TW200906419A - Orally disintegrating water soluble analgesic formulations and methods for production thereof - Google Patents

Abstract

A water soluble analgesic composition in the form of an orally disintegrating tablet, wafer, pellet, or lozenge includes a plurality of granules is provided. Each of the granules includes a substrate core and a coating disposed on the substrate core forming an agglomerated product, the coating including a salt of an analgesic, but substantially no particles of a non-salt form of the analgesic. The composition may be created by a method including the steps of: (i) providing a first solution comprising a base, (ii) adding an analgesic to the first solution to create a second solution including a salt of the analgesic, (iii) filtering the second solution to remove residual particles of the analgesic to create a filtered second solution, (iv) spray drying the filtered second solution onto a substrate to form an agglomerated product having a plurality of granules, and (v) compressing, molding, or otherwise forming the agglomerated product, optionally with other excipients, into an orally disintegrating tablet, wafer, pellet, or lozenge.

Description

200906419 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION [Invention] The present invention relates to aspirin and other analgesic compositions, and more particularly to water-soluble formulations of previously known aspirin and other analgesic compositions. Oral decomposing formulations of water-soluble aspirin and other analgesic compositions having enhanced stability and biological activity. [Prior Art] Acetylsalicylic acid (aspirin, a family of non-steroidal anti-inflammatory drugs (NSAIDs), which is known as a non-steroidal anti-inflammatory drug (NSAID), is known to have end, pain, antipyretic and anti-inflammatory properties. These multiple properties make it an ideal therapeutic agent for relieving pain, including but not limited to treating headaches, and 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 B is fermented with a serine residue at the active site of a synthetic enzyme (i.e., an enzyme that catalyzes the conversion of tetradecene to PGH2). This acetylation of PGH2 synthetase inhibits the action of the enzyme and thus inhibits prostaglandin synthesis. In the last 50 years, aspirin has also been shown to have significant anticoagulant benefits. The anticoagulant effect of aspirin is mediated by inhibition of platelets. The music can block platelet enzymes, % hydrazine enzymes by acetylating the active site of the yeast Xinjing. Inhibition of the fermentation of the enzyme can be achieved by the "T-T-blocking", an important pro-thrombotic agent. Coagulation, Lv', causes platelet activation and accumulation with alkane A2. This is an early step in thrombosis. Now, 'several platelet inhibitors are available, but aspirin is still the most popular use in this class (1) and is also A highly cost-effective anticoagulant. Aspirin (mother day 81 mg or 325 mg) suitable for 127880.doc 200906419 for sputum J sputum. unstable red pain (acute coronary myocardial infarction, myocardial infarction - grade ^ 俣 group), acute muscle infarction Prevention of stage-level prevention, secondary prevention of stroke (carotid or cerebrovascular disease), prevention of peripheral arterial thrombosis, and prevention of venous thrombosis (deep vein thrombosis, pulmonary embolism). Recently, studies have also used aspirin (alone or in combination with other medicines) to treat various types of tumors. Pharmacokinetic properties of aspirin (absorption, distribution, metabolism, and elimination)

Very important. After the enteral administration, the absorption of A. Lin involves entering the bloodstream through appropriate sputum. , absorbance and solubility, dosage form 'excipients and particle size. In general, fat-soluble, undissociated forms of the drug are easy to penetrate the membrane. "Spirit: ionization is produced in the stomach (low pH); therefore, aspirin can be worn in its non-ionized (uncharged) form. The gastric mucosa is absorbed into the bloodstream in a large amount. The main metabolic pathway of aspirin is hydrolyzed by esterase to salicylic acid which cannot inhibit the synthesis of prostaglandins. U s has been reported to be used in various pathophysiological environments (self-use: dirty = low doses for seizures and stroke prevention to agents for 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 sputum, which may cause anemia caused by blood loss. More specifically, S, the usual dose of aspirin (325 mg or 500 mg) is generally considered to be sufficient for "aspirin therapy" to reduce heart attack And/or the possibility of a stroke. However, these doses only reduce the symptoms of arthritis (also known as 'pain') and cannot treat underlying inflammation. For the etiology: efficacy control, usually (10) to 5, _mg 2 inflammatory tincture is required to maintain the plasma salicylate concentration within the i j : liter range. In the higher (four) thick m T / n 7 〇 /. . However, at lower doses, the success rate was significantly lower when the dose was 25 GG mg and the success rate was less than that of Cong. Because of the ineffective or lack of success in the middle of aspirin therapy, the second reason is that the dose is not sufficient.邛 邛 撼 ’ ’ ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' In the case of low analgesic doses, these side effects are present in adult aspirin users. However. City is now added. The prolonged use of the number of & aspirin will increase significantly, and the incidence of such undesired side effects will increase as the anti-inflammatory dose is increased. Moreover, this number will be significantly extended with the treatment plan. The gastrointestinal side effects of aspirin are often local sub-forests with their current conventional use of π 4 and the field aspirin (suspension) (4), its insoluble particle layer: attached to the gastric mucosa, This can cause irritation and inflammation

The locality of the role of the Zhuang Shishi site and the temple harmful field 丨J Aspirin in the stomach of the second L autopsy confirmed. For example, it has been documented that + stomach __ has been found in many literatures, so its effects are cumulative and direct stimulation of the η membrane is used. == Pilin is administered in solution, and no partial (IV) A w forest system can benefit from its 127880.doc 200906419 soluble form, the elderly patients and the party can ask for this soluble aspirin, because arthritis is a terrible πσ Titanium county The largest user of aspirin in the elderly group system is also the victim of the same. The acute side effects of Ί Ί 林 最 最 最 由于 由于 由于 由于 由于 由于 由于 由于 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性 急性m Bu, it is estimated that over 15 million people in the United States are swallowing. In the case of swallow tablets and other solid medicines, there is a certain degree of difficulty. As the esophageal muscle grows with age (4), older people will once again influence and make it more difficult. The low water solubility and the possibility of hydrolysis of aspirin make 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, it is more stable at lower pH and most stable at ρΗ2·4. It is well known that there are a number of soluble aspirin products that are commercially available in money and m. It is a testament to the fact that they have a variety of products or a variety of defects, especially in the United States. For example, Alka Seltzer@, the only soluble product widely available in the United States (by Bayer)

Healthcare LLC available) contains 567 mg sodium/325 mg aspirin (1,750 mg sodium/ι,000 mg aspirin for anti-inflammatory activity when taking Aika Seitzer@, may require more than 8, 〇〇〇 mg per ounce The amount of sodium causes Alka Seltzer® to be unacceptable for conventional aspirin therapy, not only because the sodium concentration is too high for the general population, but also for many elderly patients with arthritis (which also requires strict sodium limitation). Drinking R) can not bear the fork. Even the sodium concentration associated with lower doses of aspirin, which is effective in reducing the risk of heart attack and/or stroke, is unacceptably high. 0 Dominant European 'drinkable analgesics mostly positive Solution. Most of these products (such as Aika in the drinkable analgesic account for a fine suspension rather than true

Seltzer®) is sodium-based and takes a long time to dissolve and is not completely palatable. Some products are predominantly inter-systematic to prevent complete dissolution of aspirin. : Known - a kind of French soluble analgesic product "". However, this product contains non-natural cU-type lysine, which may be difficult to barely get the US fda batch to go to Dali to try to produce acceptable solubility. Aspirin produces ° σ, but it has been confirmed that none of them is completely satisfactory. For example, 'the American faecal scorpion that grants Phykitt', Philippine 131, Philippine No. 5, 665, 388 and No. 5, 723, 453 reveal that one basically contains no sodium. Soluble test of aspirin compound H has many disadvantages, and one of the disadvantages disclosed is that the bicarbonate used forms gas when the patient ingests. Another disadvantage is The relatively high pH of the disclosed compositions (i.e., greater than 8, will lead to rapid hydrolysis and instability, and thus shorten shelf life. Granted Galat's US patent 荦笫s 1ς 茱 茱 5 5, 157,03 及 and 5,77Μ31 also disclose aspirin compounds, which are similar to those of the prior art patents disclosed in the above-mentioned prior art patents. Specifically, disclosed in Such Examination of the literature composition. ,, Gan thinking timely water with more than pH 6.0 127880.doc • 10 · fish

