methods should be considered within the scope of the present invention. [0051] In the next steps of manufacture, as shown in FIGURE 1, a magma of bismuth sodium tartrate is extracted from the aqueous solution, 13, and then dissolved into a salting-in solution to initially form a colloidal solution of bismuth sodium tartrate, 14. Although it is known that the magma of bismuth sodium tartrate must be washed in order to raise its pH to a level safe for handling and fit for consumption, it is critical to the present invention that the magma of bismuth sodium tartrate be extracted from the aqueous solution at a pH of approximately 2.2 but not greater than approximately 2.3 in order for the magma to remain soluble. Applicant has discovered that extraction of the magma at a pH greater than 2.3 will result in eventual breakdown of the magma—clouding the semitransparent colloidal solution and in turn preventing the application of certain spectral techniques for strength testing, such as that described in FIGURE 8, and generally resulting in a less attractive product for human consumption.
[0052] Referring now to FIGURE 5, the preferred method 13 for extracting the magma at the desired pH is detailed. As shown in the Figure, distilled water is added to the aqueous solution of bismuth sodium tartrate after which the solution is agitated to wash the magma, 29. The magma is then allowed to settle, 30, at which time the pH of the wash liquor is tested, 31. The wash liquor is then decanted from the magma, 32, and, so long as the pH remains below about 2.2, this process is repeated for the further elimination of the strong acid remaining therein. In the event the magma is over-washed, as indicated by a measured pH greater than 2.3, the batch must be aborted, 33, and the entire manufacturing process restarted. As a consequence, in order to ensure no product loss, those of ordinary skill in the art will recognize the necessity for strict process control during this phase, including careful adjustment of the quantity of distilled water added to the wash. Finally, once the desired pH of between about 2.2 and about 2.3 is obtained, the properly extracted magma is drained and allowed to dry in preparation for salting-in, 34. In particular, Applicant has found success in adding distilled water to the aqueous solution of bismuth sodium tartrate, agitating to wash the magma, allowing the magma to settle, decanting the wash liquor from the magma, then repeating the wash/decant process. The second wash/decant process is followed by adding and blending distilled water to the magma again; pouring this mixture onto a filter; and allowing it to drain from the magma. Those of ordinary skill in the art will recognize many possible alternative techniques for removing the wash liquor from the magma. Such techniques may include placing the filter under vacuum and vacuuming all water from the magma. In any case, all such substantially equivalent methods for removing the wash liquor from the magma should be considered within the scope of the present invention.
[0053] As shown in FIGURE 6, the salting-in solution comprises a mixture of sodium bicarbonate USP and tartaric acid NF. Because the chemical reaction of sodium bicarbonate with tartaric acid causes a dramatic temperature drop, Applicant has found it desirable to preheat a sodium bicarbonate solution prior to the introduction thereto of the tartaric acid. In this manner, freezing of the solution is prevented and a complete and proper chemical reaction is ensured. In particular, Applicant has found success in raising 11.35 liters of distilled water to approximately 38degrees C in a fifteen-gallon stainless steel tank, 35. Upon reaching this temperature, 5.44 kg of sodium bicarbonate USP is mixed with the water until completely dissolved, 36, whereafter 4.64 kg of tartaric acid NF is added, 37, thereby effecting a clear salting-in solution. The dry or slightly moist magma of bismuth sodium tartrate may then be dissolved into the properly reacted salting-in solution, 14. Provided that the magma was extracted at the specified pH and that a properly proportioned salting-in solution has been effected, the magma will completely dissolve into the salting-in solution to form a substantially clear, yellowish colloidal solution of bismuth sodium tartrate.
[0054] Because Applicant has found that it is desirable to eliminate aromatic elixirs high in alcohol content in order to reduce government regulation as well as to provide a more palatable and less likely contraindicated product for human consumption or for equine, canine or feline administration, the base solution may be pasteurized., Applicant has introduced a pasteurization step 15 in the production process 10 of the base solution. As a result, the cost of production is dramatically reduced through the elimination of regulatory reporting as well as the ability to use less than chemically pure tartaric acid. Applicant has found, however, that the pasteurization must be carefully effected in order to ensure purification of the tartaric acid— particularly the killing of any yeast contaminant— without damage to the end product as may result from cooking of the sodium bicarbonate. As shown in FIGURE 7, the preferred method for pasteurization 15 of the semitransparent colloidal solution comprises raising the temperature of the solution to approximately 54.5 degrees C, 38, holding the solution at the pasteurization temperature for at least five but not more than eight minutes, 39, and thereafter cooling the solution to ambient temperature, 40. After the solution is cooled, in one embodiment, 10.6 % by wt. of glycerin is added as a preservative, 16.
