TW200841887A - Intravenous administration of water soluble analgesic formulations - Google Patents

Abstract

Provided are formulations of analgesics suitable for intravenous administration, preferably to a human. Methods of formulating analgesics for intravenous administration, as well as methods of using the formulations of analgesics suitable for intravenous administration to treat various diseases or medical conditions are also provided. In preferred embodiments, the analgesic is aspirin. The formulations allow for the delivery of aspirin to patients in need of aspirin treatment in large doses and over extended periods of time without the gastrointestinal side effects that often accompany conventional aspirin therapy.

Description

200841887 IX. Description of invention: [Technical field to which the invention belongs]

In summary, the present invention relates to aspirin and other analgesic compositions, and more particularly to water-soluble aspirin having enhanced stability and biological activity compared to previously known water-soluble aspirin and other analgesic compositions. And other analgesic compositions. The present invention provides intravenous pharmaceutical formulations of such aspirin and other analgesic compositions, as well as methods of intravenous administration of aspirin and other analgesic compositions. [Prior Art] Acetylsalicylic acid (aspirin, an important member of a family of therapeutic agents called non-steroidal anti-inflammatory drugs (NSAIDs)) is known to have analgesic, antipyretic and anti-inflammatory properties. These multiple properties make it an ideal therapeutic agent for relieving pain, including but not limited to treating headaches, reducing fever, and treating arthritis and other related indications. The mechanism of action of aspirin involves the inhibition of prostaglandins from peanuts: acid synthesis. Aspirin acetylated a serine residue located at the active site of pGH2 synthase (i.e., an enzyme that catalyzes the conversion of peanut tetrathrate to PGH2). This acetylation of the PGHj-forming enzyme inhibits the action of the enzyme and thus inhibits prostaglandin synthesis. In the past 50 years, it has also been p-Russian > κ 1 Xunyue Aspirin has significant anticoagulation. The anticoagulant effect of aspirin, Sun Yi, is mediated by platelet inhibition. Words can block platelet enzymes, % lactase by acetylating the yeast _ ^ _ ', the site. Inhibition of this enzyme can be called "coagulation of sputum sputum 2" I. Platelet activation and accumulation by ^ w alkane A2 v, this is the early stage of thrombosis I# J ^ . Several small blood phase 127879.doc 200841887 inhibitors are available today, but p-spirin is still the most commonly used drug in this category, and it is also a cost-effective anticoagulant. Aspirin (81 mg or 325 mg per sputum) is indicated for the following conditions: unstable colic (acute coronary syndrome), urgency. Secondary prevention of myocardial infarction, myocardial infarction, secondary prevention of stroke (carotid or primary cerebrovascular disease), prevention of peripheral arterial thrombosis, and prevention of venous thrombosis (deep vein thrombosis, pulmonary embolism). Recently, there have been studies using aspirin (alone or in combination with other medicines) to treat various types of tumors. The pharmacokinetic properties of aspirin (absorption, distribution, metabolism, and elimination) are important. After enteral administration, aspirin absorption involves the passage of appropriate membranes into the plasma. Absorption and solubility, dosage forms, excipients, and granules. Path-related. In general, fat-soluble, undissociated forms of the drug are easy to penetrate the membrane. Aspirin ionization is suppressed in the middle of the month (low pH), so aspirin can pass through its non-ionized (uncharged) form. The gastric membrane is absorbed into the bloodstream in a large amount. The main metabolic pathway of aspirin is hydrolyzed by esterase to a salicylic acid that cannot inhibit the synthesis of prostaglandins. t笞 has been reported to be used in various pathophysiological environments (self-use: the onset of visceral disease) And the low dose of stroke prevention to the use of rheumatoid arthritis) 'But due to its poor water solubility, the use of aspirin is limited. Side effects caused by insoluble particles that can attach to the gastrointestinal mucosa can cause stomach or Intestinal ulcers and bleeding, which may cause anemia caused by blood loss. More /, body and Lu, generally considered aspirin The usual dose (325 mg or 127879.doc 200841887 gram) is sufficient for "aspirin therapy to reduce heart attack and stroke < At H ,, ^ ie ''", these doses only reduce arthritis symptoms ( It is also "flat" and cannot treat potential inflammation. In order to achieve effective control of inflammation and arthritis, a dose of 4,000 mg to 5,000 mg or more is usually required to maintain the plasma salicylate concentration in the dry range of 120 to 350 μg/ml. At these higher dose concentrations, the success rate of treatment can exceed 70: Γ ❿ , , , , , , , , , , , , , , , , , , , , , , , , , ,

= "The success rate of 2500 mg is less than 1%. Therefore, the reason for the ineffective or lack of success in the treatment of joints in the middle of the aspirin therapy can be attributed to at least eight doses due to insufficient dose. ρ spirulina exhibits many undesired side effects. Most: see side effects are nausea, hunger (palpitations) and pain. At concentration, 'about 2.1% of adult users in aspirin usually = 〇 However, this number is significantly increased with the prolonged use of aspirin. When a higher anti-inflammatory dose is used, the incidence of such undesirable vice (4) is generally increased to about 25%. Moreover, this number will increase significantly with the prolongation of the treatment regimen. The gastrointestinal side effects of aspirin are usually local side effects, and when aspirin is used in its current form (such as suspension), its insoluble particles tend to adhere to the gastric mucosa, which can cause irritation, inflammation and damage. The local nature has been confirmed by gastroscopy and autopsy. For example, the erosion of aspirin around the insoluble particles in the stomach has been documented in many literatures. Along with images. Given Aspirin-based direct stimulation of gastrointestinal (iv) it was therefore affect the cumulative and persistent. 127879.doc

200841887 Heart and $ aspirin in the form of a solution. All aspirin sputum 0 produces a phase of soluble m-year patients especially benefited from it because arthritis is a terrible forest... the largest user of this forest, sick. The elderly population system is the victim. The acute side effects of Pilin are most susceptible to the slowing of gastric motility and the prolonged emptying time. The time during which the elderly p' insoluble a(iv) forest particles remain in contact with the gastric mucosa will thus enhance the undesirable side effects. In addition, it is estimated that there are some difficulties in the use of 150G people in the United States in the swallowing agent and other solid medicines. Because the age of the esophagus will become If, the elderly will once again influence and make it more difficult. . The low water solubility and hydrolysis potential of aspirin makes it impossible to administer in aqueous solutions, and thus aspirin is usually dispensed in the form of lozenges or capsules that require large amounts of water to minimize gastric irritation. Aspirin is readily soluble in alkaline solutions but is rapidly hydrolyzed to salicylic acid and acetic acid. In general, aspirin is more stable at lower pH and is most stable at pH Η 2.4. It is well known that several soluble aspirin products are commercially available in the United States and Europe. Regrettably, none of their products have the disadvantage of making them unacceptable, especially in the United States. For example, the only soluble product widely marketed in the United States, Alka Sehzer (& (by Bayer)

Healthcare LLC is on sale) containing 567 mg sodium/325 mg aspirin (1,750 mg sodium/1, 〇〇〇mg aspirin). In order to achieve anti-inflammatory activity when taking Aika Seltzer®, it may be necessary to consume more than 8,000 127879.doc 200841887 mg per ton. This amount makes Alka Seltzer® completely unacceptable for conventional aspirin therapy. Not only because this sodium concentration is too much for the general population, but also many elderly patients with arthritis (which also need to strictly limit sodium consumption) cannot afford it. Even sodium concentrations associated with low-dose aspirin, which are effective in reducing the risk of heart attack and/or stroke, are unacceptably high. In Europe where drinkable analgesics predominate, drinkable analgesics are mostly fine suspensions rather than true solutions. Most of these products (such as the Yang seltzer®) are predominantly sodium and require a relatively long time to dissolve and are not completely palatable. Some products are primarily simplified to prevent complete dissolution of aspirin. : Known - a French soluble analgesic product "Aspegie". However, this product contains non-small Sdl-type lysines, which may be difficult to obtain from the US FDA approval. I have already entered the big | I tried to produce acceptable soluble aspirin products, but none of them proved to be completely satisfactory. Cattle et al. grant Phykltti US Patent No. 5,665,388 and

