KR20080004531A - Scarbonporphine composition and administration - Google Patents

Abstract

Disclosed are pharmaceutical compositions comprising scarbonporphine, drugs comprising pharmaceutical compositions, methods of preparing pharmaceutical compositions, and methods of treating hyperbilirubinemia with drugs and compositions.

Description

STABONSOPORFIN COMPOSITIONS AND ADMINISTRATION}

The present invention relates to the treatment of hyperbilirubinemia with pharmaceutical compositions comprising carbonaceous phosphine, drugs comprising pharmaceutical compositions, methods of preparing pharmaceutical compositions, drugs and compositions.

Tin (IV) mesoporphyrin IX dichloride, or sccarbonporpine, is a mesoporphyrin compound having the structure:

Scarbonporphine is a pharmaceutical agent for the treatment of various diseases, including, for example, psoriasis (US Pat. No. 4,782,049 to Kappas et al.) And infant jaundice (eg US Pat. Nos. 4,684,637, 4,657,902 and 4,692,440). Has been proposed for use. Scarbonporphine is also known to inhibit heme metabolism in mammals, regulate the rate of tryptophan metabolism in mammals, and increase the rate at which heme is secreted by mammals (US Pat. No. 4,657,902). And 4,692,440).

Methods for obtaining scarbonporphine are known in the art. Protoporphyrin IX iron (III) chloride or hemin of the following structure is commonly used as starting material:

Hemin is generally hydrogenated to form the intermediate mesoporphyrin IX dihydrochloride, which is then subjected to tin insertion to yield carbonacetic phosphine. Method for producing the carbon carbon phosphine is US Patent No. 6,818,763 and US patent application no. 10 / 812,156, filed March 29, 2004, the contents of both being incorporated herein by reference.

One method of administering carbonaceous porphine is by injection solution. Although scavengporphine has been provided in aqueous solution in the past, it has been found that in scavengporphine solution with a high concentration, the scavengporphine does not dissolve properly in the solution. It would be desirable to provide compositions, pharmaceuticals and methods of preparation that may include high concentrations of carbonaceous phosphine. It would also be desirable to provide compositions and medicaments that include carbon phosphine having a stable and acceptable shelf life.

One aspect of the present invention includes scarbonporphine in an aqueous solution, wherein the concentration of scarbonporphine in the solution is at least about 4 mg / ml, preferably at least about 4.5 mg / ml, more preferably at least about 5 mg / ml relates to a pharmaceutical composition or drug. In one embodiment, the preferred range of carbonaceous phosphine concentration is about 5-40 mg / ml and 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg concentrations of / ml and 40 mg / ml.

According to one embodiment, the composition or drug has a physiological osmolality. According to another embodiment, the composition or drug is stable at room temperature for at least about 1 month. In another embodiment, the composition or drug is stable at room temperature for up to at least about 2 months, and in still other embodiments the solution or drug is stable at room temperature for at least about 3 months, and in other embodiments the solution or drug is at least about 6 Stable at room temperature for up to months. As used herein, room temperature includes, but is not limited to, a temperature of about 68 ° F to 77 ° F.

Another aspect of the invention relates to a drug comprising a s carbon porphine solution, wherein the medicament comprises s carbon porphine in a single dose of solution. In some embodiments, the solution may further comprise a base, an acid and a buffer.

Another aspect of the invention relates to a process for the preparation of a pharmaceutical composition comprising an aqueous solution of carbon phosphine, wherein the carbon phosphine is mixed with a buffer. Scarbonporphine is then dissolved through the addition of a base, which preferably raises the pH to at least about 10. After complete dissolution of the carbonaceous phosphine, the pH is then lowered within the physiological pH range by addition of acid for administration to the patient. As used herein, the physiological pH range refers to a pH range of less than about 8. As used herein, according to one or more embodiments, the physiological pH range means a pH of about 7.2 to 7.9, more preferably the physiological pH range means a pH of about 7.4 to 7.9.

Another aspect of the invention relates to a method for the manufacture of a medicament comprising an aqueous solution of carbonaceous phosphine at a concentration of at least about 4.5 mg / ml. Yet another aspect of the invention pertains to the treatment of hyperbilirubinemia with the compositions and drugs disclosed herein.