[0055] Applicant has found that it is desirable for the base solution to possess a shelf life of at least 2 years. In preferred embodiments wherein the glycerite of bismuth may be placed in bulk storage for 48 hours or more prior to dilution to elixir strength, the preservative step 16 further comprises adding at least one additional preservative agent to the glycerite of bismuth. In particular, Applicant has found success in evenly blending 4 % by wt. of potassium sorbate into the glycerite of bismuth. However, as discussed with reference to FIGURE 2, for preferred embodiments wherein the base solution is not placed in bulk storage for 48 hours or more prior to dilution to elixir strength, the at least one additional preservative agent is added to the glycerite of bismuth during the dilution step 18 (process 11) instead of during the preservative step 16 (process 10). In any case, all such substantially equivalent methods comprising addition of at least one additional preservative agent to the glycerite of bismuth should be considered within the scope of the present invention.
[0056] One particular benefit of producing bismuth sodium tartrate in a semitransparent colloidal solution is that such a solution is particularly adapted for strength testing by certain spectral methods. One embodiment of the method 17 is described with reverence to FIGURE 8, although the preferred embodiment of the method 17 is described with reference to FIGURE 9. As described in FIGURE 8, such a spectral method may comprise the preparation of a dilute sample, 41, through which a light transmission is measured, 42. As is known to those of ordinary skill in the art, the measured light transmission can then be converted to a density value based upon calibration tables for the particular spectral instrument being used, 43. The resulting density value may then be used to calculate the strength of the active ingredient, 44— in the present case bismuth sodium tartrate, which strength may be used in the second phase, 11, of manufacture to effect an accurate dilution of the glycerite of bismuth to an elixir of bismuth.
[0057] In the preferred embodiment, Applicant has found it desirable to utilize spectral methods for strength testing that have proven to be faster and more accurate than the light transmission method described with reference to FIGURE 8. In particular, Applicant has found success in performing atomic absorption spectroscopy using flame ionization to test for strength, 17. As described in FIGURE 9, the method 17 may comprise atomizing the sample of the base solution, 45; exciting the bismuth atoms by shining light at the wavelength for bismuth through the resulting vapor, 46; measuring the quantity of light detected and absorbed after going through the vapor, 47; and converting the measured quantity of light to an indicium of the density of active ingredient present within the solution, 48. The resulting density value may then be used to calculate the strength of the active ingredient, 49— in the present case bismuth sodium tartrate, which strength may be used in the second phase, 11, of manufacture to effect an accurate dilution of the glycerite of bismuth to an elixir of bismuth.
[0058] With reference to FIGURE 10, a particularly preferred variation of a method of making glycerites of bismuth for use in the various larger embodiments of the present invention is shown in schematic form. Particularly, the method of FIGURE 10 comprises various compounding steps within tanks 70 and 80, the results of which are then combined in tank 90 to produce a glycerite of bismuth at output step 95.
[0059] Tank 70 is preferably a large compounding tank in which water, nitric acid and bismuth subnitrate are compounded, as indicated at imputes 71, 72, and 73, respectively. The water added at input 71 is preferably 27.3 pound of deionized (D.I.) water. In the first phase of compounding the water is input at input 71, and 25 pounds of nitratic acid (70%) are slowly added in order to produce an acid/water mixture.. Twenty pounds of bismuth subnitrate are then added at input 73 and dissolved while blending until the material is fully dissolved. After blending, the resulting mixture is allowed to set for approximately 15 minutes with no agitation. The resulting mixture is then transferred into a transfer container to be later added into tank 90 as output 74 from tank 70.
[0060] The compounding to take place within tank 80 (which may be the same as other tanks in the process, assuming it is adequately rinsed between phases), includes the dissolving of water at input 81 with tartaric acid at input 82 and, later, sodium bicarbonate at input 83 to produce a salting-in solution as output 91 from tank 80. The particularly preferred processes for salting-in solution involves dissolving 15 pounds of tartaric acid in 63.7 pound of D.I. water, blending until completely dissolved.
