JP2006519187A - Dosage form with saccharide matrix - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a non-compressed rapid dispersion solid dosage form suitable for administration of a pharmaceutically active substance and preparation of a compressed rapid dispersion tablet.
The present invention comprises (a) a first matrix-forming agent in the form of maltodextrin having a dextrose equivalent (DE) of 1-20, and (b) a second matrix-forming agent in the form of sorbitol, (C) to provide an uncompressed rapidly dispersible solid dosage form suitable for oral mucosal administration of a pharmaceutically active substance comprising an active substance.

Description

  The present invention relates to an uncompressed rapidly dispersible solid dosage form suitable for administration of pharmaceutically active substances and preparation of compressed rapid dispersible tablets.

  Allergies are a major health problem in countries where Western lifestyles are adopted. Furthermore, in such countries, the prevalence of allergic diseases is increasing. Although allergies may not generally be considered a fatal disease, a significant number of deaths occur each year in asthma. The unusual prevalence of about 30% of teens results in substantial loss of quality of life, working days, and property, and is naturally classified as a major health problem in Western societies.

  Allergy is a complex disease. Many factors contribute to sensitization events. These include individual susceptibility defined by interactions between several genes that are not well understood at the current stage. Another important factor is exposure to allergens above a certain threshold. Several environmental factors may be important in the sensitization process, including pollution, childhood infections, parasitic infections, intestinal microbes and the like. In a state where an individual has been sensitized and an allergic immune response has been established, symptoms are directly generated by the presence of a small amount of allergen.

  The natural course of allergic disease is usually accompanied by two stages of deterioration. Initially, the symptoms and severity of the disease progress, and the disease progresses, for example from hay fever to asthma. Second, the transmission of causal allergens most often occurs, resulting in allergic multiple reactions. Chronic inflammation weakens the mucosal defense mechanism as a whole, resulting in unspecified stimulating effects that ultimately destroy mucosal tissue. Infants are primarily sensitized to food, ie milk, and can develop eczema or gastrointestinal disease, but most often are naturally free of symptoms. Such infants are at risk of later developing inhalation allergies.

  The most important allergen source is contained in the most widely spread particles of a certain size in the breathing air. These sources are extremely universal and include grass pollen and house dust mite fecal particles, both accounting for nearly 50% of all allergies. Also of global importance are animal scales, ie, cat and dog scales, other pollen such as mugwort pollen, and microfungi such as alternaria. By region, additional pollen may be prevalent, such as birch pollen in northern and central Europe, ragweed in eastern and central America, and Japanese cedar pollen. Insects, ie bee and wasp venoms, and food each account for approximately 2% of all allergies.

  Allergies, ie type I hypersensitivity, are caused by the immune system reacting inappropriately to foreign non-pathogenic substances. Important clinical signs of allergy include asthma, hay fever, eczema, and gastrointestinal disease. The allergic reaction is immediate and peaks within 20 minutes upon contact with the causative allergen. Furthermore, an allergic reaction is specific in the sense that a particular individual is sensitized to a particular allergen, but does not necessarily have to exhibit an allergic reaction with other substances known to cause allergic diseases. This allergic phenotype is characterized by significant inflammation in the mucous membrane of the target organ and the presence of IgE class allergen-specific antibodies in the circulating blood and on the surface of mast cells and basophils.

  An allergic attack begins with the reaction of a foreign allergen and an allergen-specific IgE antibody, at which time the antibody binds to a high affinity IgE-specific receptor on the surface of mast cells and basophils. Mast cells and basophils contain preformed mediators, namely histamine, tryptase, and other substances that are released when two or more receptor-bound IgE antibodies are cross-linked. IgE antibodies crosslink by simultaneous binding of one allergen molecule. Therefore, after this, a foreign substance having only one antibody-binding epitope will not initiate an allergic reaction. In addition, cross-linking of receptor-bound IgE on the surface of mast cells will release signaling molecules responsible for attracting eosinophils, allergen-specific T cells, and other types of cells to allergic reaction sites. These cells interact with allergens, IgE, and effector cells and will experience a flare-up of symptoms 12-24 hours after encountering the allergen (late phase reaction).

Management of allergic diseases includes diagnosis and treatment including prophylactic treatment. The diagnosis of allergy relates to the demonstration of allergen specific IgE and the identification of allergen sources. In many cases, careful medical history considerations will be sufficient to diagnose allergies and identify causative allergen source materials. In most cases, however, the diagnosis is supported by objective measurements such as skin prick tests, blood tests, or provocation tests.
Treatment options fall into three main categories. The first case is allergen avoidance or exposure reduction. Allergen avoidance is apparent, for example, in the case of food allergens, but may be difficult or expensive with house dust mite allergens and may not be possible with pollen allergens. The second most widely used treatment option is the formulation of classic symptomatic drugs such as antihistamines and steroids. Symptomatic drugs are safe and effective, but do not change the specific cause of the disease and do not control the spread of the disease. A third treatment option is specific allergy vaccination, which in most cases reduces or reduces allergic symptoms caused by the allergen in question.