No. 5,723,453 discloses a soluble alkaline aspirin which is substantially free of sodium, and which is not disclosed in the references: there are many formulations in the reference: One of the disadvantages is that the bicarbonate used forms a gas when the patient ingests it. ^ ^ Disadvantages are the relatively high pH of the composition (i.e., greater than 8 R m , · 〇) which results in rapid hydrolysis and instability, and thus shortens shelf life. Granted Galat's US patent flute case, 7,030 and 5,776,431 also revealed no aspirin compounds, and other aspirin compounds have similarities to 127879.doc 200841887

They disclose the shortcomings of the prior art patents described above. In particular, the compositions disclosed in these references have a final pH above pH 6. 在 when mixed with water. This can result in relatively unstable compositions, reduced shelf life, and difficulty in absorption by the body, as the aspirin component is in an easily dissociable form. This also results in relatively slow dissolution of the compositions in water, and it has been found that compositions formulated according to the Galat patent take up to 2 to 3 minutes to be substantially completely soluble in water. In addition, it is disclosed that many of the formulations in the sGalat patent need to be formed as two separate compositions (mixtures, A, and mixtures "b,,) which are disadvantageous in terms of production, packaging, and use: Formulations of these references are blended and subsequently added directly to water. It is not stated that the blended product is stable and packageable. Therefore, it is currently not possible to provide a satisfactory aspirin product that satisfies the following conditions: no sodium, rapid dissolution in water, rapid action and rapid entry into the bloodstream, and can be used for anti-inflammatory, relatively large doses required for treatment, and/or Or it can be used for a long time without causing gastrointestinal discomfort and/or damage. Accordingly, there is a need for a water-soluble analgesic composition having enhanced stability and biological activity and which does not have the above disadvantages as compared to previously known water-soluble analgesic compositions. The water-soluble analgesic composition can be used to provide an analgesic formulation suitable for intravenous administration. SUMMARY OF THE INVENTION: Static two:: an analgesic formulation for intravenous administration, a method for formulating an analgesic for use in a vein, and a use of a compound or a medical condition suitable for a static formulation. method. In the embodiment of the rut, the analgesic is aspirin. 127879.doc 200841887 Accordingly, it is an object of the present invention to provide aqueous analgesic formulations suitable for intravenous administration, preferably to humans. The analgesic formulations of the present invention have superior stability and biological activity. Further, the fourth aspect of the present invention provides a tangible analgesic agent having a topping agent. The anti-slipping composition is free of sodium and can be used to provide a sodium-free aqueous analgesic solution suitable for intravenous administration.

Another object of the present invention is to provide a capacitive analgesic composition having the above characteristics and which is rapidly soluble in water. The compositions can be rapidly mixed with an aqueous solution to provide a formulation suitable for intravenous administration of an analgesic. A further object of the present invention is to provide an aqueous analgesic formulation suitable for intravenous administration and having the above characteristics and which can rapidly deliver an analgesic to the bloodstream. * A further object of the present invention is to provide an aqueous analgesic formulation suitable for intravenous administration and having the above characteristics, and such analgesic formulations can be used to administer certain medical conditions requiring a relatively large dose, and/or can be used for a long period of time Use without f causes gastrointestinal discomfort and/or damage. Administration by intravenous route avoids any potential problems caused by the analgesic granules in the intestinal tract of the month, and thus can be used for such long-term treatment without causing gastrointestinal discomfort and/or injury. These and other objects of the present invention can be achieved in accordance with one embodiment of the present invention by providing a water-soluble analgesic composition comprising a plurality of particles: wherein the water-soluble analgesic composition can be used to produce a drug suitable for intravenous administration. Analgesic formulation. Each of the pellets comprises a matrix core and a coating disposed on the matrix core to form an agglomerated product, the coating comprising a salt of an analgesic, and the tannin is free of particles of a non-salt form analgesic. 127879.doc -12· 200841887 In certain embodiments, the matrix core is selected from the group consisting of a single listen, a disaccharide, a polysaccharide, a dipeptide, and combinations thereof. In certain such embodiments, the matrix core comprises sucrose, cellulose, xylitol or d-glucose. In some embodiments, the median diameter of the particles is in the range of from about 1 μm to about 4 μm. In some of these embodiments, the particles have a median diameter of about 200 μ. In certain embodiments, the analgesic is selected from the group consisting of aspirin, % aminosalicylic acid, ibuprofen (ibuprGfen), naproxen, and an amine group. ¥, and mouth, and into groups. In some of these embodiments, the painkiller tablet comprises aspirin. In certain embodiments, the salt of the analgesic comprises a potassium salt of an analgesic. According to another embodiment of the present invention, a method of producing a water-soluble analgesic composition useful for the production of an intravenous pharmaceutical formulation comprises the steps of: (1) providing a first solution comprising a base; (8) adding an analgesic to the first solution To produce a second solution comprising an analgesic salt; (out) filtering the second solution to remove residual analgesic particles to produce a filtered second solution; and (iv) spray drying the second solution onto the substrate, thereby Agglomerated products comprising a plurality of particles are formed. In certain embodiments, the analgesic agent is selected from the group consisting of aspirin, % amine X 酉夂 酉夂 洛, naproxen, acetaminophen, and combinations thereof. In certain of these embodiments, the analgesic comprises aspirin. In some examples, the base includes tripotassium citrate monohydrate. In certain embodiments, the first solution further comprises a surfactant. In some of these embodiments, the surfactant comprises sodium lauryl sulfate. In certain embodiments, the matrix is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides, and the group of 127879.doc-13-200841887. In certain such embodiments, the matrix comprises sucrose, fiber:,, xylitol or D-glucose. In certain embodiments, spraying onto the substrate: the step of drying the second solution through the fluidized bed is spray dried using a fluidized bed. In some embodiments, the particles have a median value of between about (10) μ and about 400 μ. Straight. In some of these embodiments, the particles have a median particle size of about 200 μ. • According to another embodiment of the present invention, it is suitable for the production of intravenous administration. 4. The water-soluble analgesic composition of the present invention comprises aspirin and tripotassium monohydrate. The aspirin accounts for the aspirin and the monohydrate. At least about 26% of the combined weight of the three clocks. > In a real case, aspirin comprises from about 26% to about 4% by weight of the combined weight of the aspirin and the monohydrate citrate. In certain embodiments, the pH of the composition is less than about 6. 在 when the gluten is in water. In one of the two examples, the water-soluble analgesic composition suitable for use in the manufacture of an intravenous pharmaceutical formulation further comprises a matrix. In certain such embodiments, the matrix is selected from the group consisting of free monosaccharides, bile, polysaccharides, dipeptides, and the like. In certain such embodiments, the matrix comprises sucrose or glucose. In certain embodiments, the matrix comprises a matrix core having aspirin coated with tripotassium citrate monohydrate. In certain embodiments, the water-soluble analgesic composition suitable for use in the manufacture of an intravenously administered formulation further comprises a surfactant. In some of these embodiments, the surfactant comprises sodium lauryl sulfate. In certain embodiments, the water-soluble analgesic composition further comprises a supplemental active ingredient selected from the group consisting of ascorbic acid, caffeine, and combinations thereof. 127879.doc -14- 200841887 According to another embodiment of the present invention, for use in the manufacture of an intravenously administered formulation, the composition of the glutamic acid analgesic composition comprising aspirin and citric acid monohydrate is the pH of the composition when dissolved in water. Less than about 6.0. In certain embodiments, the pH of the composition when dissolved in water is in the range of about 5.2 = about 6.00. In some such embodiments, the set of hydrazines is in the range of from about 5.6 to about 6.00 when dissolved in water. In some embodiments,