[0061] The pre-blend output 74 from tank 70 is then added to the dilute tartaric acid in tank 80, and the resulting mixture is then stirred until a precipitate forms. The sodium bicarbonate of input 83 is then added once the precipitate has formed in tank 80. Most preferably, the sodium bicarbonate is added slowly, in small portions with slow agitation, until 24 pounds has been added, taking care to avoid loss by effervescence. The pH of the resulting mixture is then subjected to a washing process until pH of 2.3 is obtained.
[0062] The preferred washing process for adjusting the pH of the magma mixture involves repeated cycles of adding water and decanting off excess liquid. More particularly, it is preferred that each washing cycle involves the addition of thirty five pounds of D.I. water to the mixture, then allowing a magma to settle for 20 minutes before decanting. After decanting is accomplished by sucking any clear liquid (i.e., excluding the magma, which settles to the bottom) from the top of tank 80 using a pump or other means as appropriate. The process of adding 35 pounds of water to the mixture and allowing the magma to settle again for another 20 minutes is then repeated until the clear fluid being decanted has reached a pH of 2.3, after which another 35 pounds of D.I. water is added to the tank and blended on low agitation to produce the preferred magma mixture in a slurry.
[0063] The magma slurry is then filtered and dried to produce a filter cake. The filtering process can be performed using any desired technique, but preferred methods can involve slowly pouring the magma slurry through a Buchner funnel fitted with a filter much like a coffee filter (such as 25 cm filter paper available from Eaton, #615). This process may also be augmented with either positive or negative pressure to draw the slurry through the filter and thereafter dry the filter cake with ambient air. It is typical that this process is a time consuming process that is performed by adding small quantities to the Buchner funnel, waiting and continuing in a batch-like manner due to the amount of time required. Alternative filtering techniques maybe achieved through use of centrifuges or other flow-through filters as will be evident to those of ordinary skill in the art. [0064] Once the filter cake has been prepared, it is then dissolved into a heated aqueous solution of sodium bicarbonate 87 and tartaric acid 88. More particularly, preferred techniques involve heating 79 pounds of USP water 86 in a jacketed stainless steel tank 85, slowly dissolving 17 pounds of sodium bicarbonate 87 to the heated water under slow agitation until a clear liquid forms, and then adding 15 pounds of tartaric acid 88 under slow agitation until the resulting solution no longer effervesces. While slowly agitating the resulting sodium tartrate mixture, the filter cake produced in Buchner funnel 75 is added to produce a clear magma solution, which is then heated in jacketed tank 85 to 130 degrees Fahrenheit while slowly agitating, then covering the tank and allowing it to cool.
[0065] Once the resulting clear magma solution in tank 85 is cooled to ambient temperature the solution is then filtered through Buchner funnel 96 to collect in tank 90, in which glycerin (preferably about 162 pounds) is added while slowly agitating. Twelve pounds of USP water is then added and slowly agitated for approximately 15 minutes to produce a base bismuth sodium tartrate material, at output 95, for further processing. Such further processing preferably includes pasteurization, the addition of preservatives (preferably potassium sorbate), and buffering with sodium bicarbonate to a pH of 7.2 to 7.3.
[0066] The buffered product then serves as a base glycerite of bismuth that can be tested using atomic absorption or other suitable techniques. Principal objectives of such testing are to determine the resulting bismuth content and/or other information to calculate the appropriate dilution required in order to obtain the desired amount of active ingredients in a finished product.
[0067] Referring now again to FIGURE 2, it is preferred that the glycerite of bismuth be diluted to elixir strength when finally packaged for distribution to consumers. The dilution is effected, as known to those of ordinary skill in the art, in order to obtain the specified dosage of active ingredient by volume according to the tested strength of the base, 18. In particular, Applicant has found success in diluting the glycerite of bismuth using a 1:8 ratio, wherein 47.31 liters of glycerite of bismuth is uniformly blended with 47.31 liters of glycerin and USP distilled water to 100 gallons. As discussed previously discussed with reference to FIGURE 1, preferred embodiments wherein the base solution is not placed in bulk storage for 48 hours or more prior to dilution to elixir strength, 0.5% by wt. of potassium sorbate is added to the glycerite of bismuth during the dilution step 18 (instead of during the preservative step 16). Coloring and/or flavoring agents may then be added as desired, 19. According to the preferred method of the present invention, the solution is then filtered in accordance with good manufacturing practices to ensure elimination of any foreign object as may have been introduced in the manufacture or storage of the base solution, 20.