Best Mode for Carrying Out the Invention

It should be appreciated that the various process variables described herein (only by way of example only, temperature, time and pressure) are approximate and may vary and some steps may be performed in a different order. Before describing some exemplary embodiments of the invention, it should be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention enables other embodiments and may be practiced or carried out in other ways.

In overview, one or more embodiments relate to compositions, drugs, and methods of treatment using carbonaceousporpine. As used herein, tin (IV) mesoporphyrin IX dichloride includes tin 4 ⁺ mesoporphyrin IX dichloride and carboncarbonine. Tin (IV) mesoporphyrin IX dichloride can be obtained according to several methods, for example, see US Pat. 6,818,763, and co-pending US patent application 10 / 812,156 (published No. 20040210048), which are incorporated herein by reference. However, other methods can also be used to prepare mesoporphyrin halides, such as tin mesoporphyrin IX dichloride and the present invention is not limited to the specific method of preparation of mesoporphyrin.

For example, a two-step hydrogenation process can be used to produce tin mesoporphyrin. In the first step, the reaction mixture of hemin and the hydrogenation catalyst is subjected to a first high temperature for a first time period. The first stage temperature may range from about 85-95 ° C., and the time period is at least about one hour, for example about 1-3 hours. In the hydrogenation of the second stage, the reaction mixture is cooled to a second temperature for a second time period. For example, the second temperature may be in the range of 45-50 ° C. and hydrogenated for a second time period of about 3-6 hours, substantially removing all hemin (protoporphyrin IX iron (III) chloride). Convert to mesoporphyrin IX formate. This second step can also be done in the presence of formic acid. The same catalyst as in the first step described above may be used so that the two steps of the process are performed in the same reactor. Optionally, an additional charge of hydrogen may be fed to the reactor prior to beginning the second step. In some situations, the second hydrogenation step increases the yield of mesoporphyrin IX formate while reducing the amount of impurities in the final metal mesoporphyrin halide (see also reaction below).

By the above method, the mesoporphyrin IX intermediate compound in the present invention is not isolated as dihydrochloride but is isolated as formate salt. It will of course be understood that other processes can be used for the preparation of tin (IV) mesoporphyrin IX intermediates.

Mesoporphyrin IX formate may be isolated from the formic acid solution by addition of a solvent such as ether or other organic solvent to directly lead the mesoporphyrin IX formate intermediate, which also causes drying. In particular, ethers such as, for example, methyl tert-butyl ether, diethyl ether or diisopropyl ether can be used.

According to the above method, less solvent is required compared to other processes and this small volume allows for less filtration time to obtain intermediates. A ratio of the amount of hemin to the amount of solvent may be used from about 1:10 to about 1:20. In addition, filtration and washing of mesoporphyrin IX formate is rapid. After drying, crude intermediate formate is obtained in high yield (about 80-95%), and its purity established by HPLC is about 97% or more.

The insertion of metals into mesoporphyrin IX formate to obtain metal mesoporphyrin halides is described below with particular reference to tin to produce carbon phosphine.

Annotation mesoporphyrin is made using the insertion of tin into mesoporphyrin IX formate. To make tin mesoporphyrin, mesoporphyrin IX formate is heated with tin (II) carrier in an acid such as acetic acid buffered with acetate ions in the presence of an oxidant under reflux. Tin (II) carriers such as tin (II) halides or tin (II) acetates can be used. Suitable acetate counterions include ammonium, sodium or potassium ions. Oxygen such as hydrogen peroxide as well as oxygen from air or in pure form can also be used. Mesoporphyrin IX formate can be heated with tin (II) chloride in acetic acid buffered with ammonium acetate and the reaction is carried out in the presence of air under reflux. During this process, tin mesoporphyrin dichloride is isolated from the reaction mixture by addition of water followed by filtration and then filtered to provide a filter cake. Prior to drying at about 90-100 ° C., the filter cake is ground with hot dilute hydrochloric acid at a concentration of about 0.1N-6N, for example at about 90-100 ° C. Crude substantially pure tin mesoporphyrin chloride (crude tin (IV) mesoporphyrin IX dichloride) is obtained with a yield of about 75-95% and HPLC analysis with a purity of about 95%. (See the reaction diagram below)

The tin mesoporphyrin IX dichloride obtained by the above method may be further purified by dissolving the product in an aqueous inorganic base solution such as dilute ammonium hydroxide and then treating with charcoal. The product is then reprecipitated by addition of an acid solution such as acetic acid, hydrochloric acid or mixtures thereof. The dissolution, charcoal treatment and reprecipitation steps may be repeated several times, typically about 1-3 times, to ensure the desired purity. Prior to drying, the cake is ground in hot dilute hydrochloric acid at a concentration of about 0.1N-6N at a temperature of about 90-100 ° C to remove all residual ammonium salts. Tin mesoporphyrin chloride product (tin (IV) mesoporphyrin IX dichloride or carboncarbonine) is obtained in a yield of about 50-70% with an HPLC purity of about 97% or more.