^ Lin accounts for at least about 26% of the combined weight of the aspirin and the monopotassium citrate monohydrate. The method of producing a water-soluble analgesic composition suitable for use in the production of a static and stimulating formula comprises the following steps: (1) providing aspirin, citric acid monohydrate, surfactant, and matrix. (U) producing a first solution comprising the trihydrate of monohydrated citrate; (iv) adding aspirin to the first solution to produce a second solution; (iv) adding a surface activity (IV) to the second solution; (v) (d) the first: solution to remove residual amounts of insoluble aspirin to produce a wide--drying of the second, second: two liquid ' and (, spray on the substrate) to form agglomerated products containing a plurality of particles Zhong A = Lin Zhan provides at least about 26% by weight of aspirin and monohydrate in the step (1). The pH of the composition is less than about 6.0 when dissolved in water. In certain embodiments,今丰草此~w The surface release agent comprises sodium lauryl sulfate. The 嗲~人贝系 is selected from the group consisting of early sugar, disaccharide, polysaccharide, dipeptide and the combination of the special ones. In this specific embodiment, the matrix comprises sucrose , cellulose, xylitol is still +1 ... fly glucosamine. In some embodiments, the mouth of the shell on the dry work of the filtered two-night step using fluidized bed spray 127879.doc 200841887 fog drying Method. In some embodiments, the particles have a median diameter in the range of from about (10) to about 400. In some such embodiments, the particles have a median diameter of about 200 μ. In another embodiment, there is provided a rapidly dissolving composition comprising aspirin salt, wherein the composition comprising 650 mg of aspirin is completely soluble in 100 ml of water in less than 60 seconds. The rapid dissolution combination comprising aspirin salt The product can be used to produce an aspirin # aqueous formulation suitable for intravenous administration. In certain embodiments, a portion of the composition containing 650 mg of aspirin can be completely dissolved in 1 ml of water in less than 30 seconds. In the examples, the portion of the composition containing 650 mg of aspirin is completely soluble in 100 ml of water in less than 15 seconds. In certain embodiments, the pH of the composition when dissolved in water is less than about 6.00. In certain such embodiments, the pH of the composition when dissolved in water is in the range of from about 5.2 to about 6.0. In certain embodiments, the pH of the composition is in the range of from about 5.6 to about 6.0 when dissolved in water. In the examples described in the present disclosure relating to dissolution time and pH, preferably, the water system is at room temperature (about 21 Torr and/or deionized water. Referring to the drawings in detail below) The invention and its specific features and advantages may be more clearly understood. [Embodiment] π effective amount n or "quantitatively effective" means sufficient to administer a disease or other medical condition to a patient in need thereof An analgesic dose in which the disease or condition produces a beneficial effect. The effective amount of ''or') is determined by the analgesic, disease or condition and its severity, and the ethnicity of the patient to be treated, 127879.doc -16 - 200841887 Age, weight, gender, etc. have changed. The "effective amount" or "quantity" is given to the general practitioners and only routine experiments are required. Water/excitation means no size exceeds 〇·5 microns. A water-based liquid of insoluble solids. Ideally, the aqueous analgesic solution described herein contains more than 60/〇, 70%, 8%, 9%, %, or even μ%.

(w/w) water, and the analgesic is substantially completely dissolved. Examples of aqueous solutions include water, physiological saline (including physiological saline of 9%, 〇, 木, xylitol solution, and 5% dextrose). Suitable for intravenous administration" refers to an aqueous solution comprising a dissolution analgesic that can be administered intravenously (preferably to humans) for the purpose of administering an aqueous solution comprising an analgesic agent without causing unacceptable side effects. "AUC:" means "area under the curve" and refers to the area under the serum concentration curve (concentration versus time curve). "Sodium-free" means that the amount of sodium contained in the analgesic agent is less than about 50% by weight, 参% by weight, about 10% by weight, about 5% by weight, about 2% by weight, about %, or about 0.5% by weight. An analgesic solution or a solid analgesic compound. / When the weight of the analgesic is indicated herein, the weight refers to an analgesic in the form of a nonionic form or in the form in which the analgesic is present as a salt, but does not include the weight of the counterion present in the salt. For example, when #aspirin is present in the presence of tripotassium salt, "i gram aspirin" refers to the weight of the ethyl sulphate portion of the aspirin-trans-acid tripotassium salt, excluding salt. The weight of the unloading. The present invention satisfies the unmet needs of the prior art, and the present invention is partially based on the discovery that: aspirin and sodium lauryl sulfate (which is used as a surfactant), citrate, and disaccharide (see Certain mixtures of, for example, sucrose), monosaccharides (such as D-glucose) or other non-nutritive flavoring agents (which are also used as preservatives, antioxidants, and emollients) can produce a more stable and previously stable formulation.