The final pH of 200906419. This can result in relatively unstable compositions, reduced shelf life, and difficulty in absorption by the human body. This is due to the ease of dissociation of the aspirin component. This will also result in a relatively slow dissolution of the composition in the water. It has been found that the composition formulated according to the Galat patent takes up to 2 to 3 minutes to be substantially completely soluble in water. Further, many of the formulations disclosed in the Galat patent are considered to be disadvantageous in terms of production, packaging, and use as two separate compositions (mixture "A" and mixture "βΠ). In addition, the 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 in relatively large doses for anti-inflammatory treatment, and/or Long-term use without causing gastrointestinal discomfort and/or damage. Thus, there is a need for a water-soluble analgesic composition which has enhanced stability and biological activity and which does not have the above disadvantages, compared to previously known water-soluble analgesic compositions. The present invention provides such an analgesic composition in the form of an oral decomposing lozenge, a rice paper sachet, a pill or a rhomboid tablet in the form of a suitable towel 7, a sublingual, buccal or gingival administration of an analgesic. SUMMARY OF THE INVENTION * Provided is a water-soluble analgesic composition in the form of an oral decomposing lozenge, a wafer, a pill or a rhombic tablet, which has an enhancement compared to the previously known water-soluble analgesic group D. Stability and biological activity. Another object of the present invention is to provide a water having the above characteristics and containing no sodium in the form of 127880.doc 200906419 ==: 糯 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ And can be quickly accepted: water is a water-soluble analgesic composition in the form of an oral decomposing agent, a wafer, a pill or a diamond-shaped bond. A further object of the present invention is to provide a water-soluble analgesic composition in the form of an orally dissolving lozenge, wafer, pill or lozenge tablet having the above characteristics and which acts rapidly and rapidly enters the bloodstream. A further object of the present invention is to provide a water-soluble analgesic and oral substance in the form of an oral decomposing agent, a wafer, a pill or a medicinal agent having the above characteristics and which is relatively large in the treatment of certain medical conditions. Dose use and / or long-term system can cause gastrointestinal discomfort and / or damage. 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. Each of the particles comprises a matrix core forming a coacervate product and a coating comprising an analgesic agent disposed on the matrix core, and substantially free of particles of the non-salt form analgesic. The water-soluble analgesic composition can be formulated into an orally decomposable spinner, wafer, pill or rhomboid. In certain embodiments, the matrix core is selected from the group consisting of monosaccharides, disaccharides, poly- listeners, dipeptides, and combinations thereof. In certain such embodiments, the «mastrom matrix core~ comprises cellulose, xylitol, or Yantang. In certain embodiments, the particles have a median diameter in the range of from about 100 μ to about 400 Å. In some of these embodiments, the particles such as the stomach have a median diameter of about 200 μ. In certain embodiments, the analgesic is selected from the group consisting of aspirin, 5-127880.doc -12. 200906419 aminosalicylic acid, ibuprofen (ibupr() fen), naproxen (10), and ethamine a group of phenols and combinations thereof. In certain such embodiments, the analgesic comprises aspirin. In certain embodiments, the analgesic salt comprises a potassium salt of an analgesic. According to another embodiment of the present invention, a second package of a water-soluble analgesic composition which can be formulated into an orally decomposable key, a wafer, a pill or a rhombohedral is produced: the next step (1) provides a base comprising a base a solution, (9) adding an analgesic to the solution to produce a second solution comprising an analgesic salt, (: removing the second solution to remove residual analgesic particles to produce a second solution; and (iv) The solution is sprayed onto the substrate to form a coacervate comprising a plurality of particles. "The first - in certain embodiments, the analgesic # salicylic acid, ibuprofen, hydrazine and free sputum free aspirin, 5-amino In some embodiments, the inclusions and the combinations include aspirin. In a certain yang, the early hydration of citric acid is used. In some embodiments, the solution is further developed. In some embodiments, the matrix # is selected from the group consisting of sodium citrate. In some embodiments, the disaccharide, dipeptide And the group of xylitol or listen. In the factory application, the f includes cellulose, filtration, second dissolution, and the second example of 'spray drying onto the substrate. In the example, 4:: fluidized bed spray drying method. In some solid diameters. A certain two has a median particle diameter in the range of about (10) μ to about 〜. In the embodiment, the 1 hai granule has a 127 880 of about 200 μ. 200906419 According to another embodiment of the present invention, it is orally decomposed. The water-soluble analgesic composition in the form of a lozenge, wafer, pellet or lozenge tablet comprises aspirin and tripotassium citrate monohydrate, wherein aspirin comprises at least about 26% by weight of the combined weight of aspirin and tripotassium citrate monohydrate. In certain embodiments, aspirin comprises from about 26% to about 40% by weight of the combined weight of aspirin and tripotassium citrate monohydrate. In certain embodiments, the pH of the composition when dissolved in water is less than about 6. Hey.