The method described above is substantially pure or pharmaceutical quality tin mesoporphyrin chloride (tin (IV) mesoporphyrin IX dichloride or carbon carbon) in large amounts such as amounts exceeding about 0.1 kg and comprising several kilogram amounts. In order to produce fin), it may be carried out with slight modifications to the process, such as an increased reaction or drying time as appropriate based on an increase in the scale of the starting reactants. Similarly, the temperature and pressure time can be modified as needed. Tin mesoporphyrin chloride product (tin (IV) mesoporphyrin IX dichloride or carbonaceousporpine) is obtained in a large production process of about 60-90%, with HPLC purity of about 97%.

Alternatively, carbon phosphine can be obtained by the methods disclosed in co-pending US patent application 10 / 812,156, filed March 29, 2004, the entire contents of which are incorporated herein by reference. . In overview, carboncarbonine can be prepared by isolating mesoporphyrin formate and converting mesoporphyrin formate to tin mesoporphyrin halide. Mesoporphyrin formate can be converted directly to a metal mesoporphyrin halide, or alternatively, mesoporphyrin formate can first be converted to mesoporphyrin dihydrochloride and then mesoporphyrin dihydrochloride to metal mesoporphyrin halide. .

The compositions of the present invention can be prepared and administered in a wide variety of parenteral dosage forms. Thus, the compositions of the present invention may be administered by injection, ie by intravenous, intramuscular, intradural, intradermal, subcutaneous, duodenal, or intraperitoneal injection. In addition, the compositions of the present invention may be administered transdermally.

Liquid form preparations can include solutions, suspensions, and emulsions, such as water or water propylene glycol solutions. For parenteral injection, the liquid formulation may be formulated as a solution in aqueous solution as described herein.

The pharmaceutical preparations are preferably in unit dosage form. In this form, the formulation is subdivided into unit dosages containing appropriate amounts of the active ingredient. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as in packets, in vials or ampoules.

The amount of active ingredient in a unit dosage formulation may vary from about 0.1 to about 50 mg, preferably 0.1 to about 40 mg, and more preferably 0.1 to about 20 mg, depending on the specific use of the active ingredient and the size of the patient. Or may be adjusted. The composition may also contain other suitable therapeutic agents, if desired.

In therapeutic use as a therapeutic agent for neonatal hyperbilirubinemia, the compounds used in the pharmaceutical methods of the present invention are administered at an initial dosage of about 0.1 mg to about 20 mg per kilogram body weight (IM) per day. Particular illustrative embodiments involve the use of about 0.5 mg to about 6 mg per kilogram body weight (IM) for the treatment of neonatal hyperbilirubinemia. However, the dosage may vary depending on the condition of the patient, the severity of the disease to be treated and the compound used. Determination of the appropriate dosage for a particular situation is within the field. In one embodiment, generally, treatment is initiated at a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimum effect is reached under the circumstances.

One aspect of the present invention relates to a pharmaceutical composition comprising s carbon porphine, wherein it is in the form of an aqueous solution and the concentration of s carbon porphine in the solution is about 4.5 to 40 mg / ml, and preferably about 4.5 to 25 mg / ml. In one or more embodiments, the components of the s carbonporphine composition include an acid, a base, and a buffer mixed in an aqueous solution. The composition is preferably sterile and has a physiological osmolality. The composition or drug is preferably packaged in a yellow glass vial.

Pharmaceutical compositions containing carbonaceous phosphine may be a component of a drug, wherein the drug is contained in a single dosage unit. According to one embodiment, the single dosage unit comprises at least about 0.5 ml of solution, more preferably at least about 1 ml of solution.