An aqueous solution having a lower pH (especially those having a pH between 5.2 and 6 Torr). This is superior to formulations prepared by the prior art which, when dissolved in water, are generally unpalatable and produce a solution having a pH greater than 〇. Is the novel formulation of the present invention comprising citrate, sodium lauryl sulfate, sucrose, and aspirin lower? 11 can be designed to be more easily absorbed, because these novel formulations can be formed to be more difficult to dissociate. The main decomposition pathway of salicylic acid and acetic acid by acetyl salicylic acid is hydrolyzed. In the absence of water, ethyl hydrazine does not decompose. It has been reported that the hydrolysis of aspirin is reduced in the presence of citric acid. In addition, sodium lauryl sulfate has been reported as a lubricant and stabilizer. It has also been reported in the early days that sucrose blocks the decomposition pathway of acetamidine, which is presumably achieved by providing a protective layer having a low water content which prevents hydrolysis of hydrazine acid. It is possible that the sucrose hydroxyl group is capable of forming a hydrogen bond with water and thereby inhibiting the hydrolysis of acetamidine acid to some extent. An aqueous solution of the orally administered hydrolyzable aspirin composition produces a higher concentration of plasma salicylate than the administration of aspirin in the form of a lozenge or capsule. Figure 1 shows a schematic diagram in which an aqueous solution of a water-soluble aspirin composition and a known commercial product are collected according to the plasma salicylate concentration measured in a human patient after oral administration (specifically, Bayer 8 Asi 127879. Doc -18- 200841887 Pillars) data were plotted. Both products were orally administered at the same dose of 1 mg of aspirin. The therapeutic concentration of plasma salicylate can be achieved in 5 to 10 minutes using a water-soluble aspirin composition, compared to 30 to 4 minutes in the form of a spirulina or sac. In addition, the water-soluble aspirin composition has a plasma salicylate concentration about 2 times higher than that of the commercially available product. Thus, lower doses of the water-soluble aspirin composition achieve comparable salicylates, and thus minimize the potential side effects of aspirin. According to one aspect of the invention, a method is provided according to which a number of injuries can be imposed. To ensure that a composition that is rapidly soluble in an aqueous solution (e.g., water) and does not contain any aspirin particles is obtained, aspirin is first added to a solution of potassium citrate and sodium lauryl sulfate. Subsequently, traces of aspirin particles which have not been converted to their potassium salts are removed by filtration and then the clear solution is spray dried onto the core (e.g., 纟σ日日糖) to form a coagulated product. A fluidized bed spray drying method (a method of spray drying and suspected polymerization by a combination of air suspension techniques) is used to provide a clopidogrel coating on the yellow and sugar cores. The resulting free flowing solid composition can be dissolved in an aqueous solution (e.g., water) arbitrarily to produce a clear aspirin solution (see Example 下文 below). This granulation method can provide a product comprising particles/particles having a diameter ranging from about 100 to 4 Å and a median value of about 20 Å, as shown in Figure 2. These conclusions can be confirmed by scanning::microscopy, as shown in Figure 3.6, which shows the aggregated product obtained from the method at different magnifications (magnification scale of Figure 3 is 29〇) ρ, the magnification scale of Fig. 4 is 14〇μ, the magnification ruler of Fig. 5 is 2〇〇ρ, and 127879.doc •19- 200841887 The magnification scale of Fig. 6 is 74 μ). Thus the resulting free-flowing solid composition comprises a plurality of particles comprising a matrix (e.g., 'sucrose(tetra)saccharide) and a coating condensed on the core of the matrix. The coating comprises the salt of aspirin but is substantially free of non-salt forms of aspirin particles. This does not mean that the coating does not in any case include the non-salt form of aspirin, but rather the substantially non-salt form of aspirin particles contained in the coating, & All of these particles have been filtered on the shellfish. Of course, the coating may comprise a (4) form of 51 prin, which has been previously transferred to the solution towel prior to spraying, since the amount of such dissolution cannot be filtered out as its particles. Compositions having sucrose or other non-nutritive sweeteners that can be prepared directly and that do not require a fluid bed spray drying procedure can also provide a free flowing product that is substantially soluble in water, but it may take a little longer to completely dissolve (see Examples 2, 3 and 4) below. It has been reported that the addition of certain supplemental active ingredients enhances the beneficial effects of acetyl salicylic acid. For example, a combination of acetaminophen and ascorbic acid (vitamin c) can be rapidly transferred from the small intestine to the bloodstream. This combination of aspirin and vitamin C has been reported to be extremely suitable for the treatment of cold headaches, pain and fever. In addition, it has been reported that the combination of acetaminophen and ascorbic acid can significantly reduce gastric lesions. The combination of vitamin C and the novel formulation produces a product that is sufficiently soluble in water (see Example 5 below). The intravenous administration formulation of the present invention can also be completely compatible with the added caffeine. It has been reported that caffeine can enhance the pain relief (analgesic) effect of acetaminophen and has been suggested for caffeine and other treatments for migraine. The agent is used together with I27879.doc -20- 200841887. In addition to disaccharides (e.g., sucrose), other matrices (including mono-branched (e.g., d-glucose), polysaccharides, dipeptides, etc.) can also be used in combination with acetamidine salicylic acid in the compositions described herein. Moreover, it has been reported that monoacetal and xylitol can be used in multi-layered formulations containing aspirin and can be used in such novel formulations (see Example 8 below). Cellulose (-insoluble in water) has been used in sustained release lozenge formulations of aspirin and can also be used in such new formulations (see Example 9 below). The present invention is characterized by an aqueous solution of an analgesic agent for intravenous administration to a patient (Utopia), wherein the solution has an analgesic concentration of about 1 () 〇 microgram/ml to about 15 mg. Between /ml, preferably between about 500 micrograms/platform 5, ^ brother hair rises to between about 10 grams/3⁄4 liters and even better between about 1 gram/liter to about 7 mg/ml. . In certain embodiments, the cation Y of the aqueous analgesic solution suitable for intravenous administration is 6.0. In certain embodiments, the pH is between about 5.2 and about 6.0, preferably between about 5 and 6 to about 6.0. In certain embodiments, the analgesic is selected from the group consisting of: aspirin, 5, salicylic acid, ibuprofen, naproxen, ethenamide; In certain embodiments, the analgesic is aspirin. The aqueous solution of the analgesic suitable for intravenous administration provided by the present invention is stable. In certain embodiments, the present invention provides an aqueous solution of aspirin suitable for intravenous administration, which comprises the use of a ferric chloride method for undetectable concentrations of acid. After incubation at room temperature (about 2 rc) for 2 hours, 24 hours or even 44 hours, the aspirin solution may comprise salicylic acid using a gasification iron method undetectable indifference 127879.doc 200841887. Even at room temperature (about 2 hours, after hours or even 44 hours), these aspirin solutions can be less than 〇25%, less than 0.25%, less than 1%, less than 5% or less. At a hydrolysis degree of 25% (aspirin produces salicylic acid and acetic acid). Specifically, it is expected that the present invention provides an analgesic suitable for intravenous administration when stored in a pouch that can accommodate a conventional intravenous pharmaceutical solution in the industry. The aqueous solution will remain stable as described above. The invention also provides a method of treatment or prophylaxis using an aqueous solution of an analgesic suitable for intravenous administration. In general, such aqueous analgesic formulations are useful for the treatment or prevention of use by conventional means. The analgesic agent administers any disease or condition for treatment or prevention. Accordingly, the present invention provides a method of treating a patient in need of analgesic therapy comprising intravenously administering an aqueous analgesic formulation to a patient in need thereof, preferably a human. Wherein an effective amount of an analgesic agent is administered. The aqueous analgesic formulation is used in an amount effective to treat or prevent the disease or condition for treatment or pre-treatment The patient is administered intravenously. In certain embodiments, the intravenous pharmaceutical formulation is administered in an analgesic dosage of between about 50 mg to about 20 g, preferably about 5 mg. Between about 10 grams, and more preferably between about 1 gram and about 5 grams. In certain embodiments, the analgesic is aspirin and the intravenous administration of an aqueous formulation of aspirin provides the following plasma salicylate Concentration: between about 1 μg/ml to about 5 μg/ml, about 15 μg/ml to about 4 μg/3⁄4 liter, about 20 μg/ml to about 250 μg/ml, about 2 〇 microgram /ml to about 150 micrograms/ml or between about 30 micrograms/ml to about 1 microgram/ml. In certain embodiments, the plasma salicylate concentration can be even less than 丨〇 micro 127879.doc -22 - 200841887 g/亳升. ^ Pulse administration can provide the analgesic dose to achieve the desired therapeutic effect and it usually takes several minutes to several hours for the administration of the drug, but it may take longer, for example, up to 1 day, 2 days, 3 days or more. Intravenous administration can be performed by intravenous infusion, which is close to A stable rate of administration of an analgesic between about 50 mg to about 40 g over a period of from about 1 hour to about 7 days, or even longer. Preferably, from about 2 hours to about "hours, preferably about The administration is between about 800 mg to about 20 grams, more preferably between about i grams to about 15 grams, and even more preferably between about 4 hours and about 48 hours and even more preferably about 12 hours to about 24 hours. An analgesic agent of about 1 gram. Intravenous administration can achieve the following analgesic delivery rate: about 2 mg / hour to,,, 1 g / hour, about 10 gram / hour to about 75 〇 / mg, Approximately mg/hr to about 400 mg/hr or about 5 mg/hr to about 2 mg/hr and includes the following rates: about 10 mg/hr, about 20 mg/hr, about 253⁄4 g/hr, about 3 mg/hr, about 4 mg/hr, about 5 mg/hr, about 75 love: g/hr, about 1 mg/hr, about 125 mg/small, about 1503⁄4 g/hr, About 2 mg/hr, about 250 mg/hr, about 300 g/hr, about 35 mg/hr, about 4 mg/hr, about 50 0 mg / hour and about 75 mg / hour. In a preferred embodiment, aspirin is administered by intravenous infusion, wherein about 4 mg to about 40 g of aspirin is administered at a nearly constant rate over a period of from about 1 hour to about 120 hours. Preferably, the administration is between about 800 mg to about 20 g, for about 2 hours to about 72 hours, preferably about 6 hours to about 48 hours, and even more preferably about 12 hours to about 24 hours. It is between about 1 gram to t27879.doc -23- 200841887 is 15 grams between 'and even better between about 4 grams to about 1 gram of aspirin. Intravenous administration can also be administered by intravenous bolus injection of between about 5 mg to about 5 g of analgesic agent over a period of (1) minutes to about 5 minutes. Depending on the circumstances, it can then be infused slowly for a period of from about 100 milligrams to about m hours for from about 1 hour to about 120 hours.