In certain embodiments, the water-soluble analgesic composition in the form of an orally dissolving lozenge, wafer, pill or lozenge further comprises a matrix. In certain such embodiments, the matrix is selected from the group consisting of free monosaccharides, disaccharides, polysaccharides, dipeptides, and combinations thereof. In certain of these embodiments, the matrix comprises cellulose, xylitol or sucrose. In certain embodiments, the substrate comprises a water-soluble analgesic combination in the form of a matrix of aspirin and tripotassium monohydrate, and a sputum, sputum, sputum, or diamond-shaped agent. The object-step contains a surface agent. In some of these embodiments, 1 J ^ of the surfactant is directed to; sodium azalea. The water-soluble analgesic composition in the form of an orally decomposable spinner, a green semi-myaltizing agent, a pill or a rhombohedral form of h ^ ruthenium in a lauryl group in a further embodiment I is further selected from the group consisting of ascorbic acid and coffee. ^ Sexual ingredients. Supplementation of the group consisting of carbaryl and the combination of the above: according to the present invention, the formula 'is an orally dissolving lozenge, hammer sputum capsule 'pill or diamond lozenge 糯水Lin and monohydrate ## 厉, and the mouth contains A; - potassium, when dissolved in water, it is orally decomposed to produce 127880.doc 200906419 agent, glutinous rice paper, pills or diamond-shaped spirulina about 6 〇. The pH of the composition in the form of red J is lower than in some embodiments 'in the form of a lozenge in the form of an orally dissolving lozenge, a rice wafer, a pill or a diamond lozenge when dissolved in water. The pH is in the range of from about 5.2 to about 6. In some of these actual pages, the pH of the composition in the form of an orally dissolving lozenge, wafer or pill in the form of a lozenge in water is between about 5.6 and about 6 铭. Within the scope of Chuan. In certain embodiments, aspirin comprises at least about 26% of the combination of aspirin and monohydrate human dry 彳 彳 彳 彳 棣 。 。. According to another embodiment of the present invention, a method for producing a hydrazone analgesic composition in the form of an orally dissolving lozenge, wafer, pill or lozenge tablet comprises the following steps : (i) Providing Ashi υ site, <«, 』门林林, early hydrated tripotassium citrate, surfactant, and matrix, ((1) production of 4 white stalks 3 early hydrated tricotinic citrate a first solution 'iii' (iii) adding aspirin to the first solution to produce a second solution' (d) adding a surfactant to the second solution (the side solution is removed to remove residual amount of aspirin to produce filtered The second solution '(W) is spray dried onto the substrate to pass the second solution to form agglomerated product comprising a plurality of particles' and (vii) the agglomerated product, as appropriate, with other excipients - compressed, molded or Other forms form an orally decomposable yummy yummy paper sachet, pill or diamond lozenge. Aspirin comprises at least about 26 of the combined weight of aspirin and monohydrate tripotassium monohydrate provided in step (1). Tablets for oral decomposition in water, 糯The pH of the composition in the form of a rice pouch, pill or diamond tablet is less than about 6 Torr. In certain embodiments, the surfactant comprises sodium lauryl sulfate. In an implementation of I27880.doc • 15-200906419 In one embodiment, the matrix is selected from the group consisting of « ^ ^ . , A conjugated disaccharide, polysaccharide, dipeptide, and μ, etc. In the specific examples of fibrin, + ^ ι, - μ, the matrix Package, ', xylitol or sucrose. In some cases; Μ i fog drying the first ... semi-real reading 'to the substrate spray method. In the grass this sound step using fluidized bed spray drying method in a certain In some embodiments, the r map has a median diameter of between about 100 μ and about 400 μ from the A and the temple particles. In some of the prior embodiments, the particles have about 200. μ median diameter. According to another embodiment of the present invention, a rapid proteolytic composition in the form of an aspirin salt, a wafer, a pill or a rhombohedral is provided. Ba Gu, ^ ^ Knife is an oral decomposing lozenge, glutinous rice paper capsule, pill or diamond-shaped sword form The composition in the form of 疋W (containing 65 mg of aspirin) is completely dissolved in 100 ml of water in less than 60 seconds. "In some embodiments, part of the sigma-decomposing lozenge, standard rice paper, pill or rhombus The composition in the form of a lozenge (containing 650 mg of aspirin) is completely soluble in 100 ml of water in less than 30 seconds. In some of these examples, the portion is an orally decomposing agent, wafer, pellet or diamond. The composition in the form of a suspect (containing 650 mg of aspirin) is completely soluble in 100 ml of water in less than " seconds. In some embodiments, 'is dissolved orally dissolving (iv), begging for a paper, The pH of the composition in the form of a pellet or diamond bond is less than about 6.0. In certain such embodiments, the pH of the composition in the form of a lozenge, wafer, pill or lozenge in the form of an oral disintegration is in the range of from about 5.2 to about 6.0. In certain embodiments, the pH of the composition in the form of an orally dissolving lozenge, wafer, pill or rhomboid when dissolved in water is in the range of from about 5.6 to about 6.0. Preferably, the water system is at room temperature (about 21) in the examples relating to dissolution time and pH as described in the chamber. The invention and its specific features and advantages will be more clearly understood from the description of the appended claims. [Embodiment] A tablet, a wafer, a pill, or a rhomboid tablet means that it is suitable for lining through the oral mucosa (via the sublingual, that is, the area under the tongue or the oral cavity, that is, between the cheeks and the gums) Area) a lozenge that is absorbed to deliver an analgesic: a wafer of rice, a pill or a diamond ingot, an orally dissolving lozenge, a orange rice pouch, a pill or a rhomboid tablet, which may also mean a suitable tongue Absorbent (after placement on the tongue) to deliver an analgesic lozenge, wafer, pill or diamond lozenge. When the weight of the analgesic is indicated herein, the t-heavy weight refers to an analgesic in the form of a non-ionized 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 as a lemon or a tripotassium salt, the 'aspirin' refers to the weight of the ethyl sulphate in the aspirin-potassium salt, and does not include the salt in the salt. The weight of potassium. , "effective amount" or "effective amount" means an analgesic agent that is administered to a patient in need thereof to treat a disease or other medical condition sufficient to produce a positive effect on the disease or condition. "effective amount" or "quantity effective" should vary depending on the analgesic disease, the disease or condition and its severity, and the age, weight, sex, etc. of the person to be treated. Specific analgesics <"# The decision to have a political decision is based on the skill of the person skilled in the art 127880.doc -17- 200906419 and only routine experimentation is required. 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 5% by weight, about 20% by weight.丨〇% by weight, about 5% by weight, about 2% by weight, about 1% by weight/°, or about 0.5% by weight of an analgesic solution or a solid analgesic compound. f The present invention satisfies the need for prior art And the present invention is based, in part, on the discovery that aspirin and sodium lauryl sulfate (which is used as a surfactant), citrate, and cellulose, disaccharide (such as sucrose), monosaccharide or other non-s Certain mixtures of flavoring agents, which are also used as preservatives, antioxidants, and demulcents, can produce aqueous solutions that are more stable and have lower enthalpy than previously known formulations (especially those having between 52 and 6) Qiu). This is a formulation prepared by the prior art. When dissolved in water, the formulation prepared by the prior art is generally unpalatable and produces a solution having a pH greater than that of the solution 3 citrate. Sodium lauryl sulfate, cellulose or Yan sugar and aspirin The novel formulation of the invention can be designed to be relatively easy to absorb under the lower bay piece: the form is because the new latitude formulation can be formed to be more difficult to dissociate. B:::: generates salicylic acid and The main decomposition pathway of acetic acid is ====================================================================================================== It has also been reported that sucrose can block the hydrolysis of salicylic acid == speculate that this is achieved by providing a protective layer that can prevent B from having a low water content. Possible Yan sugar 127880.doc -18- 200906419 Hydroxyl groups can be combined with water Hydrogen bonding is formed and thereby inhibits the hydrolysis of acetyl salicylic acid to a certain extent. The administration of the water-soluble aspirin composition produces a higher concentration of plasma salicylic acid than the administration of conventional aspirin in the form of a lozenge or capsule. Figure 1 shows a schematic diagram in which an aqueous solution of the composition and a known commercial product are collected according to the plasma salicylate concentration measured in a human patient after administration of the water-soluble aspirin composition (specifically, Bayer@ The data for aspirin tablets were plotted. Both products were dosed at the same dose of 1 mg of aspirin. The water-soluble aspirin composition reached the therapeutic concentration of plasma salicylate in 5_1 min. Aspirin in the form of a lozenge or capsule takes 30-40 minutes. In addition, the water-soluble aspirin composition has a plasma salicylate concentration about 2 times higher than commercially available products. Therefore, a lower dose of water-soluble aspirin composition A comparable salicylate concentration can be achieved and thereby minimizing the potential side effects of aspirin. The improved water solubility and palatability of the water soluble aspirin composition can contribute to large doses (as may be required to treat certain medical conditions) The administration of aspirin also minimizes the potential gastric side effects of commercially available aspirin in the form of tablets or capsules. The water soluble aspirin composition can also be formulated as an orally dissolving lozenge, wafer, pill or lozenge tablet having similar advantageous characteristics. According to one aspect of the present invention, there is provided a method of formulating the components of the water-soluble aspirin composition described herein in accordance with the method, the water-soluble spirulin composition being formulated into an orally dissolving