[0068] make administration to the animal easier.
[0069] Treatment of the affected equine, canine, or feline is effected by administration of the bismuth sodium tartrate solution. Administration may be oral, via injection, or via other known means. While doseages may be adjusted, it has been found that a range of 0.5 mL to 4 ml_ per 10 pounds of horse, dog, or cat is effective. The frequency of the administrations can also be varied per the severity of the infection and sickness of the animal, as well as the response to treatment.
[0070] The inventors have discovered that the solution of this invention is effective as a method of treating the colic affected equine, of treating the parvo infected canine and treating the gastrointestinally infected feline.
[0071] Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limited sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the inventions will become apparent to persons skilled in the art upon the reference to the description of the invention. It is, therefore, contemplated that the appended claims will cover such modifications that fall within the scope of the invention.
[0072] Finally, Applicant has found that it is critical to package the elixir of bismuth at a pH of at least 7.2 but not more than 7.3 in order to obtain significant shelf life without degeneration of the semitransparent colloidal solution. Although it is generally known that the pH should be neutral or higher to avoid exacerbation of the medical indication for which the product is used, a pH of approximately 7.3 has been empirically discovered as an upper limit of this rule of thumb. Buffering the end product to a pH above the critical range will result in the formation over time of undesirable precipitates within the solution. Because this will result in a product generally unsuitable for ordinary consumer markets, care should be observed in obtaining the desired end pH. According to the preferred method of manufacture, the end pH is obtained by adding sodium bicarbonate USP as necessary to arrive at the critical range, 21.
[0073] While the foregoing description is exemplary of the preferred embodiment of the present invention, those of ordinary skill in the relevant arts will recognize the many variations, alterations, modifications, substitutions and the like as are readily possible, especially in light of this description, the accompanying drawings and claims drawn thereto. For example, many additional embodiments of the present invention are contemplated, including but not limited to formulations of bismuth sodium tartrate suitable for animal consumption, as well as those suitable for human consumption. Animals for which formulations of bismuth sodium tartrate may be beneficial include, but are not limited to, minor species, as well as dogs, cats, horses, cattle, swine, chickens and turkeys. As used herein, references to "minor species" are understood to generally refer to any species other than other than dogs, cats, horses, cattle, swine, chickens and turkeys, including those that are kept as household pets, those kept for display and educational purposes in zoos and public aquariums, and those that are raised commercially as food or for recreational fishing, including but not limited to, sheep, goats, game birds, emu, ranched deer, elk, rabbits, hamsters, ferrets, and cavies (e.g. guinea pigs), lizards, tortoises, caged birds, and free- ranging wildlife.
[0074] It is contemplated that the at least one preservative agent (FIGURE 1) useful in embodiments of the present invention may vary widely, including, but not limited to, potassium sorbate, sodium benzoate7 and salicylic acid. In particular, Applicant has found it preferable to use exemplary preservative agents, such as potassium sorbate, which are less likely to be contraindicated for human consumption and for animal consumption. Conversely, Applicant has found that some preservative agents may be desirable for use in formulations for human consumption, while being unacceptable for animal consumption, and vice versa. For example, sodium benzoate may be useful as a preservative agent in formulations for human consumption, yet contraindicated for use in formulations for certain animals, such as felines. Those of ordinary skill in the art will readily recognize further examples of preservative agents that may be desirable and/or undesirable in formulations for human and/or animal consumption and employ them accordingly without undue experimentation.