  Conventional specific allergy vaccination is a causative treatment for allergic diseases. This will intervene in the basic immune mechanism and continually improve the patient's immune status. Thus, the protective effect of certain allergy vaccinations will extend beyond the treatment period as opposed to symptomatic treatment. Some patients who receive treatment are cured, and in addition, most patients reduce the severity and symptoms of the disease, or at least reduce the worsening of the disease. Thus, certain allergy vaccinations have a prophylactic effect that reduces the risk of hay fever progressing to asthma and reduces the risk of new sensitization.

  The immune mechanism underlying the successful allergy vaccination is not known in detail. A particular immune response, such as antibody production against a particular pathogen, is known as an adaptive immune response. This response can be distinguished from an innate immune response that is a non-specific response to a pathogen. Allergic vaccines should address adaptive immune responses including antigen-specific cells and molecules such as T cells and antibody producing B cells. B cells cannot mature and become antibody producing cells without the help of correspondingly specific T cells. T cells that participate in stimulating an allergic immune response are mainly Th2-type. Establishing a new equilibrium between Th1 and Th2 cells has been proposed to be useful and important for the immune mechanism of certain allergic vaccinations. Whether this is due to a decrease in Th2 cells, a shift from Th2 to Th1 cells, or up-regulation of Th1 cells is controversial. In recent years, regulatory T cells have been proposed to be important for the mechanism of allergy vaccination. According to this model, regulatory T cells, ie Th3 or Tr1 cells, down-regulate corresponding antigen-specific Th1 and Th2 cells. Despite such ambiguities, it is generally believed that active vaccines will have the ability to stimulate allergen-specific T cells, preferably TH1 cells.

  Certain allergy vaccinations, despite their advantages, have not been widely used for two main reasons. One reason is the inconvenience associated with traditional vaccination programs that involve repeated vaccinations, ie injections over several months. Another reason is even more important, that is the risk of allergic side reactions. Regular vaccination against infectious agents is efficiently performed using single or several high dose immunizations. However, this approach cannot be used for allergy vaccination because a pathological immune response has already occurred.

  Thus, conventional specific allergy vaccination is performed using multiple subcutaneous immunizations administered over a long period of time. This process is divided into two phases: a dose escalation phase and a maintenance phase. In the dose escalation phase, administration is started starting with a small dose, and generally with increasing doses over a period of 16 weeks. Once the recommended maintenance dose is reached, this dose is administered during the maintenance phase, generally injected every 6 weeks. After each injection, the patient should be observed medically for 30 minutes due to the risk of anaphylactic side reactions that can be very rare but in principle fatal. The clinic should also be equipped to support emergency care. Vaccines based on different routes of administration will eliminate or reduce the risk of allergic side reactions inherent in current subcutaneous-based vaccines and will be more widely used, and further, It is certain that inoculation may be possible.

Attempts to improve vaccines for specific allergy vaccination have been made for over 30 years and include a wide variety of methods. Some methods address the allergen itself by modifying IgE reactivity. Other methods address the route of administration.
The immune system can be accessed from the oral cavity, and sublingual administration of allergens is a known route of administration.

  Conventionally, allergic vaccines using the oral mucosal route consist of an allergen solution up to a daily dose. In contrast, the therapeutic (cumulative) maintenance dose given was more than 5 to 500 times that of maintaining comparable subcutaneous doses. The obvious drawback of this dosage form and route of administration is the problem associated with patients self-administering the exact dose exactly (if several drops need to be administered, the homogeneity of the individual drops , Accuracy of administration site, etc.). There is also a need to cool the drug and to include a preservative in the formulation.

Netien et al., “Galenica 16-drug homeopathy”, 2nd edition, 1986, pp. 77-99, is a solid particle (granule) of lactose, sucrose, or mixtures thereof for sublingual administration of drugs such as allergens. Alternatively, a liquid solution impregnated on a conventional compressed tablet is disclosed. However, these dosage forms have significant drawbacks such as the impregnation procedure.
DD-A-0107208 discloses a process for preparing conventional compressed tablets containing allergens. Upon administration, the tablets are dissolved in saliva and then allergen is absorbed through the mucous membrane of the oral cavity. The formulation contains water insoluble excipients, ie talc powder, and paraffins and fatty acids, which is undesirable because it will leave an unpleasant residue in the patient's mouth. Furthermore, friction during the tableting process can be detrimental to the physical stability of the allergen.
EP 278877 discloses a pharmaceutical composition for use on a solid support, eg sublingual sucrose / lactose coated with an allergen solution. The resulting formulation is claimed to degrade rapidly but not instantaneously. However, it is not disclosed how to achieve the objective. In addition, the formulation contains a reducing sugar in the form of lactose, which is likely to react with allergens.

To ensure that a particular allergen dose is present in the oral mucosa as much as possible, and to ensure that the degradation product contacts the mucosa, the dosage form is instantaneous when contacted with oral saliva. Decomposing is extremely important. Rapidly dispersing solid dosage forms are those that readily release the active ingredients into the oral cavity, which are well known in the art.
U.S. Pat. No. 4,371,516 discloses a pharmaceutical dosage form containing an active ingredient that degrades readily in water. The pharmaceutical dosage form comprises an open matrix network of carrier material that degrades within 10 seconds.