lozenge and a glutinous rice pouch , pills or diamond tablets. To ensure a homogeneous product that is rapidly soluble in water and does not contain any of the Spirulin particles, aspirin is first added to a solution of citric acid and sodium lauryl sulfate. Subsequently, traces of aspirin particles that have not been converted to their potassium salts are removed by filtration and then the clear solution is spray dried onto a core (e.g., crystalline cellulose, xylitol or sucrose) to form a coacervate. A coating of aspirin is provided on the cellulose, xylitol or sucrose core using a fluidized bed spray drying process, a combination of spray drying and coacervation by means of air suspension techniques. The resulting free-flowing solid coagulated product can be dissolved in water arbitrarily to produce a clear/monthly palatable aspirin solution (see Example 下文 below). This granulation process can provide a product comprising particles having a diameter ranging from about 100 to 400 μ and a median particle size of about 2 μ μ, as shown in FIG. These conclusions can be confirmed by scanning electron microscopy, as shown in Fig. 3-6, which illustrate the aggregated product obtained from the method at different magnifications of seven (the magnification scale of Fig. 3 is 卩, Fig. 4 The magnification scale is 14 〇 μ, the magnification scale of Fig. 5 is 2 〇〇 ρ, and the magnification scale of Fig. 6 is 7.4 μ). U Thus, the resulting free-flowing solid solid coacervate comprises a plurality of particles. The particles are comprised of a matrix (e.g., cellulose, xylitol or sucrose) and a coating on a 3 kel matrix core. The coating comprises the salt of aspirin but is substantially free of particles of the non-salt form of aspirin. This does not mean that the coating does not include the non-salt form of aspirin itself in the case of (iv), but means that it does not substantially contain the non-salt form of aspirin particles contained in the coating, as this is essentially due to the above process. All of these particles have been passed. Of course, the coating may comprise an amount of non-salt form of aspirin which has been previously dissolved in the solution prior to spraying, since the amounts of such dissolution are not removed as such. 127880.doc •20· 200906419 ^^ Compositions with residual or other non-nutritive sweeteners that require a fluidized bed spray drying process may also provide free-flowing products that are substantially soluble in water, but may require a little longer Time to completely dissolve Examples 2, 3 and 4) below. Work: Report: Add! Some supplemental active ingredients can enhance the beneficial effects of acetaminophen _, + cases and g ’ 醯 醯 醯 扬 与 抗 抗 α α α α α α α α α α α α α α α α α 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此 此Aspirin and vitamins have been reported, and the mouth is particularly suitable for the treatment of cold headaches, pain and fever. In addition, Bu Jia has: the combination of Daoyi salicylic acid and ascorbic acid can significantly reduce the product of stomach water (see below, the combination of the physic and the ligand can produce sufficient solubility: = can also be fully compatible with the added caffeine It has been reported to be used in the treatment of migraine =) and it has been suggested that a combination of caffeine formulations can be used for lifting. Caffeine and the new product are filled with water/water (see Example 6 below). In addition to sugar), other matrices (including cellulose, single brew, medium first =) also. It can be used in combination with ethyl salicylic acid for the combination of the new formula, 眛 early sugar, D_glucose (dextrose) in combination with acetaminophen: Ί has the additional effect of reducing gastrointestinal damage caused by painkillers Beneficial = nano hydration « acid three unloading, D-glucose and laurel example 7). The formulation is fully compatible and provides a uniform aqueous solution (see, in addition, I., xylitol can be used in multiple layers containing aspirin for these novel formulations (see Example 8 below). Fiber 127880.doc 200906419 (a water-insoluble brewing, p X sugar) has been used in the formulation of aspirin and can also be used in the novel, dh dh can be compressed into tablets , glutinous rice paper, pellets or diamonds (see Example 9 of τ). 某些 In some embodiments, the mouth of the present invention is 丨丨 丨 丨 丨 # # 服 服 胖 胖 、 、 、 、 、 、 、 、 、 、 、 、 、 、 The agent can be a sublingually administered key agent, (4) a paper bag: a pill or a love-shaped key agent, that is, a key agent, a wafer, a pill or a diamond suitable for delivering an analgesic through the area under the tongue. A sublingually administered lozenge, a semi-secret sputum, a narrow confucian water-sucking capsule, a pill or a diamond-shaped spirulina = below: and fixed at the same place until the sublingually administered lozenge :, 糯 纸 纸 纸 、 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域 域Lozenges, standard rice pouches, pills or diamond-shaped lozenges should be rapidly reversible, at the end of the (four) speed. = Compressed or external m ^ or diamond shaped lozenges containing the analgesic agents described herein. Except for excipients containing such granule compression or molding agents, standard rice paper, pills or diamond squirts, such as lactose, dextrose, and axe (except in the granules) Other sugars known as sucrose, or other excipients known in the art. Other excipients that may be used include rapid decomposition of the agents> agents, for example, Ac-Di-Sol, ΚλΠ.λϊ sodium Lldon CL or glycolic acid starch for the convenience of rapid absorption, can rob the ^ 4 particles and additional excipients (if the treatment (for example, screening or micronization) to reduce the particle size. +All 仏 仏 约 _ μ, preferably ΗΗ) -200 μ) After 'the particles and additional excipients can be blended together and then destroyed with 127880.doc -22- 200906419 / Liquid to prepare a usable substance without excessive (4) such ingredients or traits. The η, η, wet components are then compressed or molded to form an oral decomposition = lozenge, wafer, pellet or pellet. Specifically, it can be compressed using a tablet machine at a medium compression force. s, 7 The water-soluble analgesic compound described herein is dissolved in a suitable aqueous solution and after Ik, the solution containing the dissolved analgesic can be dried to produce the orally decomposable rotary agent of the present invention, a orange rice paper, a pill or a diamond. Key agent. ', the method of producing a rapidly decomposing tablet, wafer, pellet or diamond bond known in the art can be used to produce the orally dissolving agent, wafer, pellet or diamond lozenge of the present invention. For example, U.S. Patent No. W3U describes a method for producing a rapid decomposition bond comprising a drug in the form of a multiparticulate (e.g., granular or microencapsulated) form by formulating the drug with one or more Aqueous insoluble inorganic excipients, one or more decomposers, and optionally one or more substantially water-soluble excipients, the amount of such ingredients being such that the intraoral decomposition time is about 75 seconds or less (eg, 40 seconds or less, preferably less than 3 sec, optimal, less than 2 sec. U.S. Patent No. 7,125,562 describes a rapidly decomposing tablet prepared by blending two phases, the first phase comprising methylcellulose and a diluent and the second phase comprising at least two selected from the group consisting of a decomposing agent, a wetting agent, The composition of the lubricant and the second diluent. U.S. Patent No. 5,5,1,861 discloses a method of producing a rapidly dissolving tablet by compression molding in a semi-dry state. U.S. Patent No. 5,837,285 discloses a fast dissolving tablet containing a drug which has a rapidly dissolving pharmaceutical additive as a basic component of a tablet and which is produced using a kneaded mixture of the drug 127880.doc 23·200906419 , the door is sorrowful, the kneading mixture I is reduced to ", the door is incorporated herein by reference. The disclosure of the patent is the oral decomposing lozenge of the present invention, the m-sac, the pill or Diamond-shaped lozenge protectant £ η 中 中 & This, in the lozenge, glutinous rice paper, pill or rhuba 2 red field of saliva, the yang is preferably slightly acidic (for example, small 1 乂 good about 4 to about 6) The modified aspirin is released from the tablet or the sugar rice paper capsule: "Qualitative. This may be accomplished by incorporating one or more buffering agents (eg, sodium and disodium sulphate and sulphate H, and sulphuric acid) in an effective buffer amount in the lozenge, wafer, pill, or love form. The combination of town alumina is achieved as an excipient. The sputum disintegrating tablet, wafer, pill or rhomboid agent of the present invention may have a suitable size, shape, weight, viscosity or hardness. A coin-type disc or wafer of paper having a diameter of from about 4 mm to about 15 mm and a thickness of from about 5 mm to about 2 mm can be made to vary generally with the diameter. In certain embodiments, the orally dissolving tablet, lozenge, pill, or lozenge of the present invention is placed in the lower portion of the human tongue for from about 5 seconds to about 2 seconds, from about 5 seconds to about 90 seconds, and about 5 seconds. The analgesic contents are released from seconds to about 60 seconds, from about 5 seconds to about 3 seconds, or from about 1 second to about 60 seconds. In certain embodiments: the orally dissolving lozenge, wafer, pill, or lozenge of the present invention is in the range of from about 1 second to about 120 seconds when placed in a human saliva or a solution similar to human saliva. Completely dissolved from 10 seconds to about 90 seconds, from about 10 seconds to about 6 seconds, from about 1 second to about 3 seconds, or from about 20 seconds to about 60 seconds. The present invention provides an orally dissolving lozenge comprising granules, wafers 127880.doc-24·200906419, pills or rhomboid tablets. The particles comprise: (a) a matrix core; and (b) disposed on the matrix core A coating of agglomerated product is formed which comprises a salt of an analgesic agent but is substantially free of particles of the analgesic in a non-salt form. In some cases, the salt of the δ Hai analgesic includes the potassium salt of the analgesic. In certain embodiments, the analgesic agent is selected from the group consisting of aspirin, amidosalicylic acid, ibuprofen, citrin, galaxanthin, acetaminophen, and combinations thereof. Group. In certain embodiments, the analgesic is aspirin. In certain embodiments, the matrix is selected from the group consisting of cellulose, (tetra), disaccharides, polysaccharides, dipeptides, and the like, in, in, and in groups. In certain embodiments, the matrix is cellulose, xylitol or sucrose. In certain embodiments, the particles comprise: (i) an analgesic; (ii) tripotassium citrate monohydrate;