The solution may be provided in pharmaceutical form by containing the solution in a suitable container such as an ampoule or vial. According to some embodiments, the solution is stable and has a shelf life of at least about 3 months. In other embodiments, the solution has a shelf life of at least about 6 months.

Another aspect of the present invention relates to a method for preparing a pharmaceutical composition comprising a large amount of carbonaceous phosphine. In one or more embodiments, the carbon carbonfin is present in an amount of at least about 4.5 mg / ml. In an exemplary embodiment, a predetermined amount of scorphoporphine is mixed with a buffer in an aqueous solution. There are a number of buffers suitable for making pharmaceutical compositions. Examples of such buffers are alkaline earth metal buffers, calcium buffers, magnesium buffers, aluminum buffers, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, magnesium citrate, Aluminum hydroxide, aluminum hydroxide / magnesium carbonate, aluminum hydroxide / sodium bicarbonate co-precipitation, aluminum glycine acid, magnesium aluminum hydroxide, aluminum phosphate, sodium citrate, calcium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, sodium dihydrogen phosphate, Potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, tribasic sodium phosphate 12-hydrate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium carbonate, potassium metaphosphate, calcium acetate, calcium glycophosphate, Calcium chloride, calcium hydroxide Calcium, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, sodium phosphate, potassium phosphate, calcium phosphate, magnesium phosphate, potassium citrate, trihydroxymethylaminomethane, amino acids, acid salts of amino acids, alkali salts of amino acids, and the above Combination of ones. The buffer used should be able to be used at a concentration effective to raise the pH of the solution to about 10 or more when a base is added to the solution. In addition, the buffer should be pharmaceutically acceptable.

According to one or more embodiments, the method of preparing the pharmaceutical composition further comprises adjusting the pH of the solution to a pH of at least about 10 to facilitate dissolution of s carbonporphine in the solution. This can be achieved through the addition of strong bases to the solution. Strong bases with low pKb values facilitate the dissolution of large amounts of carbon phosphine. The base used in this method may be any pharmaceutically acceptable strong base such as metal hydroxide or other hydroxide base. Currently preferred bases include pharmaceutically acceptable Group I and II metal hydroxides. Sodium hydroxide has proven to be suitable. Other suitable bases may include potassium hydroxide, calcium hydroxide, ammonium hydroxide, tetraethylammonium hydroxide, 10% ethanolamine or magnesium hydroxide. The base should be pharmaceutically acceptable and effective to raise the pH of the solution to about 10 or greater.

According to one or more embodiments of the invention, the pH of the solution is adjusted to a pH range of less than 8, for example to a pH of about 7.2 to 7.9, more preferably about 7.4 to 7.9. This can be accomplished by adding a pharmaceutically effective strong acid in a dilute concentration to the solution corresponding to the base used to raise the pH. One example of a suitable acid is 0.3 N hydrochloric acid. Other suitable acids may include nitric acid, perchloric acid or hydroiodic acid. In a preferred embodiment, the pH range of the s carbonporphine solution should be in a form that can be administered such that the pH range is preferably about 7.4 to 7.9.

Another aspect of the invention relates to a method for lowering bilirubin levels in a mammal comprising parenteral administration of a s carbonporphine solution having a scarbonporphine concentration of at least 4.5 mg / ml. The recipient intended for this medication to treat hyperbilirubinemia is a human, in particular an infant, but may be effective in other mammals as well.

 Another aspect of the invention relates to a method for the manufacture of a medicament comprising an aqueous solution of carbonaceous phosphine at a concentration of at least about 4.5 mg / ml. This aqueous solution may further comprise an acid, a base and a buffer. One way to pack this aqueous solution is in a vial. Preferably, the vial is a type I yellow glass tube vial to protect the composition from light. According to one or more embodiments, the drug is stable and has a shelf life of at least about 1 month, preferably at least about 3 months. In another embodiment, the drug has a shelf life of at least about 6 months at room temperature.

In some embodiments, the drug or composition exhibits a physiological osmolality. As used herein, the term "physiological osmolarity" means that the drug or composition does not cause irritation or side effects when administered to a patient. Previous formulations did not exhibit physiological osmolality, and administration of the composition caused irritation in the patient. Suitable ranges for osmolality according to certain embodiments are about 270-328 mOsmol / L, more preferably about 280-300 mOsmol / L osmolality.

Exemplary embodiments of the invention will be further described for illustrative purposes with reference to the following non-limiting examples.