[0075] It is further contemplated that the products of the present invention may be utilized for the treatment of a variety of conditions in humans. Applicant has found success in treating various maladies of the gastrointestinal tract, including upset stomach, acid indigestion, and heartburn, using an over the counter dosage of 7.5 ml, twice in a 24 hour period for adults, and .5 ml, twice in a 24 hour period for children, each with a strength of 16.25 mg/ml bismuth sodium tartrate. As will be understood by those skilled in the art, the prescriptive strength for adults may be a multiple of the over the counter strength for adults, and the prescriptive dosage for children may be based on body mass. Anecdotal evidence suggests bismuth sodium tartrate may be beneficial for treating indigestion, nausea and diarrhea, as well as oral ulcers, including but not limited to oral ulcerative mucositis caused by the toxicity of drug and radiation therapy for cancer, cold sores on the lips and face caused by herpes simplex, and aphthous ulcers. Further, bismuth subsalicylate is useful in treating gastric disorders such as colitis, diarrhea, and peptic ulcers. Bismuth compounds are used in burn bandage dressings, antiseptic powders, salves and ointments, and in the treatment of venereal diseases. Bismuth-compound pre-treatment reduces the renal and lethal toxicity of several forms of chemotherapy and may help combat AIDS. The deodorizing action of bismuth compounds is beneficial for colostomy patients. Bismuth compounds alleviate diaper rash. Bismuth-based antiseptic powders, ointments and burn bandages help heal wounds and remove warts. Will, Rich gave me this info as possible ideas to further coverage. I am not sure how to use it, or if it can be used as novel. Possibly in the alternative embodiments 3 paragraphs down? Doubt it, so didn't do it.
[0076] It is further contemplated that the products of the present invention may also be utilized for the treatment of a variety of conditions in major and minor species of animals. In particular, when administered to animals including, but not limited to, dogs, cats, horses, and ferrets, Applicant has found success in providing diarrhea relief using a preferred over the counter dosage of 1 cc per 10 lbs. of animal weight, and a preferred prescriptive dosage of 1 cc per 20 lbs. of animal weight. Anecdotal evidence suggests bismuth sodium tartrate may be beneficial in treating parvovirus. Bismuth sodium tartrate may reduce the death rate in parvovirus by limiting the effect of parvovirus on the intestines. Particularly, bismuth sodium tartrate may effectively eliminate the symptoms of vomiting, diarrhea and electrolyte imbalance brought on by parvovirus.
[0077] Still further, various alternative embodiments and formulations for administration of bismuth sodium tartrate are contemplated, including but not limited to those suitable for oral, rectal, topical, buccal, and transdermal administration. In general, the formulations are prepared by uniformly admixing the active ingredient with liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. The carrier must, of course, be acceptable in the sense of being compatible with the bismuth sodium tartrate and any other ingredients in the formulation and must not be harmful to the patient. The carrier is preferably formulated with the active ingredient as a unit-dose formulation, for example, a tablet, which may contain from 0.1% to 99% by weight of the active ingredient. Formulations suitable for oral administration include, but are not limited to, solution, powder or granules, and in discrete units, including but not limited to, capsules, cachets, lozenges, tablets, and dissolvable strips, each containing a predetermined amount of the active ingredient. Formulations suitable for buccal administration are preferably presented as unit dose lozenges. Formulations suitable for rectal administration are preferably presented as unit dose suppositories. Formulations suitable for topical application to the skin include, but are not limited to, ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers, which may be used, include, but are not limited to, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof. Formulations suitable for transdermal administration may also be presented as medicated bandages or discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
[0078] Alternative embodiments are also contemplated wherein one or more active ingredient, active compound, therapeutic agent, prophylactic agent, or drug may be combined with the bismuth sodium tartrate solution, including but not limited to, chemical elements, elemental molecules, complex molecules, antimicrobial agents, H2 blockers, and proton pump inhibitors. Antimicrobial agents include, but are not limited to, antibacterial agents, such as antibiotic and bacteriostatic agents, antiviral agents and antifungal agents. Prophylactic agents include, but are not limited to, anti- inflammatory agents, such as aspirin, acetaminophen or ibuprofen, salicylic acid, salicyloyl salicylic acid, and salicylamide.