Lj (iii) Surfactant. In certain embodiments, the analgesic is a cup and the aspirin comprises aspirin and hydrazine hydrated citric acid = 0 / . # ^ "The combination weight of 豕 - - potassium is at least about 26 weight / 。. In other embodiments The aspirin: from about 26% to about 40% of the combined weight of the combination of -^, ΛU j ^林 and early hydrated 豕 二 ^ 钾 。. In some embodiments, when containing about 6 doses,妩 舂 舂 舂 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅 宅Some people have a dose of A or a diamond tablet having & preferably having < about 5.2 and about 6 〇 127880.doc -25- 200906419 even more preferably having a pH between about 5.6 and about 6 。. ': Some implementations In one embodiment, the oral decomposing lozenge, solicited sachet, pill or lozenge comprises from about 50 mg to Yorkshire 5 25 analgesic, preferably from about 150 mg to about 3 g and even more preferably about 5 〇〇mg to u analgesic. In some cases, 1 hai oral decomposing lozenge, standard rice paper, pill or rhomboid 匕 contains about 75 A gram to about 325 mg analgesic. In certain embodiments, the oral decomposing lozenge, standard rice pouch, pill, or lozenge lozenge comprises about 81 mg, 325 mg, or 5 mg of an analgesic. - A method of preparing a water-soluble analgesic composition in the form of an oral decomposing (four), wafer, pill or rhombohide tablet, the method comprising: providing a first solution comprising the test;: adding an analgesic to the first solution Producing a second solution comprising a salt of the analgesic; 过滤 filtering the second solution to remove residual analgesic particles to produce a filtered second solution; and spray drying the transitioned second solution onto the substrate to form an inclusion Agglomerated product of a plurality of particles; and the coagulated product is compressed, molded or otherwise formed with an oral decomposing agent, a wafer, a pill or a diamond bond, as the case may be. In certain embodiments of the method of dissolving a water-soluble analgesic composition in the form of a lozenge, wafer, pill or lozenge lozenge: • the analgesic is selected from the group consisting of aspirin, 5- Salicylic acid, ibuprofen, 127880.doc • 26· 200906419 No, the 曰 乙 酿 胺 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 且 夕 夕 夕 夕 夕 夕 夕 夕The analgesic agent comprises a monohydrate hydrazine acid; the acid: the first solution further comprises a surfactant, preferably the lauryl sulphate is selected from the group consisting of a single hearing, a double enzyme, a polysaccharide, a second skin, and the like. , the group is preferably cellulose; the step of spray drying the substrate through the 滹_ ϋ Α π first solution is carried out by a fluidized bed spray drying method; and/or • the particles have The median diameter is in the range of about 1 〇〇μ to 400 400 μ, and the 4 particles preferably have a median diameter of about 2 〇〇 μ. In some embodiments, the analgesic is aspirin, the system is monohydrated and the aspirin accounts for aspirin and monohydrate citrate. The mouth weight is at least about 26% by weight, preferably aspirin and The monohydrated citric acid is unloaded and the human II μ + & σ ΐ is from about 26% to about 4 〇 weight 〇/0. The decomposition characteristics of the orally decomposable tablets, wafers, pills or lozenges are evaluated at each temperature (e.g., room temperature or 37 ± 2 t) T in a USP decomposition apparatus without a disk. The present invention provides a method for administering a therapeutic agent comprising administering an oral decomposing agent, a standard rice paper bag, a pill or a diamond-shaped key agent containing an analgesic to a patient in need thereof, to treat the *de, road, and , + 曰 曰 > ^. The person is required to deliver the analgesic that is effective. In a preferred embodiment, the patient is a human. This month's month also provides a method of treatment or prevention using an oral decomposing lozenge comprising an analgesic, a savory rice capsule, a pill or a diamond lozenge. In general, 127880.doc -27. 200906419 The invention discloses an oral decomposing tablet, a wafer, a pill or a diamond tablet containing an analgesic for treating or preventing treatment by using the analgesic in a conventional manner. Any disease or condition. The oral decomposing lozenge, wafer, pill or pellet is administered to a patient in need of such treatment in an amount effective to treat the disease or condition. In certain embodiments, the π-disintegration (four), (iv) paper, pill or diamond-shaped agent is administered to provide a daily dosage of an analgesic: between about 5 g mg to about 20 g, preferably about 5 〇〇 to about 1 gram, and more preferably between about 1 gram to about 5 gram. In certain embodiments, the analgesic is aspirin and administration of the oral decomposing lozenge, wafer, pill or lozenge provides plasma salicylate concentration of from about 10 micrograms per milliliter to about 5 〇〇 micrograms/ml, about Μ micrograms/ml to about 400 micrograms/ml, about 2 micrograms/ml to about 25 micrograms/ml, about 20 micrograms/ml to about 15 micrograms/ml, or about 3 inches. Between micrograms per milliliter to about 100 micrograms per milliliter. In certain embodiments, the blood salicylate concentration can be even less than 10 micrograms per milliliter. The administration of the orally decomposing lozenge, wafer, pill or lozenge tablet should be such that the analgesic dose and the analgesic administration duration are sufficient to achieve the desired therapeutic effect. This usually takes minutes to hours, but may take longer, for example, up to 1 day, 2 days, 3 days or more. In another embodiment, the invention provides an oral decomposing lozenge comprising an analgesic, a wafer, a pill or a lozenge for administration from about 10 hours to about 7 days or longer, preferably about 1 Maintain an analgesic or analgesic metabolite plasma concentration of 127880.doc •28·200906419 from about 10 micrograms/ml to about 500 micrograms per hour to about 76 hours and more preferably from about 24 hours to about 48 hours. ML, from about 15 μg/ml to about 400 μg/ml, from about 20 μg/ml to about 25 μg/ml, from about 20 μg/ml to about 150 μg/ml, or from about 3 μg/ml to about 100 μg /ml between. In another embodiment, the present invention provides an oral decomposing agent comprising aspirin, a wafer, a pill or a rhomboid tablet. The rate should be from about 1 hour to about 7 days or longer. Preferably, the salicylate plasma concentration is maintained between about 1 hour and about 76 hours, and more preferably between about 24 hours and about 48 hours, between about 1 microgram per milliliter to about 5 micrograms per milliliter, about 15 minutes. From micrograms per milliliter to about 400 micrograms per milliliter, from about 2 micrograms per milliliter to about 250 micrograms per milliliter, from about 20 micrograms per milliliter to about 1 5 micrograms per milliliter, or from about 30 micrograms per milliliter to about 100 micrograms per milliliter. . The oral decomposing lozenge, wafer, pill or rhomboid tablet of the present invention can maintain 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 of analgesic agents can be provided. In certain embodiments, a substantially constant high concentration analgesic can be provided. Thus, the present invention provides an oral decomposing lozenge, wafer, pill or lozenge for administration of an analgesic to maintain the plasma concentration of the analgesic or analgesic metabolite at 5 μg/ml ± 1 〇〇 /〇, i 〇μg/ml ± i 〇0/〇, 15 μg/ml ±1 0%, 20 μg/ml ±1〇%, 25 μg/ml ±10%, 30 μg/ml ±ι〇〇 /0, 4 〇 microgram / ml ± 1%, 6 〇 microgram / ml ± 10%, or 75 microgram / ml ± 10%, up to about i hours, 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 127880.doc -29-200906419 an oral decomposing lozenge, wafer, pill or diamond lozenge for administration of aspirin to maintain a plasma concentration of salicylate at 5 Micrograms/ml ± 10 〇 / 〇, 10 μg / ml ± 10%, 15 μg / ml ± 10%, 20 μg / ml ± 10%, 25 μg / ml ± 10%, 30 μg / ml ± 1 〇〇/0, 40 μg/ml ± 10%, 60 μg/ml ± 10%, or 75 μg/ml ± 1%, for 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 present invention also provides an oral decomposing tablet, a wafer, a pill or a diamond tablet for administration of an analgesic agent to maintain a plasma concentration of an analgesic or analgesic metabolite at 100 μg/ml ± 10%, 110 μg. /ml ± 10%, 120 μg / ml ± 10%, 130 μg / ml ± 10%, M 〇 microgram / ml ± 10%, 150 μg / ml ± 10%, 175 μg / ml ± 10%, 200 μg / ML ± 10%, or 250 μg / ml ± 1 〇〇 / 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. In certain embodiments, the present invention provides an oral decomposing lozenge, wafer, pill or lozenge for administration of aspirin to maintain a salicylate plasma concentration of 100 μg/ml ± 10%, 110 Μg/ml ±1〇〇/0, 120 μg/ml ±10%, 130 μg/ml ±10%, 140 μg/ml ±1〇%, 150 μg/ml ±10%, 175 μg/ml ±10% 200 μg/ml ± 10%, or 250 μg/ml ± 10%, for 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 present invention also provides an oral decomposing lozenge for administration of an analgesic agent, glutinous rice paper 127880.doc -30-200906419 capsule, pill or diamond lozenge to maintain the plasma concentration of the analgesic or analgesic metabolite at 250 micrograms /ml ± 10%, 300 μg / ml ± 1%, 4 μg / ml ± 10%, or 5 μg / ml ± 1%, up to about i hours, 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 present invention provides an oral decomposing lozenge, a sugar rice sachet, a pill or a diamond lozenge for administration of aspirin to maintain a plasma concentration of salicylate at 25 〇 『 gram / ml ±1 〇%, 300 μg/ml ± ι 〇〇 / 〇, 4 〇〇 μg / ml ± 10%, or 500 μg / ml ± 1 〇〇 / 0, up to about j hours, 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 an oral decomposing lozenge comprising an aspirin, a wafer, a pill or a lozenge tablet for administration in about 1 minute, preferably about 5 minutes and even more preferably in about 20 minutes. The blood obtained between about 12 micrograms/home to about 350 micrograms per milliliter is allowed to reach the salicylate concentration.血浆After reaching a plasma salicylate concentration of about 120 μg/ml to about 350 μg/ml, the plasma salicylate concentration between about 120 μg/ml and about 350 μg/ml can be maintained 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 another embodiment, the invention provides an oral decomposing lozenge comprising an analgesic, a wafer, a pill or a lozenge tablet for administration to a 6 hour AUC of the analgesic or analgesic metabolite of between about 〇.3 mM*hr to about 15 mM*hr, preferably between about 2 mM*hr to about 1 mM hr*hr and even more preferably between about 3 mM hr to about 8 mM*hr. In another embodiment, the invention provides 127880.doc • 31 - 200906419 an oral decomposing lozenge comprising an analgesic, a glutinous rice capsule 'pill or a diamond lozenge to administer the analgesic or analgesic metabolite 2 The hourly Auc is between about 0.6 mM*hr to about 30 mM*hr, preferably between about 4 mM*hr to about 2 mM hr*hr and even more preferably between about 6 mM*hr to about 16 mM*hr. In another embodiment, the present invention provides an oral decomposing agent, a standard rice pouch, a pill, or a diamond lozenge comprising an analgesic such that the 24 hour AUC of the analgesic or analgesic metabolite is between about 1.2 mM *hr to about 60 mM*hr, preferably between about 8 mM*hr to about 40 mM*hr and even more preferably between about 12, , , , mM*hr to about 32 mM*hr. In another embodiment, the present invention provides an oral decomposing agent comprising aspirin, a wafer, a pill or a rhomboid tablet to administer a 6 hour AUC of salicylate from 0.3 mM*hr to about 15 mM *hr, preferably between about 2 mM*hr to about 1 mM hr*hr and even more preferably between about 3 mM*hr to about 8 mM*hr. In another embodiment, the present invention provides an oral decomposing lozenge comprising an aspirin, a wafer, a pill or a lozenge tablet for administration of a 12 hour AUC of the salicylate of from about 0.6 mM*hr to about 30 mM. *hr, preferably between about 4 mM*hr to about 20 mM*hr and even more preferably between about 6 mM*hr to about 16 mM*hr. In another embodiment, the invention provides an oral decomposing lozenge comprising aspirin, a wafer, a pill, or a rhomboid tablet to administer a 24 hour AUC of salicylate between about 1.2 mM*hr to about 60 mM *hr, preferably between about 8 mM*hr to about 40 mM*hr and even more preferably between about 12 mM*hr to about 32 mM*hr. Examples The following are useful for producing the oral decomposing lozenges and wafers of the present invention 127880.doc -32- 200906419