In a preferred embodiment, aspirin can be administered by intravenous bolus injection of between about 100 mg to about gram of aspirin in from 2 minutes to about 5 minutes. Depending on the situation, then the infusion can be slowed for a period of about 1 〇〇 to about 12 hrs. The intravenous administration of an analgesic can also be repeated as needed. For example, the drug may be administered daily or every other day for 2 to 14 days, or every 3 days for 3 to 15 days, or once every 3 to 16 weeks, or during any other suitable time period. Repeat the drug. In another embodiment, the invention provides an analgesic intravenous administration at a rate of from about H, to about 7 days or longer, preferably from about 1 hour to about 76 hours, and more preferably about The following analgesic or analgesic metabolite plasma concentrations are maintained within 24 hours to (four) hours: between about 1 μg/ml to about 5 μg/ml, about 15 μg/ml to about 0.1 μg/ml, about shoulder / House rose to about 250 micrograms per milliliter, about 2 micrograms per milliliter to about 15 micrograms per milliliter or about 30 micrograms per milliliter to about 1 microgram per milliliter. In another embodiment, the invention provides intravenous administration of aspirin at a rate of from 1 hour to about 7 days or longer, preferably from about 1Q hours to (four) hours and more preferably from about 24 hours to about 48 hours. Maintain the following salicylate plasma concentration 127879.doc -24 - 200841887 degrees: between about 10 micrograms / ml to about 500 micrograms / ml, about 15 micrograms / ml to about 400 micrograms / ml, about 2 micrograms / ml To about 25 μg/ml, about 20 μg/ml to about 15 μg/ml or about 3 μg/ml to about 1 μg/ml. The intravenous pharmaceutical formulation of the present invention maintains a desired, substantially constant blood analgesic concentration. In certain embodiments, a substantially constant low concentration analgesic can be provided. In certain embodiments, a substantially constant intermediate concentration analgesic can be provided. In certain embodiments, a substantially constant high concentration analgesic can be provided. Therefore, the present invention provides an analgesic intravenous administration to maintain the plasma concentration of an analgesic or analgesic metabolite at 5 μg/ml soil 10 〇 / 〇, 1 〇 microgram / ml soil 10 〇 / 〇, 15 μg / ml ± 1 〇〇/0, 2〇μg/ml ±10〇/〇, 25μg/ml ±10%, 30μg/ml ±1〇〇/0, 4〇μg/ml±ι〇〇/ο, 6〇μg / House lift ± 10% or 75 μg / ml ± 1 〇〇 / 0, up to about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours , about 144 hours or longer. In certain embodiments, the invention provides intravenous administration of aspirin to maintain a salicylate plasma concentration of 5 micrograms per milliliter ± 10%, 10 micrograms per milliliter ± 1%, 15 micrograms per milliliter ± 1%, 2 〇μg / ml ± 10%, 25 μg / ml ± ι〇%, 30 μg / ml soil 1 〇 0 / 〇, 4 〇 microgram / ml ± 10%, 60 μg / ml ± 10 〇 / 〇 or 75 μg / ML ± 1 〇 0 / 〇, up to about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours or longer. The invention also provides an analgesic intravenous administration to maintain the plasma sputum of the analgesic or analgesic metabolite at 100 μg/ml soil 10%, microgram/ml + I27879.doc -25-200841887 10%, 120 μg/ml ±10%, 130 μg/ml ± 10%, 140 μg/ml ± 10%, 15 μg/ml ± 10%, 175 μg/ml ± 10%, 200 μg/ml ± 10% or 250 μg/ml ± 10%, up to about 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours or longer. In certain embodiments, the invention provides intravenous administration of aspirin to maintain salicylate plasma concentrations at 100 micrograms per milliliter ± 10%, 110 micrograms per milliliter ± 10%, 120 micrograms per milliliter of soil, 10%, 130 micrograms per second. ML ± 10%, 140 μg / ml ± 1 〇〇 / 0, 150 μg / ml ± 10%, 175 μg / ml ± 10%, 200 μg / ml ± 10% or 25 0 μg / ml ± 10%, up to About 1 hour, about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, about 144 hours or longer. The invention also provides an analgesic intravenous administration to maintain the plasma concentration of the analgesic or analgesic metabolite at 250 micrograms per milliliter ± 10%, 300 micrograms per milliliter of soil 10%, 400 micrograms per milliliter ± 1% or 500 micrograms per minute. ML ± 1 〇 0 / 〇, up to about 1 hour, about 2 hours, about 4 hours 'about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours or about 144 hours. In certain embodiments, the invention provides intravenous administration of aspirin to maintain salicylate plasma concentrations at 250 micrograms per milliliter of soil 10%, 3 micrograms per milliliter ± 1 〇 0/〇, 4 micrograms per milliliter. ±10% or 500 μg/ml of soil 10 〇/〇 for about 2 hours, about 4 hours, about 8 hours, about 12 hours, about 24 hours, about 48 hours, about 96 hours, or about 144 hours. In certain embodiments, the invention provides for intravenous administration of aspirin to obtain 127879.doc -26 - 200841887 at about 120 micrograms in about 1 knives, preferably within about 5 minutes and even more preferably within about 20 minutes. Plasma salicylate concentration between milliliters to about 35 micrograms per milliliter. After reaching a plasma salicylate concentration of from about 120 micrograms/ml to about 35 micrograms/ml, the plasma salicylate concentration between about 120 micrograms/ml and about 35 micrograms/ml can be maintained for about 2 hours. About 4 hours, about 8 hours, about 12 hours, about 24 hours, about hours, about 96 hours, or about 144 hours. In another embodiment, the invention provides an intravenous administration of an analgesic such that the 6-hour Auc of the analgesic or analgesic metabolite is between about 3 mM* hours to about mM* hours, preferably about 2 mM. * hours to about 1 mM * hours and even more preferably between about 3 mM * hours to about 8 mM * hours. In another embodiment, the invention provides intravenous administration of an analgesic such that the 12 hour AUC of the analgesic or analgesic metabolite is between about 0.6 mM* hours to about 30 mM* hours, preferably between about 4 mM* hours. Approximately 20 mM* hours and even more preferably between about 6 mM* hours to about 16 mM* hours. In another embodiment, the invention provides intravenous administration of an analgesic such that the 24 hour AUC of the analgesic or analgesic metabolite is between about 1.2 mM* hours to about 60 mM* hours, preferably between about 8 mM* hours. Approximately 40 mM* hours and even more preferably between about 12 mM* hours to about 32 mM* hours. In another embodiment, the invention provides intravenous administration of aspirin such that the 6 hour AUC of the salicylate ranges from 0.3 mM*hr to about 15 mM*hr, preferably from about 2 mM*hr to about 1 hr. Even more preferably between about 3 mM* hours to about 8 mM* hours. In another embodiment, the invention is: intravenously administered to aspirin such that the 12 hour AUC of the salicylate is between about 0.6 mM*hr and about 30 mM*hr, preferably between about 4 mM*hr 127879.doc -27- 200841887 to about 20 mM* hours and even more preferably between about 6 mM* hours to about 16 mM* hours. In another embodiment, the invention provides intravenous administration of aspirin such that the 24-hour AUC of the salicylate ranges from about 1.25 mM*hr to about 60 mM*hr, preferably from about 8 mM*hr to about 40. mM* hours and even more preferably between about 12 mM* hours to about 32 mM* hours. The present invention provides a method of preparing an intravenously administered formulation of an analgesic. In general, the method of preparing an intravenous administration formulation is well known in the art and can be found, for example, in "Remington: The Science and Practice 〇fpharmacyn (2nd edition, editor A·R·G_aro AR, 2〇〇〇) , LiPPinc〇tt Williams & Wilkins). The water-soluble analgesic compositions described herein can be formulated using known methods for preparing intravenous administration formulations. The formulation for intravenous administration of the present invention may be, for example, any one of aqueous solutions such as sterile water, isotonic saline, isotonic dextran, or other aqueous solutions commonly used in the preparation of intravenous pharmaceutical formulations or such The combination is prepared. In certain embodiments, the pH of the intravenous administration formulation can be adjusted to about the normal pH of human blood (i.e., pH 7.4). Preferably, this can be performed immediately prior to administration of the intravenously administered formulation. The present invention provides a method of preparing an analgesic formulation suitable for intravenous, bacteriological, comprising: (a) & an analgesic containing granules; 屌M composition comprising: (i) a matrix core; Ii) a coating of a depolymerization product formed on the core of the matrix, the coating comprising a salt of an analgesic agent, but a solid particle; a non-salt form of a 3-side analgesic 127879.doc -28- 200841887 (8) the analgesic The composition is dissolved in an aqueous solution to produce an analgesic formulation suitable for intravenous administration; wherein the pH of the analgesic formulation suitable for intravenous administration is less than about 6.0 〇-. In certain embodiments, the salt of the analgesic is the potassium salt of the analgesic. In certain embodiments of the above methods, the step of obtaining an analgesic composition comprises: providing a first solution comprising a base; adding the analgesic to the first solution to produce a second solution comprising a salt of an analgesic; The second solution is filtered to remove residual analgesic particles to produce a filtered first solution; and the filtered second solution is sprayed onto the base to form agglomerated product comprising a plurality of particles. In some embodiments, the test comprises triclination of citric acid monohydrate. In some embodiments, the first solution further comprises a surfactant, preferably a lauric sulfate steel. In certain embodiments, the matrix is selected from the group consisting of mono-branched, disaccharide: poly-, dipeptide, and combinations thereof. Preferably, the substrate is sucrose, cellulose, xylitol or D-glucose. In certain embodiments, the step of drying the filtered second solution onto the base shell is a fluidized bed spray drying process. The invention also includes a method of preparing an intravenously administered formulation of an analgesic comprising: 127879.doc -29. 200841887 (a) providing a solid analgesic composition comprising: (i) an analgesic; (ii) a single Hydrating tripotassium citrate; and (iii) a surfactant; (9) dissolving the solid analgesic composition in an aqueous solution to form an intravenous administration formulation of the analgesic; /, medium 4 analgesic intravenous administration formulation The yang is lower than about & ^In a two-pronged example, the positive pain agent is selected from the group consisting of aspirin, aminosalicylic acid, ibuprofen, naproxen, and ethenamide. In certain embodiments, the analgesic is aspirin. In certain embodiments, the dissolution is completed in less than about 15 seconds, less than about 3 seconds, less than about 6, less than about 12 seconds, or less than about 240 seconds. In some embodiments, the dissolution is from about 15 seconds to about leap seconds, preferably from about % seconds to about (3) seconds. The example plant is an exemplary intravenous and sputum preparation prepared from a water-soluble aspirin composition. 4 The following solubility test is carried out using deionized water and rapid magnetic force, which is carried out under the temperature of hunger. 2 Add the whole amount of the composition to the water in portions. It should also be understood that the term "completely dissolved" means that there is no visible particle in the solution of the composition mixed with water after a specified period of time. Example 1 Aspirin (625.0 g) was added portionwise to i 75 〇 单 单 单 单 单 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二 二】27879.do< -30 - 200841887 To remove traces of insoluble aspirin by filtration. A fluidized bed spray processor was used (inlet temperature: 45 to 47 ° C; outlet temperature: 38 to 39. The resulting clear solution was slowly applied to 2623.5 g of sucrose. The resulting agglomerates contained a median particle size of about 200 μ Granular product. Detected by ferric chloride method with a low degree of hydrolysis of 25%, no detectable concentration of salicylic acid. Take one-part (5.2 g 'containing 650 mg of aspirin) to obtain a free-flowing product. Add to 100 ml of water with stirring and mixing. It is palatable and can be completely dissolved in 15 seconds. The pH is 5.87. ^ Example 2 Shake 30 g of aspirin and 7 g of monohydrate lemon with rocker equipment a mixture of tripotassium, 100.0 grams of sucrose and 6 milligrams of sodium lauryl sulfate to ensure homogeneity. The resulting free-flow product is stable at 50t for at least 3 weeks and at 75. Ultraviolet light (2 $ 4 nm) is very stable for at least 1 week. It is detected by ferric chloride method which can detect low hydrolysis degree of G.25%, no detectable concentration of salicylic acid. Stirring and mixing Lu adds 3 33 grams to 150 ml of purified water The mixture (containing 鸠mg a. spirin), which is palatable and substantially dissolves in 15 seconds, completely dissolves in 18 sec seconds, and has a pH of 5.67. Example 3 Full shake using a rocker device 3 〇〇 A mixture of gram of aspirin, 7 grams of monohydrate, potassium, 2 parts, aspartame, and 36 mg of sodium lauryl sulfate to ensure homogeneity. Stable for at least 3 weeks and at 7fC for at least 2 weeks. Detected by ferric chloride method with a degree of hydrolysis of 0.2%, no detectable concentration of 127879.doc -31 - 200841887 degrees Acid. 2.00 grams of this mixture (containing 500 mg of aspirin) was added to 150 ml of purified water while stirring and mixing, which was palatable and substantially soluble in 15 seconds, completely dissolved in 240 seconds, and had a pH of 5.93. Example 4 A mixture of 30.0 g of aspirin, 70.0 g of tripotassium citrate monohydrate, 20.0 g of sucralose and 36 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure homogeneity. The resulting free flowing product was at 50 °C. Stable for at least 3 weeks. Detected with ferric chloride method capable of detecting a degree of hydrolysis as low as 0.2 5%, no detectable concentration of salicylic acid. Add 2,0 g of this mixture (containing 5) to 1 5 ml of purified water while stirring and mixing. 〇〇mg of aspirin), which is palatable and can be dissolved in substantially 30 seconds, completely dissolved in 210 seconds, and has a pH of 5.74. Example 5 Part of the product of Example 1 (4.75 g, containing 5 61 mg of aspirin) Mix well with 200 mg of Vitamin C. The resulting free flowing product was dissolved in 100 liters of water while mixing. The free-flowing product is fully soluble in 3 sec seconds with a pH of 5.63 and is palatable. Example 6 A portion of the product of Example 1 (4.75 g, containing 561 mg of aspirin) was thoroughly mixed with 50 mg of caffeine. The resulting free flowing product was dissolved in 100 ml of water while stirring and mixing. The free-flowing product is fully soluble in 3 seconds and has a pH of 5 to 86 and is palatable. Example 7 A shaker apparatus was used to thoroughly shake a mixture of η·8 g of aspirin, 331 g of monohydrate 127879.doc -32- 200841887 dipotassium citrate, 70.0 g of D-glucose (dextrose) and 3 g of sodium sulphate. Ensure homogeneity, produce white free flow 1::: Test with ferric chloride method with a detectable low hydrolysis of 0.25%, no detectable concentration of salicylic acid. Adding 316 grams of this mixture to 38 ml of purified water with agitation was fully soluble in 30 seconds. The solution contained 丨^克 (5. 〇%) D·glucose and 325 mg of aspirin, and the cation was 5 ingredients. Example 8 48 g of aspirin, 134 g of tripotassium citrate monohydrate, 20·0 g of crystalline xylitol and 12 mg of sodium lauryl sulfate were shaken well using a rocker apparatus to ensure uniformity and white free flow. product. With stirring and mixing, add 2·6 gram of this mixture (containing 325 mg of aspirin) to 100 ml of purified water. It is palatable and can be dissolved in 15 seconds, completely dissolved in 6 seconds, and the pH is 5.99. . Example 9 A shaker apparatus was used to sufficiently shake a mixture of 4.8 g of aspirin, 3.4 g of monohydrated dipotassium citrate, 2 g of microcrystalline cellulose, and 12 mg of sodium lauryl sulfate to ensure uniformity and white freedom. Flow product. The free-flowing product is insoluble in water and can be compressed into pellets or wafers. As can be seen from the above examples, the pH of each intravenously administered formulation is below 6 〇 as described above, which provides a number of distinct advantages. By varying the amount of aspirin in the composition used to prepare the intravenous administration formulation according to the amount of tripotassium citrate monohydrate, it is ensured that the pH is maintained within the desired range (i.e., <6<6>). More specifically, when the aspirin content is greater than about 26% by weight of the combined weight of aspirin and tripotassium citrate monohydrate (ie, between 26% and 127879.doc -33 - 200841887 40% of aspirin), the resulting solution Less than 6 〇. For example, Example 1 above has an aspirin content of about 263% and _ is 5.87, while Example 2 above has an aspirin content of about 3% and a mouth of 5.67. On the other hand, when the aspirin content is less than about %% (i.e., between 0/〇 and 26% of aspirin), the pH of the resulting solution is greater than 6 〇. For example, Example 5 of U.S. Patent No. 5,776,431 to Galat has an aspirin content of about 20,000 angstroms/inch. 11 is 612. The relationship between the percentage of aspirin content and the pH of the resulting solution is shown in Figure 7. The above teachings, findings, procedures and methods specifically discuss acetaminophen (aspirin) as an active therapeutic agent for the formulation, and they are also applicable to other analgesics. Therefore, the present invention is not limited to the intravenous administration of aspirin. Rather, it generally covers intravenous administration of analgesics. For example, the invention encompasses formulations in which a water insoluble salicylic acid derivative is used as an active therapeutic agent. For example, 5-aminosalicylic acid (mesalamine) can be used to treat inflammatory bowel disease, for example, ulcerative colitis. Mesalazine is insoluble in water and is therefore commonly used in extended release capsules or as a suppository. Usually, a larger dose of mesalamine (4 g/day) is required to treat inflammatory bowel disease. It has been reported that the solubility-pH characteristic curve of mesalazine is increased at ρΗ<2·0 and ρΗ>5·5. According to the teachings of the present application, the three-week formulation of Mesalamine produces a pH of 6.8 6 whereby a rapidly acting homogeneous aqueous solution can be obtained. The formulation can comprise a variety of matrices including sucrose. Other water insoluble analgesics (including acetaminophen (see Example 11 below), ibuprofen (see Example 12) and naproxen (see Example 13 below) can be prepared using this novel formulation procedure. 127879.doc -34 - 200841887 The following are a number of exemplary formulations of the water-soluble analgesic compositions of the present invention which employ an analgesic effect other than acetyl salicylic acid (aspirin) as an active therapeutic agent. Example 10