Example  One

S carbon porphine  Preparation of Aqueous Solution

The desired volume of batch for the solution was determined. The amount of s carbon porphine required for the batch was calculated and recorded. Bases required for adjusting the pH of the batch (eg 1N sodium chloride, NaOH) and acids (eg 0.3N hydrochloric acid, HCl) were calculated and recorded. The planned final weight of the solution batch was calculated and recorded based on the constituents and theoretical density of the s carbon porphine injection.

The empty mixing vessel was purged with nitrogen NF for at least 15 minutes. Purification was continued through the formulation process. Water for injection is added to the vessel. The temperature of the mixing vessel was measured and adjusted to about 15 ° C to 30 ° C. The mixing vessel was maintained within this temperature range throughout the process. Mixing started at 400-600 rpm and mixing was maintained at this rate throughout the process. Buffer (eg, sodium triphosphate hexahydrate) was added and the solution was mixed for 30 to 35 minutes until the buffer was completely dissolved. Scarbonporphine was added to the mixing vessel. The contents of the container are now mixed for approximately 30 to 35 minutes. A 10 ml sample of the bulk solution was recovered and its pH measured. If the pH was below about 10, small increments of 1N sodium hydroxide solution were added to help dissolve the s carbonporphine.

The pH was increased above about 10 and the amount of sodium hydroxide added was recorded. The solution was then observed to determine if s carbonporphine was dissolved. The contents of the container were mixed for approximately 30 to 35 minutes. Another 10 ml sample of the bulk solution was recovered and its pH measured.

45 내지 50분간 혼합하였다. 10 ml 샘플을 회수하고 그것의 pH를 기록하였다. 용액의 최종 중량을 또한 측정하였다.If the pH was above about 8, it was adjusted down by adding small increments of 0.3 N hydrochloric acid solution. The amount of acid added was recorded. The amount of water for injection added to determine the final weight of the solution was determined. Water for injection is added until the final weight of the solution is reached. Then the contents of the container

Mix for 45-50 minutes. 10 ml sample was recovered and its pH recorded. The final weight of the solution was also measured.

Example  2

S carbon porphine  solution

A 23 L carbonporphine solution containing the following ingredients was prepared according to Example 1:

Ingredient Volume / ml Volume / 23L

S carbon porphine 0.02Og 460.Og

Tribasic Sodium Phosphate 12-hydrate, ACS 0.017g 391.Og

Sodium Hydroxide NF (1N Solution) 0.090ml 2.0L

Hydrochloric acid NF (0.3N solution) 0.090ml 2.0L

Injectable water USP 1.0ml Sufficient volume up to 23.0L

Nitrogen NF As Above Space As Above Space

Example  3

S carbon porphine  Solution stability test

Samples prepared according to Examples 1 and 2 were subjected to stability tests as follows. Stability samples were stored at three conditions (4 ° C ± 2 ° C, 25 ° C ± 2 ° C / 60% ± 5% RH and 40 ° C ± 2 ° C / 75% ± 5% RH) and monitored as follows: 4 At 0 ° C. ± 2 ° C. for 0, 3, 6, 9, 12, 18, 24, 36, 48, and 60 months; For 0, 3, 6, 9, 12, 18, 24, 36, 48, and 60 months at 25 ° C ± 2 ° C / 60% ± 5% RH; 0, 1, 2, 3, 4, 5, and 6 months at 40 ° C ± 2 ° C / 75% ± 5% RH. At indicated time intervals for each storage condition, stability samples were tested for appearance, analysis, purity, pH, identification, and sterility. Appearance, peak purity (by diode array detector (DAD)), component identification (UV), and stability according to USP were satisfactory at each test point unless otherwise indicated. Stability testing was performed initially and at 12 and 24 months.

Limitations:

pH: 7.4 to 8.0

Volume in container: More than 1.5 ml can be recovered per vial.

Granular material (USP <877>):

Up to 6,000 parts ≧ 10 μm / vial.

Up to 600 parts ≧ 25 μm / vial.

Assay: 95.0% to 105.0% label

Impurities (total): 3% or less

Sterile (USP <71>): Sterile

Bacterial Endotoxin (USP <85>): contains less than 0.7 EU / mg of S carbon porphine injection

EU = endotoxin unit

All measurement variables were within acceptable ranges.