Aspirin (625·0 g) was added portionwise to 175 Torr (1 g) of monohydrated tribasic acid in 10.0 liters of water (containing 15 g of sodium lauryl sulfate). A water-soluble aspirin composition of a medicament, pill or diamond lozenge. It should be understood that the following solubility test should be used

' ...", - one ~ ~ code w work. The corpse juice suspected polymer contained a granular product having a median particle size of about 200 μ. The test was carried out using a ferric chloride method which can detect low hydrazine hydrolysis, and no detectable concentration of salicylic acid. A portion (5.2 g, containing 650 mg of aspirin) was added to the free-flow product, which was added to 100 ml of water with stirring and mixing. It was palatable and completely dissolved in 15 seconds and had a pH of 5.87. Example 2 A shaker apparatus was used to sufficiently shake 30.0 g of aspirin, 7 g. of monohydrate, a mixture of dipotassium citrate, 100.0 g of sucrose and 6 g of sodium lauryl sulfate to ensure homogeneity. The resulting free flowing product remained stable at 5 Torr for at least 3 weeks and at 75 C for at least 2 weeks and was very stable to ultraviolet light (254 nm) for at least 1 week. Detection was carried out using a ferric chloride method capable of detecting hydrolysis as low as 0 25% 'no detectable concentration of salicylic acid. While stirring and mixing 127880.doc -33- 200906419 Add 3.33 grams of this mixture (containing 5 mg of aspirin) to 150 ml of purified water. 'It is palatable and can dissolve in substantially 15 seconds, within 1 80 seconds. Completely dissolved and pH 5.67. Example 3 A mixture of 30.0 g of aspirin, 70.0 g of monopotassium citrate monohydrate, 20_0 g of aspartame and 36 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure uniformity. The resulting free flowing product remained stable at 5 °C for at least 3 weeks and at 75t for at least 2 weeks. The test was carried out using a gasification iron method capable of detecting hydrolysis as low as 0.25%, and no salicylic acid having a detectable concentration. Add 2 grams of this mixture (containing 500 mg of aspirin) to 150 ml of purified water while stirring and mixing. It is palatable and can be dissolved in 15 seconds, completely dissolved in 240 seconds, and the pH is 5.93. . Example 4 A mixture of 30.0 g of aspirin, 70.0 g of monopotassium citrate monohydrate, 20.0 g of sucralose and 36 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure uniformity. The resulting free flowing product remained stable at 50 °C for at least 3 weeks β. Detection was carried out using a ferric chloride method capable of detecting hydrolysis as low as 0.25%, with no detectable concentration of salicylic acid. To the 15 liters of purified water, 2.00 grams of this mixture (containing 500 mg of aspirin) was added while stirring and mixing, which was palatable and substantially dissolved in 30 seconds, completely dissolved in 210 seconds, and had a pH of 5.74. Example 5 A portion of the product of Example 1 (4.75 grams' containing 561 mg of aspirin) was thoroughly mixed with 2 mg of vitamin C. The resulting free stream 127880.doc -34· 200906419 was dissolved in 100 ml of water during mixing and mixing. The free-flowing product is fully soluble in 30 seconds with a pH of 5.63 and is palatable. Example 6 A portion of the product of Example 1 (4 75 grams, containing 561 mg of aspirin) was thoroughly mixed with 50 grams of caffeine. The resulting free flowing product was dissolved in 100 ml of water while stirring and mixing. The free-flowing product was fully soluble in 3 seconds and had a pH of 5.86 and was palatable. Example 7 A shaker apparatus was used to sufficiently shake a mixture of 118 g of aspirin, 331 g of tripotassium citrate monohydrate, 70.0 g of glucosinolate (dextrose) and 3 mg of sodium lauryl sulfate to ensure uniformity and white color. Free flowing product. The test was carried out using a ferric chloride method capable of detecting hydrolysis as low as 0.25%, and no detectable concentration of salicylic acid. 316 g of this mixture was added to 3 S ml of purified water at the time of mixing, and the mixture was sufficiently dissolved in 30 seconds. The solution contains 1 - 93 grams (5.0%) D-glucose and 325 mg of aspirin, and? 11 is 5 84. Example 8 A shaker apparatus was used to sufficiently shake a mixture of 4·8 g of aspirin, 134 g of monohydrate, hydrated I potassium, 20.0 g of crystalline xylitol, and 2 mg of sodium lauryl sulfate to ensure uniformity. Flow product. To 6 ml of purified water, 2 6 g of this mixture (containing 325 mg of aspirin) was added under stirring and mixing, which was palatable and substantially dissolved in 15 seconds, completely dissolved in 60 seconds, and had a pH of 5.99. Example 9 A shaker apparatus was used to sufficiently shake a mixture of 48 g of aspirin, 3.4 g of monohydrated lemon 127880.doc -35· 200906419 tripotassium citrate, 20.0 g of microcrystalline cellulose and 12 mg of sodium lauryl sulfate to ensure Uniformity produces a white free-flowing 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 solution produced from the water soluble composition is 6.0, which provides a number of distinct advantages as described above. By changing the aspirin content of the composition according to the amount of tripotassium citrate monohydrate, it is ensured that the pH is kept within the desired range (i.e., <6 〇) ^ more specifically, when

When the content of spirulin exceeds about 26% of the combined weight of aspirin and tripotassium citrate monohydrate (i.e., between 26% and 40% of aspirin), the pH of the resulting solution is less than 6.0. For example, the above example! It has an aspirin content of about 26% and a pH of 5.87, while the above Example 2 has an aspirin content of about 3% and a pH of 5.67. On the other hand, when the aspirin content is less than about 26% (i.e., between 〇% and 26% of aspirin), the pH of the resulting solution is greater than 6.0. For example, Example 5 of U.S. Patent No. 5,776,43, which is assigned to GaUt, has an aspirin content of about 20.0% and? 11 is 6 · 12. The relationship between the percentage of aspirin content and the resulting solution p H is shown in Figure 7. Specifically, the above teachings, findings, procedures, and methods for the active therapeutic agent of acetaminophen (aspirin) as a formulation are also applicable to other: pain agents' because the present invention is not limited to water-soluble aspirate # composition Instead, water soluble analgesic compositions are generally encompassed. For example, the present invention encompasses formulations in which a water-free, scutane-conjugated salicylic acid derivative is used as an active therapeutic agent. For example, 5_ face makeup salicylic acid (mesalamine) can be used to treat inflammatory bowel disease, such as ulcerative colon 127880.doc • 36· 200906419 inflammation. Mesalazine is insoluble in water and is used to treat inflammatory bowel disease by topical capsules. It has been reported that mesalazine: solution, (4 g/day) is elevated by ^<2μΡΗ>5_5. According to this please == two salazine formulations to produce 6 86 of the benefits of the month of the case of the case of the valley, the United States. 4 this can be quickly (four) and quickly enter the bloodstream of the average _ k,, six. He, L, see Example 1 below)). The formulation is palatable and can contain a variety of bases, including cellulose, xylitol or