A mixture of 800 mg of mesalazine, 10 g of monopotassium citrate monohydrate, 14.92 g of cane tart and 8 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure homogeneity, resulting in an off-white free-flowing product. When the mixture was mixed, 6 · 39 g of this mixture (containing 3 2 5 mg of methadone) was dissolved in 100 ml of purified water to dissolve most in 15 seconds and completely dissolve in 25 seconds. The pH of the solution was 6.86 and was palatable. Example 11 A shaker apparatus was used to sufficiently shake a mixture of 1·2 g of acetaminophen, 3.35 g of monohydrate #tribasic potassium, 5.0 g of sucrose, and 3 mg of sodium lauryl sulfate to ensure uniformity and white freedom. Flow product. When stirred, 2·7 g of this mixture (containing 325 mg of acetaminophen) was added to 1 Torr of purified water to dissolve mostly in 15 seconds and completely dissolve in 45 seconds. The pH of the solution was 7·80 and was palatable. Example 12 A mixture of 125 mg of ibuprofen, 2.50 g of monohydrate, dipotassium citrate, 3.73 g of sucrose, and 2 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure homogeneity, resulting in a white free-flowing product. The mixture (containing 125 mg of ibuprofen) was added to 75 ml of purified water while stirring to dissolve on the shell within 15 seconds and completely dissolve in 240 seconds. The solution is ρ Η ^ 7.23 and is palatable. 127879.doc -35- 200841887 Example 13 Using a rocker arm, shake the mixture of 1253⁄4 g of naproxen, 2.5 g of monopotassium citrate monohydrate, 3.73 g of sucrose and 2 mg of sodium lauryl sulfate to ensure homogeneity. Produces a white free flowing product. The mixture (containing 125 mg of ibuprofen) added to one milliliter of purified water upon scrambling was substantially dissolved in 15 seconds and completely dissolved in 60 seconds. What about the solution? 11 is 74 适 and palatable 〇 Example 14 Aspirin (375.0 g) was added portionwise to 1 〇 5 g of monohydrate trichosting acid in a solution of 6.0 liters of water (containing 9 g of sodium lauryl sulfate) . Continue mechanical stirring for 15 minutes until the solution is nearly uniform. Vacuum filtration to a 4G male phase was carried out by a 2 liter liter medium sintered glass funnel to remove traces of insoluble aspirin. The resulting clear solution was filled into a non-recorded steel reservoir and slowly applied to 3 IM S grams of sucrose using a 22 aliter granulator fluidized bed spray processor. Stirring and filtration as described in the first part was added to 1050.0 g of monohydrated citric acid and the second part of aspirin was dissolved in another 6. liters of water (containing 9 g of sodium lauryl sulfate). (375 grams). The π water solution is also filled into a stainless steel reservoir and applied to the sucrose already stored in the fluidized bed squirt processor. & Aspirin (total weight: 75〇·〇克) I hydrated citric acid three unloading (total weight i: 21GG.0g) and sodium lauryl sulfate (total weight: gram) are guided to the total volume as follows 12. 〇 liter of water: The above aspirin solution (14,772 grams) was sprayed into the fluidized bed 5) over 567 minutes. The initial spray rate for the first 323 minute spray was 21 grams of "clock. A final spray rate of 35 grams per minute was obtained. The inlet air temperature ranged from 45 ° C to 47 t throughout the 127879.doc -36 - 200841887 process. This resulted in a product temperature between 38 ° C and 39 ° C during the spray and a final product temperature of 42 ° C after drying. The total treatment time in GPCG 5 was 574 minutes. The theoretical president of matter is measured at 89% (5,327 kg). The available yield is 79% (4.751 kg), and the deviation of 576.576 kg is caused by filter particles. The resulting aggregate contains a median particle size of about 2〇. 〇μ granular product and contains