Example  4

S carbon porphine  Solution Osmall  density

A preparation with the following ingredients was prepared:

Ingredients amount / ml volume / 25ml

1.S carbonporphine 20.02 mg 500.5 mg

2. Tribasic Sodium Phosphate Tetrahydrate, ACS 16.0 mg 400.2 mg

3. 19 ml sufficient amount up to 75% of the final volume of reverse osmosis water

4. 500 μl of sodium hydroxide NF (1N solution) to pH> 10

5. 900 μl of hydrochloric acid NF (0.3N solution) to pH 7.4-7.8

6. Sufficient amount to the final volume of reverse osmosis water

Components 1, 2 and 3 were mixed together and then component 4 was added to titrate the solution to a pH of about 10.56. Component 5 was then added to titrate the solution to a pH of 7.62. Sufficient water was added to the desired volume.

Osmolality was measured using a Wescore 5500 vapor pressure osmometer. Prior to determining the osmolality concentration of the sample, the osmotic system was assayed using osmolality standards of 290 mmol / kg, 1000 mmol / kg and 100 mmol / kg. Osmolality values were 255, 252 and 256 mmol / kg, with an average value of 254 mmol / kg.

Example  5

S carbon porphine  Solution Osmall  density

A preparation with the following ingredients was prepared:

Ingredients amount / ml volume / 25ml

1.S carbonporphine 20.03 mg 500.7 mg

2. Tribasic Sodium Phosphate Tetrahydrate, ACS 17.0 mg 425 mg

3. 19 ml sufficient amount up to 75% of the final volume of reverse osmosis water

4. Sodium hydroxide NF (1N solution) 1 ml titration up to pH> 10

5. 1 ml of hydrochloric acid NF (0.3N solution) until pH 7.4-7.8

6. Sufficient amount to the final volume of reverse osmosis water

Components 1, 2 and 3 were mixed together and then component 4 was added to titrate the solution to a pH of about 10.56. Component 5 was then added to titrate the solution to a pH of 7.62. Sufficient water was added to the desired volume.

Osmolality was measured using a Wescore 5500 vapor pressure osmometer. Prior to determining the osmolality concentration of the sample, the osmotic system was assayed using osmolality standards of 290 mmol / kg, 1000 mmol / kg and 100 mmol / kg. Osmolality values were 292, 289 and 284 mmol / kg, with an average value of 288 mmol / kg.

Example  6

S carbon porphine  Urinary excretion of the solution

Two carbonsporphine preparations with different osmolalities were measured from the muscle compartment to the central circulation compartment as markers of drug uptake. Prior art preparations having a nonphysiological osmolality of 400 mOsmol / L or 40 mg of preparations having a physiological osmolality of 270-328 mOsmol / L prepared according to the invention are given intramuscularly to healthy adult volunteers. Administered. Urinary samples were collected until 48 hours after dosing and excreted tin mesoporphyrin was measured by fluorescence and expressed as% of dose administered.

Preparation Prior art The present invention Osmol concentration (mOsmol / L) 400 270-328 Urinary excretion (% of dose) 0.20-0.38 0.79-8.35

Urinary tin mesoporphyrin was not detected 24 hours after administration of the nonphysiological s carbonporphine preparation, whereas urinary tin mesoporphyrin was detected in the urine until 48 hours after administration of the physiological s carbonporphine preparation. The data suggested greater drug uptake into the circulation of scarbonporphine from preparations with physiological osmolality, compared to the preparations which were somewhat high osmolal, thereby indicating an increase in the bioavailability of the drug.

What has been described above relates to various embodiments of the invention, but other further embodiments of the invention may be devised without departing from the basic scope thereof, and the scope thereof is determined by the claims that follow. do.