Sugar 0 His water-insoluble analgesic (Ibuprofen (see example below using this novel formulation procedure to prepare its acetaminophen (see Example H below), I2) and naproxen (see Example 13 below) ). Hereinafter, several exemplary formulations of a water-soluble analgesic composition using an analgesic other than acetyl salicylic acid (aspirin) as an active therapeutic agent are used. Example 10 Shake well with a mixture of 8 mg of mesalazine, 1 〇. 〇 monohydrate & potassium dihydrogenate, 14.92 g of sucrose and 8 mg of sodium lauryl sulfate to ensure uniformity Sex, producing an off-white free-flowing product. 6 39 grams of this mixture (containing 325 mg of methadone) was added to 100 ml of purified water with stirring to dissolve mostly in 15 seconds and completely dissolve in 25 seconds. The pH of the solution was 6,86 and was palatable. Example 11 A mixture of 1-20 g of acetaminophen, 3.35 g of tripotassium monohydrate, 5.0 g of sucrose and 3 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure homogeneity, resulting in a white free-flowing product. To the mixture, 2.7 g of this mixture (containing 325 mg of acetaminophen) was added to 100 127880.doc -37·200906419 ml of purified water for most of the dissolution in 15 seconds and completely dissolved in 45 seconds. This solution has a pH of 7.80 and is palatable. Example 12 A mixture of 125 mg of ibuprofen, 2.50 g of tripotassium citrate monohydrate, 3 · 73 g of sucrose and 2 mg of sodium lauryl sulfate was thoroughly shaken using a rocker apparatus to ensure uniformity, resulting in a white free-flowing product. The mixture (containing 125 mg of ibuprofen) added to 75 ml of purified water while stirring was substantially dissolved in 15 seconds and completely dissolved in 240 seconds. The solution has a pH of 7 23 and is palatable. Example 13 A mixture of 125 mg of naproxen, 2.50 g of tripotassium citrate monohydrate, 3.73 g of sucrose and 2 mg of sodium lauryl sulfate was thoroughly shaken using a rocker arm to ensure homogeneity, resulting in a white free-flowing product. The mixture (containing 125 mg of ibuprofen) added to 75 ml of purified water upon stirring was substantially dissolved in 15 seconds and completely dissolved in 60 seconds. This solution has 74 〇 ipH and is palatable. Example 14 Aspirin (375.0 g) was added portionwise to (8) gram of monohydrated rod-like acid tripotassium in a solution of 6.0 liters of water (containing 9 g of sodium lauryl sulfate). Hold the mechanical stirring for 15 minutes until the solution is nearly uniform. Vacuum filtration to 4 liters of liters 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 mu gram sugar using a 22 liter granulator fluidized bed spray processor. 127880.doc • 38-

The statistic is 89% (the deviation of 5.327 metrics 0.576 kg is from 200906419. If the text is added to the first part, the mixture is added and filtered to 1050.0 g of tris-potassium monohydrate, which is stored in another 6 liters of water. The second part of the solution (containing 9 grams of sodium lauryl sulfate) aspirin (375.0 grams also filled the clear aqueous solution into a non-recorded steel reservoir and applied to the sugar stored in the fluidized bed spray processor Aspirin (total weight: 750.0 g), tripotassium citrate monohydrate (total weight: 21 phantom and lauryl sulphur & total weight S · 丨 · 8 g) was introduced to the total volume as follows In the water of 12. G liters: The above aspirin solution (14,772 g) was passed through the (6) minute mist to the fluidized bed spray processor _5). The initial spray rate of the first 323 minute spray was 21 g/min. The final spray rate of gram per minute. The temperature of the gas is 4 liters throughout the process, which is between valence and valence. This produces a product temperature of 38 during the spray. (: to 39. The final product temperature was 42 t. The total processing time in GPCG 5 was ^ minutes. The theoretical total amount of material discharged from GPCG 5) can be obtained by using 79 ° / (4.751 kg), filter particles. The obtained aggregate contains a granular product having a median diameter of about · μ and contains n pieces Aspirin (measured by HPLC analysis) using a ferric chloride method that can detect hydrolysis as low as 0.25%, no detectable concentration of salicylic acid. The result of mixing and mixing in 1 GG ml of water The fraction (5.2 g, containing 614 mg of aspirin) is palatable and can be completely dissolved in (four) seconds and has a pH of 5.87. The water-soluble analgesic composition in the form of an orally decomposable lozenge or tablet form of the present invention is a glutinous rice paper pouch. Agents, using known analgesic pills or lings, thus 127880.doc -39-200906419: These compositions are substantially useful for preventing the known formulations of the agents from being treated, etc. However, The above-mentioned Taiwu [know disease, disease, patient capsule, pill or diamond-shaped tablet disintegration tablet, glutinous rice woven benefits, pre-(4) ρ, ΓΓ residue has many compounds can have a wider range of applications. Oral A water-soluble analgesic composition in the form of a medicinal agent, a medicinal agent, and a pill (4) form (4), which does not contain fish, can be rapidly dissolved in water, acts quickly and rapidly enters the bloodstream, and can be combined with a certain amount - and a large dose is required The medical condition and/or may be used for a long period of time without causing gastrointestinal discomfort and/or injury. The present invention is described with respect to the specific arrangements of the various parts, features and the like, but is not intended to be exhaustive of all possible arrangements or features. In fact, many other modifications and variations can be identified by those skilled in the art. [Schematic Description] Figure 1 illustrates the change in salicylate concentration of a water-soluble aspirin composition with a well-known commercially available aspirin formulation over time. This is based on data collected from human patients. Figure 2 illustrates the repurchase of the product/〇 as a function of the median diameter of the particles of the water-soluble aspirin composition described herein. Figures 3-6 show scanning electron micrographs of the water-soluble aspirin compositions described herein at different magnifications: Figure 3 (magnification scale: 29〇4; Figure 4 (magnification ruler: 14〇μ); Figure 5 (magnification scale: 2 μμ); and Figure 6 (magnification ruler: 7.4 μ). 127880.doc -40- 200906419 Figure 7 illustrates the relationship between pH and % by weight of aspirin, the weight % of which is based on The combined weight of the aspirin of the water-soluble aspirin composition and the three-times of citric acid monohydrate described herein.

127880.doc -41 -

Claims (1)