11 articles of aspirin (measured by HPLC analysis). The test was carried out using a ferric chloride method which can detect a degree of hydrolysis as low as 0.25%, and no salicylic acid of detectable concentration. The resulting free-flowing product portion (5.2 g, containing 614 mg of aspirin), which was stored in 100 ml of water while stirring and mixing, was palatable and completely soluble in % seconds and had a pH of 5.87. Since the analgesic formulations of the present invention use known analgesics, the formula (4) can be used to prevent and treat all known conditions and diseases currently treated with known formulations of such analgesics. , type of scholar, etc. However, many of the advantages of the formulations of the analgesic intravenous steroids of the present invention discussed above are expected to be broadly applicable to such formulations. See the ~I invention provides an intravenously administered formulation of an analgesic agent that is supplemented with a previously known analgesic formulation: the analgesic intravenous formulation is not sodium and can be administered to the blood. Rapid delivery of analgesics, ', can be used in certain medical conditions and does not lead to L to large agents! Use 'and/or may be longer +曰V to cause bowel discomfort and/or injury. Although the description of the various parts, the text, and the like is described in detail with reference to the 127879.doc-37-200841887, it is not intended to exhaust all possible permutations or features, and in fact, those skilled in the art may Identify many other improvements and variations. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the time-dependent change in salicylate concentration of a water-soluble aspirin composition and a well-known commercially available aspirin formulation based on data collected after oral administration to a human patient. Figure 2 illustrates the weight percent of product as a function of the median diameter of the particles of the water-soluble aspirin composition suitable for use in the manufacture of the intravenous pharmaceutical formulation of the present invention. 3-6 show scanning electron micrographs of water-soluble aspirin compositions suitable for use in the production of intravenous pharmaceutical medicinal formulations of the invention at different magnifications. Figure 3 (magnification scale: 29 〇 μ); Figure 4 (magnification Magnification: ι4〇...; Figure 5 (magnification ruler: 20 μ); and Figure 6 (magnification ruler: 4 μ). Figure 7 shows the relationship between pH and % by weight of aspirin, the weight of the aspirin % is based on the combined weight of aspirin and tripotassium citrate monohydrate, which are suitable for the production of the water-soluble aspirin composition of the intravenous pharmaceutical formulation of the present invention. 127879.doc 38-