[0079] Particularly, it is known by those skilled in the art that companion therapy medications administered two or more times every 24 hours, may effectively treat Helicobacter pylori infections, thereby eliminating the negative symptoms associated with conditions including, but not limited to, Gastro Esophageal Reflux Disorder (GERD), hiatal hernias, upset stomach, and heartburn. Such companion therapy medications include, but are not limited to, an antibiotic such as penicillin or clarithromycin, and a proton pump inhibitor such as omeprazole or an H2 blocker, and a formulation comprising bismuth sodium tartrate solution. One alternative embodiment described herein includes consolidation of the companion therapy medications including the formulation comprising bismuth, thereby reducing to one, the number of medications administered two or more times every 24 hours. It is further contemplated that strength of the single medication may be formulated for administration of the preferred daily dosage in a single dose per 24 hours. Another alternative embodiment contemplated herein includes consolidation of the antibiotic, proton pump inhibitor or H2 blocker, and the formulation comprising bismuth, into the single medication administered two or more times every 24 hours. Yet another alternative embodiment includes consolidation of the antibiotic, proton pump inhibitor or H2 blocker, and the bismuth formulation, into the single medication formulated for administration of the preferred daily dosage in a single dose per 24 hours.
[0080] As will be known to those of ordinary skill in the art, one of several spectral methods 17 may be employed in determining the density value of the active ingredient in the base solution, including but not limited to, the light transmission method described in FIGURE 8, atomic absorption spectroscopy using flame ionization, as described in FIGURE 9, atomic emission spectroscopy, plasma emission spectroscopy, ultraviolet spectroscopy, and infrared spectroscopy.
[0081] It is further contemplated that at least one embodiment of the bismuth sodium tartrate described herein may be formed in one single manufacturing process comprising the steps described with reference to FIGURES 1 and 2.
[0082] In any case, because the scope of the present invention is much broader than any particular embodiment, the foregoing detailed description should not be construed as a limitation of the scope of the present invention, which is limited only by the claims appended hereto.

Claims

What is claimed is:
1. A method for preparing a pharmaceutical solution to treat parvovirus, the method comprising the steps of: producing an aqueous solution of bismuth sodium tartrate; extracting a precipitate of bismuth sodium tartrate from the aqueous solution, the precipitate having a pH of approximately 2.2; dissolving the precipitate into a salting-in mixture to form the semitransparent colloidal solution of bismuth sodium tartrate; diluting the semitransparent colloidal solution of bismuth sodium tartrate to an elixir strength; and wherein the diluting step includes adding a preservative to the semitransparent colloidal solution of bismuth sodium tartrate.
2. The method of claim 1, wherein the precipitate is extracted from the aqueous solution at a pH of at least 2.2 but not more than 2.3.
3. The method of claim 1, wherein the preservative includes at least one substance selected from the group including glycerin, potassium sorbate, sodium benzoate, and salicylic acid.
4. The method of claim 3, wherein the at least one substance is potassium sorbate.
5. The method of claim 4, wherein the semitransparent colloidal solution of bismuth sodium tartrate is suitable for consumption by an animal.
6. The method of claim 5, wherein the animal is selected from a group including minor species, dogs, cats, horses, cattle, swine, chickens and turkeys.
7. The method of claim 1, further comprising the step of buffering the elixir strength semitransparent colloidal solution of bismuth sodium tartrate to a pH of at least 7.2 but not more than 7.3.
8. The method of claim 7, wherein the buffering step comprises the addition of a quantity of sodium bicarbonate to the elixir strength semitransparent colloidal solution of bismuth sodium tartrate.
9. A method for preparing a pharmaceutical solution to minimize dehydration due to gastrointestinal disorders, the method comprising the steps of: producing an aqueous solution of bismuth sodium tartrate; extracting a precipitate of bismuth sodium tartrate from the aqueous solution, the precipitate having a pH of approximately 2.2; dissolving the precipitate into a salting-in mixture to form the semitransparent colloidal solution of bismuth sodium tartrate; diluting the semitransparent colloidal solution of bismuth sodium tartrate to an elixir strength; and wherein the diluting step includes adding a preservative to the semitransparent colloidal solution of bismuth sodium tartrate.
10. A method for making a pharmaceutical solution for minimizing fluid loss in patients due to gastrointestinal disorders, the method comprising the steps of: producing an aqueous solution of bismuth sodium tartrate; extracting a precipitate of bismuth sodium tartrate from the aqueous solution, the precipitate having a pH of approximately 2.2; dissolving the precipitate into a salting-in mixture to form the semitransparent colloidal solution of bismuth sodium tartrate; diluting the semitransparent colloidal solution of bismuth sodium tartrate to an elixir strength; and wherein the diluting step includes adding a preservative to the semitransparent colloidal solution of bismuth sodium tartrate.
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