Lyophilized fish gelatin-based carriers as disclosed in WO 00/61117 are designed to release the active ingredient instantaneously when administered into the oral cavity and in contact with saliva. It describes a vaccine against hay fever as an active ingredient.
The lyophilized modified starch carrier as disclosed in WO 00/44351 is designed to release the active ingredient instantaneously when administered into the oral cavity and in contact with saliva. A vaccine against hay fever is described as an active ingredient. The modified starch carrier can be dextrin and starch before gelation.

WO 99/21579 discloses a rapid dispersion dosage form containing vaccines and adjuvants for oral use.
WO 02/13858 discloses a fast dissolving drug composition comprising a vaccine in the form of a fast dissolving “cake” for oral use. The purpose of WO 02/13858 appears to provide a viral or bacterial vaccine that will remain intact in the gastrointestinal tract. This is achieved by incorporating an antacid such as calcium carbonate into the cake to protect the antigen against the acidic content of the stomach.

WO 00/51568 discloses rapidly disintegrating, compressible, low friability tablets designed to dissolve in less than 30 seconds upon contact with saliva in the mouth to form a swallowable suspension.
US-A-5,648,093 discloses rapidly dispersible incompressible solid dosage forms. In a particular example, a dosage form consisting of maltodextrin, mannitol and xanthan gum is disclosed.
WO 91/09591 (Example 25) discloses preparing a placebo carrier matrix in which the matrix consists of maltodextrin (DE10), mannitol and xanthan gum by dissolving in the solid state.

US-B2-6337082 describes a saccharide-based matrix for use in foods containing maltodextrins, gelling agents, and sugars having a DE of less than 40, preferably 20-40, alternatively 10-20. Yes. The gelling agent can be, for example, xanthan gum or gelatin. Many suitable sugars have been shown to include sorbitol. The matrix is shown to disperse instantaneously in water and form a suspension. The matrix is formed in a process with simultaneous flash heating and applied physical force. The resulting matrix is in the form of particles, chips, flakes, or spicula. In this example, a specific composition of maltodextrin, sorbitol, and food ingredients with a DE of 36 is spun into a white narrow flake matrix.
WO 00/57856 discloses a drug in a rapidly dispersing dosage form that is administered upon contact with the peripheral membrane, the dosage form comprising 50% to 99% of a carrier and optionally a diluent. As a carrier, maltodextrin having a DE of 3 to 50 among many compounds is shown. Sorbitol has been shown among many compounds as a diluent.

(Outline of the present invention)
The present invention generally relates to the following matters.
A pharmaceutical comprising (a) a first matrix-forming agent in the form of maltodextrin having a dextrose equivalent (DE) of 1 to 20, (b) a second matrix-forming agent in the form of sorbitol, and (c) an active substance. A non-compressed rapidly dispersible solid dosage form suitable for oral mucosal administration of the active substance.
A dosage form according to the present invention comprising one or more further matrix forming agents.
The dosage form according to the invention, wherein the further matrix-forming agent is a monosaccharide, disaccharide or trisaccharide.
A dosage form according to the present invention wherein the further matrix forming agent is mannitol.
A dosage form according to the present invention further comprising polyethylene glycol (PEG).
A dosage form according to the present invention wherein maltodextrin is present in an amount of 3-40% (w / w), preferably 10-35 (w / w), more preferably 15-25% (w / w) of the dosing solution.
A dosage form according to the present invention wherein mannitol is present in an amount of 1-20% (w / w), preferably 2-10% (w / w), more preferably 3-6 (w / w) of the dosing solution.
Sorbitol is present in an amount of 0.01-10% (w / w), preferably 0.05-5% (w / w), more preferably 0.1-2% (w / w) of the administered solution. A dosage form according to the invention.
A dosage form according to the present invention wherein PEG is present in an amount of 1-20% (w / w), preferably 2-15% (w / w), more preferably 3-10% (w / w).
A dosage form according to the invention wherein the active substance is an allergen.

The present invention is based on the surprising discovery that it is possible to use maltodextrin as a primary matrix forming agent instead of conventional primary matrix forming agents such as gelatin and starch for rapidly dispersing incompressible dosage forms. Yes. Because maltodextrins are partially hydrolyzed, maltodextrins have the advantage over starch that they dissolve or degrade rapidly. At the same time, surprisingly, uncompressed solid dosage forms that use maltodextrin as a matrix-forming agent avoid degradation of the active substance and release of the active substance from the dosage form during manufacture, packaging, transportation, handling, and storage. Therefore, it has been found to have sufficient mechanical strength to remain stable and intact, which is highly desirable for some active substances such as allergens.
Furthermore, surprisingly, sorbitol has been shown to greatly increase the mechanical strength of dosage forms, even in very small amounts.