Claims (1)

200841887 X. Patent application scope: · i An aqueous solution containing analgesics for intravenous administration to humans, wherein the concentration of the analgesic agent of the Loose solution is between 100 μg/ml and about 15 mg/ml and the pH of the aqueous solution Less than about 6 〇. The aqueous solution of claim 1, wherein the analgesic is selected from the group consisting of aspiramide salicylic acid, ibuprofen, naproxen, acetaminophen, and combinations thereof. . 3. The aqueous solution according to item 2, wherein the analgesic agent is aspirin and the solution comprises sodium lauryl sulfate and dissolved monohydrated potassium monopotassium. 4. The aqueous solution of claim 3, wherein the aspirin comprises at least about 26% by weight of the combined weight of the aspirin and the monohydrate citrate. 5. The aqueous solution of claim 4, wherein the aspirin comprises from about 26% to about 40% by weight of the combined weight of the aspirin and the 'combined monopotassium citrate monohydrate. 如6. The pH is from about to about 7. The aqueous solution of claim 6 wherein the pH is from about 5.6 to about 6.0. 8. A method of preparing an analgesic formulation suitable for intravenous administration comprising: (a) providing an analgesic composition comprising granules comprising: (I) a matrix core; and (II) disposed on a substrate a coating of agglomerated product on the core, the coating comprising a salt of an analgesic, but not containing the analgesic form of the particles; ^ (b) dissolving the analgesic composition in an aqueous solution to produce a suitable 127879.doc 200841887 An analgesic formulation for intravenous administration; wherein the pH of the analgesic formulation suitable for intravenous administration is less than about 6.0. The method of claim 8 wherein the analgesic salt is the potassium salt of the analgesic 〇10. The method of claim 9, wherein: the step of providing an analgesic composition comprises (a) providing a first solution comprising a base; (b) adding an analgesic to the first solution to produce the inclusion a second solution of the salt of the analgesic; (4) filtering the second solution to remove residual analgesic particles to produce a filtered second solution; and (d) spray drying the substrate onto the substrate. To form inclusion The plurality of particles agglomerated product. Citric acid η. The method of claim 395, wherein the test comprises dissolved monohydrate triple unloading. 12. The method of claim 10, wherein the surfactant is active. The cardiac solution further comprises the method of claim 13. = claim 12, wherein the lauryl sulfate (4) 2 method is a method wherein the matrix is a group consisting of a polysaccharide, a dipeptide, and a combination thereof. Mistakes 'Cellulose, xylose 15. The method of claim 14 wherein the matrix is a glycitol or D. glucose. The method of claim 10, wherein the step of spray drying the filtered second solution onto the substrate is carried out by a fluidized bed spray drying method. 17. A method of preparing an analgesic formulation suitable for intravenous administration, comprising: (a) providing a solid analgesic composition comprising: (i) an analgesic; (ϋ) tripotassium citrate monohydrate; and (iii) a surfactant; (b) dissolving the analgesic composition in an aqueous solution to produce an analgesic formulation suitable for intravenous administration; wherein the application is for intravenous administration The pH of the analgesic formulation is less than about wherein the analgesic composition comprises particles, and the method-specific particles of claim 17 comprise: (a) a matrix core; (b) a salt, particle disposed on the matrix nucleus comprising an analgesic. A coating of a reduced polymerization product is formed on the heart, but the package is substantially free of the non-salt form of the analgesic. 19. The method of claim 18, wherein the sugar, the polysaccharide, the dipeptide, and the combination of the combinations. 20. The method of claim 19, wherein the core of the sylvestre octadecyl ketone comprises sucralose, xylitol or D-glucose. 21. A method of intravenous administration of an analgesic comprising: (a) providing a solid analgesic composition comprising: 127879.doc 200841887 (i) an analgesic; (11) tripotassium citrate monohydrate; (iii) a surfactant; (9) dissolving the analgesic composition in an aqueous solution to produce an analgesic formulation suitable for intravenous administration; wherein the pH of the analgesic formulation suitable for intravenous infusion is low. At about 6.0; (c) intravenously administering the analgesic formulation suitable for intravenous administration to a patient in need thereof. The method of claim 21, wherein the analgesic agent is selected from the group consisting of aspirin, 5-aminosalicylic acid, ibuprofen, naproxen, acetaminophen, and combinations thereof. 23. The method of claim 22, wherein the analgesic is aspirin. 24. The method of claim 23, wherein the aspirin is administered intravenously at a daily dose of from about 1 mg to about gram. 25. The method of claim 23, wherein the aspirin is administered intravenously at a dose of from about 5 mg to about $ gram. 26. The method of claim 23, wherein the aspirin is administered intravenously at a dose of from about 1 gram to about 3 grams. 27. The method of claim 23, wherein the aspirin is administered intravenously to maintain a plasma salicylate concentration of from about 10 micrograms per milliliter to about 500 micrograms per milliliter for at least about 6 hours. 28. The method of claim 23, wherein the aspirin is administered intravenously to maintain a plasma salicylate concentration of from about 10 micrograms per milliliter to about 500 micrograms per milliliter of 127879.doc 200841887 for at least about 24 hours. 29. The method of claim 23, wherein the aspirin is administered intravenously to maintain the plasma salicylate at a level of from about 50 micrograms per milliliter to about 1 (10) micrograms per milliliter for at least about 6 hours. 3. The method of claim 23, wherein the aspirin is administered intravenously to maintain a plasma salicylate concentration of from about 50 micrograms per milliliter to about 1 microgram per milliliter for at least about 24 hours. The method of claim 23, wherein the aspirin is administered intravenously to maintain the blood salicylate concentration at from about 120 μg/ml to about 35 μg/ml for at least about 6 hours. 32. The method of claim 23, wherein the aspirin is administered intravenously to maintain a plasma salicylate concentration of from about 120 micrograms/ml to about 35 micrograms per milliliter for at least about 24 hours. 33. The method of claim 23, wherein the aspirin is administered intravenously such that the salicylic acid salt has a 6 hour AUC of between about 0.3 mM*hours to about 15 mM*hours. A method of treating or preventing a human disease or a medical condition, comprising administering an effective amount of an analgesic aqueous solution to a human in need of such treatment or prevention, wherein the pH of the aqueous analgesic solution is less than about 6. 127879.doc