Claims (30)

A pharmaceutical composition comprising s carbonporphine in an aqueous solution at a concentration of at least about 20 mg / ml and having a physiological osmolality. A pharmaceutical composition comprising carbonaceous phosphine in an aqueous solution at a concentration of at least about 20 mg / ml and having a shelf life at room temperature of at least about 3 months. The pharmaceutical composition of claim 1, wherein the composition has a shelf life at room temperature of at least about 3 months. The pharmaceutical composition of claim 1, wherein the composition has a shelf life at room temperature of at least about 6 months. The pharmaceutical composition of claim 1, wherein the composition has an osmolality of about 270 to 328 mOsmol / L. The pharmaceutical composition of claim 1, wherein the composition has an osmolality of about 250 to 300 mOsmol / kg. A pharmaceutical comprising the pharmaceutical composition of claim 1 in a single dosage unit. Mixing a predetermined amount of scorphoporpine with a buffer in an aqueous solution; Increasing the pH of the solution to a pH of at least about 10 to facilitate dissolution of s carbonporphine in the solution; And  Reducing the pH of the solution to a pH of at least about 8 or less. 9. The method of claim 8, wherein the pH of the s carbonporphine solution is reduced to about 7.4 to 7.9. The buffer according to claim 8, wherein the buffer is an alkaline earth metal buffer, calcium buffer, magnesium buffer, aluminum buffer, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, magnesium oxide, magnesium aluminate, magnesium carbonate, magnesium silicate, Magnesium Citrate, Aluminum Hydroxide, Aluminum Hydroxide / Magnesium Carbonate, Aluminum Hydroxide / Sodium Bicarbonate Coprecipitation, Aluminum Glycinate, Aluminum Magnesium Hydroxide, Aluminum Phosphate, Sodium Citrate, Calcium Citrate, Sodium Tartrate, Sodium Acetate, Sodium Carbonate, Sodium Polyphosphate Sodium hydrogen, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogen phosphate, tribasic sodium phosphate 12-hydrate, dipotassium hydrogen phosphate, trisodium phosphate, tripotassium phosphate, potassium carbonate, potassium metaphosphate, calcium acetate, glycerol Calcium Phosphate, Calcium Chloride, Fisheries Calcium, calcium lactate, calcium carbonate, calcium gluconate, calcium bicarbonate, sodium phosphate, potassium phosphate, calcium phosphate, magnesium phosphate, potassium citrate, trihydroxymethylaminomethane, amino acids, acid salts of amino acids, alkali salts of amino acids, and the above Characterized in that it is selected from the group consisting of a combination of ones. 9. The method of claim 8 wherein the pH is increased by addition of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, 10% ethanolamine and magnesium hydroxide. 9. The method of claim 8 wherein the pH is lowered by the addition of hydrochloric acid. A pharmaceutical composition made by the method of claim 8. A method of lowering bilirubin levels in a mammal comprising parenteral administration of the pharmaceutical composition of claim 13 to the mammal. The method of claim 14, wherein the mammal is a human. The method of claim 15, wherein the person is an infant. A method of lowering bilirubin levels in a mammal comprising parenteral administration of the drug of claim 5 to the mammal. 18. The method of claim 17, wherein the mammal is a human. 19. The method of claim 18, wherein the human is an infant. A method of increasing the bioavailability of s carbonporine following intramuscular administration in a human patient, comprising intramuscularly administering to the human patient a pharmaceutical composition comprising s carbonporpine in an aqueous solution having a physiological osmolality . The method of claim 20, wherein the osmolality is between about 270 and 328 mOsmol / L. 21. The method of claim 20, wherein the amount of carbon phosphine administered is at least about 20 mg. 21. The method of claim 20, wherein the concentration of carbonaceous phosphine in the pharmaceutical composition is at least about 20 mg / ml. 21. The method of claim 20, wherein urinary excretion of s carbonporphine is at least about 2 times greater than urinary excretion of s carbonporphine in an aqueous solution having a nonphysiological osmolality. 25. The method of claim 24, wherein urinary excretion of s carbonporphine is at least about four times greater than urinary excretion of s carbonporphine in an aqueous solution having a nonphysiological osmolality. 27. The method of claim 25, wherein the nonphysiological osmolality is high osmol. 26. The method of claim 25, wherein the osmolality, which is high osmol, is about 400 mOsmol / L. 27. The method of claim 25, wherein urinary excretion of s carbonporphine is greater after about 24 hours to about 48 hours after administration of the pharmaceutical composition. The pharmaceutical composition of claim 20, wherein the pharmaceutical composition is Mixing a predetermined amount of scorphoporpine with a buffer in an aqueous solution; Increasing the pH of the solution to at least about 10 by addition of a base; And And reducing the pH of the solution to at least about 8 or less by the addition of an acid. 30. The method of claim 29, wherein the concentration of carbonaceous phosphine in the pharmaceutical composition is at least about 20 mg / ml.