  For supplying allergens from the oral mucosa to the mucosa, uncompressed rapidly dispersed solid dosage forms that release the active ingredient almost instantaneously upon contact with saliva in the oral cavity are very suitable. However, a priori, the use of this particular dosage form for allergens is accompanied by severe problems. This type of solid dosage form is characterized by a low mechanical strength compared to compressed tablets due to the inherent properties of an uncompressed matrix that is generally wafer-like and brittle. This can result in the release of residual particles containing allergens while the patient handles this dosage form. Allergens can be particularly harmful when the active ingredient is an allergen because it can induce an allergic reaction or cause an allergic response in a treated individual and the sensitization or allergic reaction is dose dependent. It is. The maximum permissible level of environmental contamination in the dust, for example in the form of allergens, has been proposed to be as low as 2 micrograms of major allergen / gram room dust, depending on the allergen in question. ("Allergy, Principles and Practice" (1993 4th edition), "Mosby-Year book", Volume I, page 520)

Such uncompressed rapidly dispersing solid dosage forms made by removing liquid from a solidification system containing a matrix forming agent, active ingredients, and other suitable excipients can be made in situ.
The dosage form is sealed to release residues from the dosage form for in-situ manufacturing, ie, to remove the solvent from the solidification system of the active ingredients and matrix-forming excipients in the final container or blister pack. It is impossible to coat the dosage form so that it does not. Furthermore, it is impossible to coat the dosage form as it will ruin the property that the dosage form releases instantaneously.

Thus, allergen-containing rapid dispersion that releases allergens quickly in the oral cavity and at the same time ideally mechanically robust so that no residue is released from the dosage form to the environment while the patient is handling the dosage form A solid dosage form is required.
There is also a need for an allergen-containing rapidly dispersible solid dosage form in which the active ingredient has sufficient chemical stability to allow manufacture, transportation, storage, and particularly patient handling.

  It is now surprisingly possible to produce a low-fragility, uncompressed, rapidly dispersible solid dosage form containing an allergen that is robust enough and does not release harmful amounts of residue when handled by a patient. It was found. Furthermore, it has surprisingly been found that these formulations are actually stable at room temperature. Cold storage during manufacturing, transportation, or pharmacy storage is often expensive due to the need to closely monitor the cooling equipment, and can also be a reliable cooling equipment. These discoveries are very important with respect to the final product handling procedure, since it is also expensive to invest. Further, for patient compliance, the dosage form is preferably capable of being stored at room temperature. Articles of the European Pharmacopeia on allergen products indicate that the moisture level should not exceed 5% for freeze-dried products (ie allergen extracts in vials) . Surprisingly, it has been found that even dosage forms according to the invention in which the water content exceeds 5%, the maximum level required, are stable at room temperature. Without being bound by theory, this can be explained by the fact that the rapidly dispersible solid dosage form excipient binds the water remaining in the dosage form and reduces the water activity of the allergen vaccine administration formulation. Therefore, by reducing the water activity of the formulation, it is possible to obtain a stable formulation in which the allergen does not degrade even if the water content is higher than the maximum level of 5% prescribed for the allergen extract in the vial.

To ensure sufficient shelf life of the final product, the stability of the solid dosage form can be measured with respect to the physical and chemical properties of the solid dosage form or its individual components.
Water activity is one of the important factors contributing to product shelf life. It is known that the water activity of a product affects bacterial growth and drug stability, potency, and viscosity. Protein stability is also significantly affected by water activity due to its vulnerability. Most proteins should maintain a conformation that retains activity. Maintaining low water activity levels can help to prevent or induce conformational changes, which in turn is important to ensure that allergen forms of proteins are stable. It becomes. Protein hydrolysis is influenced by water activity regardless of whether it is caused by an enzyme.

Water activity is measured using methods known to those skilled in the art, for example, cold mirror dew point technology, methods of measuring relative humidity with sensors that change electrical resistance or capacitance, or methods using lithium chloride electrodes. .
The water activity of the preferred solid dosage form does not exceed 25%, preferably 0.1% to 20%, more preferably 0.5 to 15%, still more preferably 2 to 8%, most preferably 4 to 7%. is there.
The water content of the solid dosage form determined by the method described in Example 1 preferably does not exceed 25%, preferably 0.1% to 20%, more preferably 0.5 to 15%, even more preferably 2. -8%, most preferably 4-7%.

  Several laboratory tests are available to characterize allergens. The most widely used techniques are sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing (IEF), cross immunoelectrophoresis (CIE), and rocket immunoelectrophoresis (RIE). Quantification of individual allergens can be performed by various quantitative immunoelectrophoresis techniques (QIE), radial immunodiffusion (RIE), or enzyme-linked immunosorbent assay (ELISA). Measurement of total allergen titer is most often performed by radioallergic adsorption test (RAST), (LIA), or related techniques. Also, a technique based on ELISA can be used.

Acceptable limit guidelines that are usually applied for tests that measure biopotency are found, for example, in the European Medicines Evaluation Bureau CPMP_BWP_243_96, which is a memorandum for guidelines on allergen products.
Preferably, for the purposes of the present invention, the stability of the active ingredient, generally allergen, is assessed by allergen titer measurements such as total allergen activity and major allergen content.

“Initial allergen activity” or “initial content of at least one major allergen” of a solid dosage form means the value after the production of the solid dosage form is finished.
According to the method described in Example 1, the loss of total allergen activity is preferably less than 50% of total initial activity, more preferably less than 30% of total initial activity, even more preferably less than 20% of total initial activity, Most preferably, it should be less than 15% of the total initial activity.