200906419 X. Patent application scope: Sugar rice paper bag, pellet An oral decomposing lozenge or diamond lozenge containing a plurality of granules, the granules comprising: a matrix core, and a package disposed on the matrix core to form agglomerated product a coating comprising an analgesic salt 'but substantially free of particles of the analgesic non-salt form 0 2_such as a requesting machine for oral decomposing tablets, wafers, pills or diamond-shaped bonds' wherein the matrix core It is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides, and combinations thereof. 3. The oral decomposing lozenge, wafer, pill or rhombohedral of claim 2, wherein the matrix core comprises cellulose, xylitol or sucrose. 4. An oral decomposing lozenge, wafer, pill or diamond lozenge as claimed, wherein the particles have a median diameter of from about 1 μm to about 4 Å. 5_. The oral decomposing lozenge, wafer, pellet or rhomboid tablet of claim 4, wherein the particles have a median diameter of about 2 μm. 6_ The oral decomposing tablet, the wafer, the pill or the rhomboform of claim 1, wherein the analgesic is selected from the group consisting of aspirin, 5-aminosalicylic acid, ibuprofen (ibUpr〇fen), naphthalene A group consisting of napr〇xen, acetaminophen, and combinations of these. 7. The oral decomposing lozenge, wafer, pill or diamond agent of claim 6, wherein the analgesic comprises aspirin. 8. The oral decomposing lozenge, wafer, pill or rhombus 127880.doc 200906419, wherein the salt of the analgesic comprises the potassium salt of the analgesic. 9. A method of producing an oral decomposing tablet, wafer, pellet or diamond bond comprising the steps of: 0) providing a first solution comprising a base; (b) adding an analgesic to the first a solution to produce a second solution comprising the salt of the analgesic; ()k; a solution to remove residual analgesic particles to produce a filtered second solution; (4) spray drying the substrate to the filtered The second solution is formed to form agglomerated product comprising a plurality of particles; and (e) the agglomerated product is expelled or slurried into an oral decomposing lozenge, a wafer, a pill or a rhomboform. 10. The method of claim 9, wherein the analgesic agent is selected from the group consisting of aspirin, salicylic acid, ibuprofen, naproxen, ethenamine. 11. For example. The method of claim 10, wherein the analgesic comprises aspirin. The method of item 9 wherein the test comprises triclination of citric acid monohydrate. 13. The method of claim 9, wherein the agent is the same. The mulch further comprises a surface activity. The method of claim 13, wherein the surface is alive. ^ 月 月 月 硫酸 · · · · · · · · · · · · · · · · · · · · · · · · 15 15 15 。 。 。 。 。 。 。 。 。 。 。 。 。 。 16. The method of claim 15, wherein the base comprises cellulose, xylitol or 127880.doc 200906419 sucrose. 17. The method of claim 9, wherein the step of spray drying the filtered second solution onto the substrate is carried out by a fluidized bed spray drying method. The method of claim 9, wherein the median diameter of the particles is in the range of from about 1 p to about 40 μm. 1 9. If you ask for an item! The method of 8 wherein the median diameter of the particles is about . 20. An oral decomposing lozenge, wafer, pellet or lozenge comprising: aspirin; tripotassium citrate monohydrate; and wherein the aspirin comprises a combined weight of the aspirin and the monohydrate citric acid for three hours At least about 26% by weight. 21. The oral decomposing lozenge according to claim 2, Gans-% ικ t #1 'Pill or diamond-shaped red magic, wherein the aspirin accounts for about 26% by weight of the combined weight of the three potassium to _Lin and 5 Hai early hydration The bark acid is simmered to about 4% by weight. 22_If the oral decomposition agent of claim 2 is used, the complex is “Hai, and the human private/m's capsule, pill or diamond 23 is dissolved in water, and its enthalpy is less than about 60. Oral administration of claim 20, wherein the tablet comprises a matrix Y m sachet, a pill or a rhombus. 24. The oral decomposing agent of claim 23, wherein the matrix is selected from the group consisting of a single capsule a group consisting of a combination of the agent, the pill, or the rhombohedron. A sugar, a polysaccharide, a dipeptide, and a π as in the oral agent of claim 24, wherein the matrix comprises cellulose: a sachet, a pill or a rhombus, and xylose Alcohol or sucrose. 127880.doc 200906419 The oral decomposing lozenge, wafer, pellet or diamond lozenge of claim 23, wherein the matrix comprises a core which has been coated with the aspirin and the monohydrate citrate. An oral decomposing lozenge, a labeling pouch, a pill or a rhomborance of claim 20, which further comprises a surfactant. 28. An orally dissolving lozenge, wafer, pellet or rhombus according to claim 27. Lozenge wherein the surfactant comprises sodium lauryl sulfate An oral decomposing lozenge, a standard rice pouch, a pill or a rhomboform of claim 20, which further comprises a supplementary active ingredient selected from the group consisting of ascorbic acid, caffeine and combinations thereof. An oral decomposing lozenge, a wafer, a pill or a rhomboid, comprising: a aspirin; tripotassium monohydrate; and when the composition is soluble in water, the pH is less than about 6 Torr. </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; An oral decomposing lozenge, a semi-sac, a pill or a rhombus as claimed in claim 31, wherein the composition is dissolved in water, and the pot is in the range of from about 5.6 to about A, as claimed in claim 30. Decomposing tablets, glutinous rice granules, wherein the aspirin accounts for at least about 26% by weight of the combined weight of the aspirin disk and the hydrating citric acid. 127880.doc 200906419 34. Oral decomposing lozenges, wafers, pills or The keying agent' further comprises a matrix. 35. The oral system of claim 34, the smear capsule, the pill or the diamond bond 1 is selected from the group consisting of monosaccharides, disaccharides, polysaccharides, dipeptides And a combination of the above. 36. The oral decomposing tablet, wafer, pellet or diamond bond 1 of claim 35, wherein the substrate comprises cellulose, xylitol or Yan sugar. 37. The oral decomposing lozenge, sputum sac, pouch or lozenge of claim 34, wherein the matrix comprises a core to which the aspirin has been applied and the monohydrate of the sulphuric acid. 38. The orally dissolving lozenge, wafer, pellet or lozenge of claim 30, which further comprises a surfactant. 39. The oral decomposing lozenge, wafer, pill or lozenge of claim 38, wherein the surfactant comprises sodium lauryl sulfate. The oral decomposing lozenge, wafer, pill or rhombus as claimed in claim 30, which further comprises a supplementary active ingredient selected from the group consisting of ascorbic acid, caffeine and combinations thereof. 4L - a method for producing an orally decomposing lozenge, a savory rice pouch, a pill or a rhombus, comprising the steps of: θ (a) providing aspirin, citric acid monohydrate lacquer active agent and a substrate Lin accounted for at least about 26% by weight of the combined weight of the aspirin and the monohydrated barium citrate. (b) Producing a sulphur-containing saponin-like acid-dissolved, dissolved, night. (c) Adding aspirin to the first solution to produce the first - ☆ 纩 127880. doc 200906419 (4) adding a surfactant to the second solution. (4) ϋ ϋ this removal of the residual amount of the filtered second solution; Producing (f) spray drying the agglomerated product of the plurality of particles of the filtered second material onto the base λ; and mashing the liquid to form ω containing the condensed product, which is compressed or molded into an oral rice paper bag, pill or rhomboid a β-solution tablet, wherein when the composition is dissolved in water, the ρ Η is less than 42. The method of claim 41, wherein the surfactant = nano. The method of claim 41, wherein the matrix is selected from the group consisting of a polysaccharide, a dipeptide, and combinations thereof. 44. The method of claim 43, wherein the substrate comprises sucrose. Freely listening to cellulose, disaccharide, xylitol or 45. The method of claim 4, wherein the step of drying to the base of the second solution is carried out by using a fluidized bed spray drying method The method of claim 41, wherein the median diameter of the particles is in the range of from about (10) to about 400 μ. 47. The method of claim 46, wherein the median diameter of the particles is about 2~. 48. A rapidly dissolving composition comprising aspirin salt in the form of an orally dissolving lozenge, a sugar-coated pouch, a pill or a lozenge lozenge, wherein the portion comprising 650 mg of aspirin can be completed in less than (eight) seconds I is dissolved in 100 ml of water. / 49. A rapidly dissolving composition in the form of an oral decomposing lozenge, wafer, pill or diatom 127880.doc 200906419 in the form of claim 48, wherein the composition comprising 650 mg of aspirin may be less than Completely dissolved in 1 〇〇 ml of water in 30 seconds. 5. A rapidly dissolving composition in the form of an oral decomposing lozenge, wafer, pill or lozenge in the form of claim 49, wherein the composition comprising 65 mg of aspirin is partially complete in less than 15 seconds Dissolved in 1 ml of water. 51. The rapidly dissolving composition in the form of an oral decomposing agent, sputum, sachet, pill or lozenge according to claim 48, wherein the composition has a pH of less than about 6.0 when dissolved in water. 52. The rapidly dissolving composition in the form of an oral decomposing lozenge, wafer, or pellet in the form of claim 51, wherein the composition is in a range of from about 5.2 to about 6.0 when dissolved. . Ridge in water. 53. The oral decomposing tablet, the wafer, the pellet in the form of a rapid dissolving composition in the form of a tablet, wherein the composition 11 or rheumatism has a pH of from about 5.6 to about Within the scope of 6.0. 54. A method of treating a human disease or a medical condition comprising administering to a human in ♦/oral therapy an oral decomposing agent comprising an effective amount of an analgesic agent, a pill, a pellet or a lozenge Wherein the oral decomposition: a buckwheat paper, a pill or a diamond spinner can be in about $minutes, about 1 to 8 minutes, about 15 minutes, about 20 minutes, or about 5 to about 25 minutes, 2 minutes or An effective amount of the analgesic is delivered in about 10 to about 15 minutes: to about the human blood flow to be treated. '钟丨至需要127880.doc