  Several tests can be performed on the classification of allergens as major allergens. Allergens are usually classified as major allergens when at least 25% of patients show strong IgE binding (score 3) and 50% of patients show at least moderate binding (score 2), Determined by CRIE (CRIE strong binding, ie visible IgE binding on X-ray film after 1 day, CRIE moderate binding, ie binding after 3 days, CRIE weak binding, ie binding after 10 days). If at least 10% of patients have strong IgE binding, this allergen is classified as a moderate allergen, and the specific binding apparent in less than 10% of patients is a trace allergen. Other methods can also be used to determine, for example, IgE binding in IgE blots.

According to the method described in Example 1, the loss of the allergen content of at least one major allergen is preferably less than 50% of the total initial content, more preferably less than 30% of the total initial content, more preferably the total initial content. Less than 20%, most preferably less than 15% of the initial content.
In one embodiment of the solid allergen dosage form, the loss of total allergen activity is less than 50% of the total initial activity according to the method described in Example 1.
In another embodiment of solid allergen administration, the loss of allergen content of at least one major allergen is less than 50% of the initial content according to the method described in Example 1.

The dosage form of the present invention does not change much in terms of physical and chemical properties such as allergen titer, mechanical robustness, and sensory organ properties after manufacture to ensure sufficient shelf life of the final product It is stable in meaning.
That is, the stability of a solid dosage form is the stability of sensory organ properties such as friability, tensile strength, peak load to break, stability of physical properties, generally dispersion time, and visual appearance of the dosage form. It is preferable to evaluate with additional parameters such as mechanical robustness such as property.

  These can be evaluated, for example, by measuring the peak load or tensile strength until breakage of the solid dosage form of the present invention. As is apparent from the equation from which the tensile strength can be calculated, the tensile strength value can be obtained by several parameters, which are influenced by variables, such as the thickness or diameter of the solid dosage form, and the change in value. Will contribute. Therefore, the peak load to break is considered to be a more accurate parameter for evaluating the robustness of the solid dosage unit of the present invention.

To ensure that the solid dosage form is sufficiently robust during storage and when handled by the patient, the dosage form must have a certain resistance to external forces, while at the same time the solid dosage form is Should be broken down reliably and quickly in the mouth.
In yet another embodiment of the present invention, the solid dosage form preferably has a tensile strength of less than 1.1 N / mm ² , more preferably less than 0.8 N / mm ² . Generally, the dosage form tensile strength is 0.2~0.5N / mm ^2. As the tensile strength decreases, the mechanical strength and stability of the dosage form decreases and becomes faster to disperse.

  The rapid dispersion dosage form preferably breaks down instantaneously or rapidly upon contact with saliva in the mouth to ensure maximum exposure to tissue with mucosal immune response capability before the allergen is swallowed. In a preferred embodiment, the solid dosage form is less than about 90 seconds, preferably less than 60 seconds, preferably less than 30 seconds, more preferably less than 20 seconds, more preferably less than 15 seconds, more preferably oral. In less than 10 seconds, more preferably less than 5 seconds, and most preferably less than about 2 seconds.

  In a preferred embodiment of the invention, the composition of the invention is a rapidly dispersible solid dosage form comprising a solid network of allergens and an optional water soluble or water dispersible matrix. The network is in the solid state and is obtained by sublimating the solvent from a composition comprising a solution of allergen and matrix. More preferably, the network is obtained by lyophilization.

Excipients In a preferred embodiment of the present invention, the dosage form further comprises one or more excipients in addition to the matrix forming agent.
Pharmaceutically acceptable excipients that form part of the matrix of the rapidly dispersible solid dosage form according to the present invention include adjuvants, antacids, diluents, activators, mucoadhesives, flavoring agents, taste masking agents. Suitable excipients such as preservatives, antioxidants, surfactants, thickeners, colorants, pH adjusters, and sweeteners. These excipients are selected according to conventional pharmaceutical practice as understood by those skilled in the art of formulating allergen vaccines.

  In a preferred embodiment of the invention, the dosage form includes a protein stabilizer. Examples of protein stabilizers include polyethylene glycol (PEG), such as PEG300, PEG400, PEG600, PEG1000, PEG1500, PEG3000, PEG3050, PEG4000, PEH6000, PEG2000, and PEG35000, and amino acids such as glycine, alanine, arginine, Monosaccharides, disaccharides, and trisaccharides such as trehalose and sucrose, polyvinyl alcohol (PVA), polyoxyethylene sorbitan fatty acid esters (polysorbate, tween or span), human serum albumin (HSA), and bovine serum It is albumin (BSA). Preferably, PEG is used as a protein stabilizer. In addition to being a protein stabilizer, PEG is believed to impart elastic properties to the dosage form matrix.

Suitable colorants include red, black, and yellow iron oxides and “FD & C” dyes such as “FD & C” Blue No. 2 and “FD & C” Red No. 40. Suitable flavoring agents include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry, and grape flavors, and combinations thereof. Suitable pH adjusting agents include citric acid, tartaric acid, phosphoric acid, hydrochloric acid, and maleic acid. Suitable sweeteners include aspartame, acesulfame K, and thaumatin. Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin-containing compounds, adsorbents, or microencapsulated activators.
Adjuvants are usually used to promote absorption of allergens as well as to promote the immunostimulatory properties of allergens.

In one embodiment of the invention, at least one adjuvant is incorporated into the dosage form according to the invention. Examples of suitable adjuvants are aluminum salts, non-toxic bacterial debris, cytokines, cholera toxin (and its non-toxified fraction), chitosan, homologous heat-labile enterobacteria (and detoxified fraction), saponin, lipopolysaccharide Bacterial products such as saccharides (LPS) and muramyl dipeptide (MDP), liposomes, CpG (immunostimulatory DNA sequences), lactide / glycolide homocopolymers in the form of particulate polymers, and the like. The reason for using adjuvants in allergen vaccines is often due to the fact that the allergen in question cannot penetrate the barrier through. Thus, adjuvants can act as absorption enhancers or can act as immunostimulants. However, the use of adjuvants has significant drawbacks such as unintentionally stimulating various mechanisms of immune response and systemic lupus erythematosus, and passing harmful substances through the mucosal barrier ability. May be accompanied. In addition, from an industrial point of view, the addition of adjuvants can lead to significant manufac- turing documentation for pharmaceutical registration and constitute additional manufacturing and material costs.
In another preferred embodiment of the present invention, the rapidly dispersible solid dosage form according to the present invention does not contain an adjuvant.
Also surprisingly, in order to promote the immunostimulatory properties of the allergen in question, it is not always necessary to incorporate adjuvants into the rapidly dispersible solid dosage form, i.e., the solid dosage form has a specific immune response. It has been found that it can be improved.

  While the uncompressed rapidly dispersible solid dosage form according to the present invention can itself be somewhat mucoadhesive, in a preferred embodiment of the present invention said dosage form is used to increase the time the dosage form contacts the oral mucosa. It may be necessary to add more mucoadhesive excipients to the form. Suitable mucoadhesive excipients include polyacrylic acid polymers such as carbomers and carbomer derivatives, cellulose derivatives such as hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and sodium carboxymethylcellulose, gelatin, sodium alginate, With natural polymers such as pectin and glycerol.

Matrix former In a preferred embodiment of the present invention, the maltodextrin has a DE of 1-15, more preferably 1-10.
In a preferred embodiment of the invention, the further matrix forming agent is a monosaccharide, disaccharide or trisaccharide. Examples of monosaccharides, disaccharides, and trisaccharides are mannose, glucose, galactose, mannitol, mannose, galactitol, erythritol, inositol, threitol, maltitol, trehalose, sucrose, maltose, maltotriose, lactose, palatinose , And lactulose. Preferred monosaccharides, disaccharides, and trisaccharides are mannose and mannitol.
In a preferred embodiment of the dosage form of the present invention, this further matrix forming agent is mannitol.

Other matrix forming agents suitable for use in accordance with the present invention include animal or plant proteins such as gelatin, soy, wheat and psyllium seed proteins, gums such as acacia, guar, agar and xanthan, starch and modified starch. Polysaccharides such as, cyclosaccharides such as cyclodextrins, alginate, carboxymethylcellulose, carrageenan, dextran, pectin, synthetic polymers such as polyvinylpyrrolidone, and gelatin-acacia complexes, Substances from polypeptide / protein or polysaccharide complexes are included.
Other matrix forming agents suitable for use in accordance with the present invention include inorganic salts such as sodium phosphate, sodium chloride and aluminum silicate, and glycine, L-alanine, L-aspartic acid, L-glutamic acid, L-hydroxy And amino acids having 2 to 12 carbon atoms such as proline, L-isoleucine, L-leucine, and L-phenylalanine.

As mentioned above, the present invention allows the production of rapidly dispersed incompressible dosage forms using maltodextrin as the primary matrix former and sorbitol as the secondary matrix former.
Furthermore, the present invention makes it possible to produce rapidly dispersible incompressible dosage forms having a matrix composed of maltodextrin, sorbitol, and monosaccharides, disaccharides, and trisaccharides. Thus, in another preferred embodiment of the invention, the matrix does not contain maltodextrins, sorbitol, and other matrix forming agents other than monosaccharides, disaccharides, and trisaccharides. More particularly, the matrix preferably does not contain a polymer matrix forming agent, more particularly the matrix preferably does not contain gelatin and / or starch and / or gum.
The total dry matter content of the dosing solution is preferably greater than 20% (w / w), more preferably greater than 30% (w / w), even more preferably greater than 40% (w / w), More preferably it is larger than 50% (w / w), most preferably larger than 60% (w / w). The total dry matter content of the dosing solution will depend on the size of the tablet produced.

Drug Active Substance The drug active substance used in the dosage form of the present invention can be any active substance that can be administered through the oral mucosal route. Oral mucosal administration is where it is desirable to administer rapidly and / or because, for example, it is difficult to carry the active substance across the mucosa and / or because the active substance degrades while passing through the gastrointestinal system It is particularly appropriate when it is difficult to administer through the intestinal mucosa. Administration through the oral mucosal route is suitable, for example, for proteins.

Examples of suitable active substances include, but are not limited to:
Analgesics and anti-inflammatory agents: alloxypurine, auranofin, azapropazone, benolylate, diflunisal, etodolac, fenbufen, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamic acid, mefenamic acid, nabumetone, naproxen, Oxaprozin, oxyphenbutazone, phenylbutazone, piroxicam, sulindac.
Antiparasitic agents: albendazole, bephenium hydroxynaphthoate, cambendazole, dichlorophen, ivermectin, mebendazole, oxamniquin, oxfendazole, oxantel embonate, praziquantel, pirantel embonate, thiabendazole.
Antiarrhythmic agents: amiodarone HCl, disopyramide, flecainide acetate, quinidine sulfate.
Antibacterial agents: venetamine penicillin, sinoxacin, ciprofloxacin HCl, clarithromycin, clofazimine, cloxacillin, demeclocycline, doxycycline, erythromycin, ethionamide, imipenem, nalidixic acid, nitrofurantoin, rifampicin, spiramycin, sulfabenza Mido, sulfadoxine, sulfamerazine, sulfacetamide, sulfadiazine, sulfafurazole, sulfamethoxazole, sulfapyridine, tetracycline, trimethoprim.
Anticoagulants: Dicoumarol, Dipyridamole, Nikumarone, Pheninedione.
Antidepressants: Amoxapine, cycladindol, maprotiline HCl, mianserin HCl, nortriptyline HCl, trazodone HCl, trimipramine maleate.
Antidiabetic agents: acetohexamide, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide.
Antiepileptic agents: beclamide, carbamazepine, clonazepam, ethotoin, methoin, methosuximide, methylphenobarbitone, oxcarbazepine, parameterdione, phenacemide, phenobarbitone, phenytoin, fenceximide, primidone, sultiam, valproic acid.
Antifungal agents: amphotericin, butconazole nitrate, clotrimazole, econazole nitrate, fluconazole, flucytosine, griseofulvin, itraconazole, ketoconazole, miconazole, natamycin, nystatin, sulconazole nitrate, terbinafine HCl, terconazole, thioconazole, undecenoic acid.
Anti-ventilants: allopurinol, probenecid, sulfinpyrazone.
Antihypertensive agents: amlodipine, benidipine, dalodipine, dilitazem HCl, diazoxide, felodipine, guanabenz acetate, indramin, isradipine, minoxidil, nicardipine HCl, nifedipine, nimodipine, phenoxybenzamine HCl, pyrazosin HCL, reserpine, terazosin HCl.
Antimalarial agents: amodiaquine, chloroquine, chlorproguanyl HCl, halophanthrin HCl, mefloquine HCl, proguanyl HCl, pyrimethamine, quinine sulfate.
Antimigraine agents: dihydroergotamine mesylate, ergotamine tartrate, methyselside maleate, pizotifen maleate, sumatriptan succinate.
Antimuscarinic agents: atropine, benzhexol HCl, biperidene, etopropazine HCl, hyoscine butyl bromide, hyoscyamine, mepenzolate bromide, orphennadrine, oxyphenethylthymine HCl, tropicamide.
Antitumor agents and immunosuppressants: aminoglutethimide, amsacrine, azathioprine, busulfan, chlorambucil, cyclosporine, dacarbazine, estramustine, etoposide, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitozantrone, procarbazine HCl, Tamoxifen citrate, test lactone.
Antiprotozoal agents: benznidazole, clioquinol, clioquinol, diiodohydroxyquinoline, diloxanide furoate, dinitramide, fluzolidone, metronidazole, nimorazole, nitrofurazone, ornidazole, tinidazole.
Antithyroid agents: carbimazole, propylthiouracil.
Anti-anxiety agents, sedatives, hypnotics, and neuroleptic agents: alprazolam, amylobarbitone, barbitone, bentazepam, bromazepam, bromperidol, brotizolam, butobarbitone, carbomar, chlordiazepoxide, chlormethiazole, chlorpromazine, clobazam, clothiazepam, Clozapine, diazepam, droperidol, etinamate, flunanizone, flunitrazepam, fluopromazine, flupenthixol decanoate, fluphenazine decanoate, flurazepam, haloperidol, lorazepam, lormetazepam, medazepam, meprobamate, metacarone, midazom pendazom , Perphenazine pimozide, prochlorperazine, sulpiride, temazepam, thioridazine, tri Zoramu, zopiclone.
β-blocker: acebutolol, alprenolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol.
Cardiotonic agents: amrinone, digitoxin, digoxin, enoximone, lanatoside C, medigoxin.
Corticosteroids: beclomethasone, betamethasone, budesonide, cortisone acetate, dezoxymethazone, dexamethasone, fludrocortisone acetate, flunizolide, flucortron, fluticasone propionate, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone.
Diuretics: acetazolamide, amiloride, bendrofluazide, bumetanide, chlorothiazide, chlorthalidone, ethacrynic acid, frusemide, metolazone, spironolactone, triamterene.
Enzyme: Antiparkinsonian agent: bromocriptine mesylate, lisuride maleate.
Gastrointestinal agents: bisacodyl, cimetidine, cisapride, diphenoxylate HCl, domperidone, famotidine, loperamide, mesalazine, nizatidine, omeprazole, ondansetron HCL, ranitidine HCl, sulfasalazine.
Histamine H, receptor antagonist: acribastine, astemizole, cinnarizine, cyclidine, cyproheptadine HCl, dimenhydrinate HCl, flunarizine HCl, meclozine HCl, oxatomide, terfenadine, triprolidine.
Lipid regulators: bezafibrate, clofibrate, fenofibrate, gemfibrozil, probucol.
Local anesthetic agent: neuromuscular agent: pyridostigmine.
Nitrate and other anti-anginal agents: amyl nitrate, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, pentaerythritol tetranitrate.
Nutrients: beta carotene, vitamin A, vitamin B2, vitamin D, vitamin E, vitamin K.
Opioid analgesics: codeine, dextropropoxyphene, diamorphine, dihydrocodeine, meptazinol, methadone, morphine, nalbuphine, pentazocine.
Oral vaccines: vaccines designed to prevent or reduce disease symptoms (the following are representative but not exhaustive): influenza, tuberculosis, meningitis, hepatitis, pertussis, polio Tetanus, diphtheria, malaria, cholera, herpes, typhoid, HIV, AIDS, measles, Lyme disease, traveler's diarrhea, hepatitis A, B and C, otitis media, dengue fever, rabies, parainfluenza, rubella, yellow fever, Shigellosis, Legionella disease, Toxoplasmosis, Q fever, hemorrhagic fever, Argentine hemorrhagic fever, caries, Chagas disease, urinary tract infection caused by E. coli, pneumococcal infection, epidemic parotitis, and chikungunya fever.
Vaccines that prevent or reduce symptoms of other diseases (the following is a representative list of causative organisms, but not exhaustive): Vibrio, Salmonella, Bordetella, Hemoproteus, Toxoplasma, Cytomegalovirus, Chlamydia species, Streptococcus species, Norwalk virus, E. coli, Helicobacter pylori, Rotavirus, Neisseria gonorrhoeae, Neisseria meningitidis, Adenovirus, EB virus, Japanese encephalitis virus, Carini pneumonia, Herpes simplex, Clostridium species, Respiration Organ syncytia, Klebsiella species, Shigella species, Pseudomonas aeruginosa, parvovirus, Campylobacter species, Rickettsia species, Varicella zoster, Yersinia species, Ross River virus, C. Virus, Rhodococcus equi, Catarrhal molaxella, Borrelia burgdorferi, and Pasteurella haemolytica.
Vaccines for non-infectious immune modulation disease states such as local and systemic allergic conditions such as hay fever, asthma, indirect rheumatism, and carcinoma.
Vaccines for veterinary use include coccidiosis, Newcastle disease, endemic pneumonia, feline leukemia, atrophic rhinitis, erysipelas, foot and mouth disease, swine pneumonia, and other disease states that affect pets and livestock, and others Infectious and autoimmune disease states.
Proteins, peptides, and recombinant drugs: insulin (hexamer / dimer / monomer form), glucagon, growth hormone (somatotropin), polypeptide or derivative thereof (preferably, molecular weight 1000-300,000), Calcitonin and its synthetic modifications, enkephalins, interferons (especially alpha 2 interferons for cold treatment), LHRH and analogs (nafarelin, buserelin, zoladex), GHRH (growth hormone releasing hormone), secretin, bradykin antagonist, GRF (Growth hormone releasing factor), THF, TRH (thyroid stimulating hormone releasing hormone), ACTH analog, IGF (insulin-like growth factor), CGRP (calcitonin gene related peptide), atrial natriuretic peptide, vasopressin Fine analogs (DDAVP, lypressin), factor VIII, G-CSF (granulocyte colony stimulating factor), EPO (erythropoietin).
Sex hormones: clomiphene citrate, danazol, ethinyl estradiol, medroxyprogesterone acetate, mestranol, methyltestosterone, norethisterone, norgestrel, estradiol, complex estrogen, progesterone, stanozolol, stilbestrol, testosterone, tibolone.
Spermicide: Nonoxynol 9.
Stimulants: amphetamine, dexamphetamine, dexfenfluramine, fenfluramine, mazindol, pemoline.

In a preferred embodiment of the invention, the pharmaceutically active substance is an allergen. The remainder of this section and most other parts of the description of the invention will be described with respect to this embodiment of the invention.
According to the present invention, the allergen vaccine is provided in a rapidly dispersible solid dosage form that dissolves rapidly upon contact with saliva in the oral cavity, allowing the allergen to come into close contact with and act on mucosal immune related tissues. . In a preferred embodiment of the invention, the allergen according to the invention is any natural protein that has been reported to cause allergic, ie IgE-mediated reactions, when repeatedly exposed to an individual. Examples of natural allergens include pollen allergens (trees, broadleaf herbs, weeds, and grass pollen allergens), insect allergens (inhalable, saliva and venom allergens such as mite allergens, cockroaches and small insect allergens) , Hymenoptera venom allergens), animal hair and fueer allergens (eg, from dogs, cats, horses, rats, mice, etc.), and food allergens. Important pollen allergens from trees, grasses, and broadleaf herbs are generally birch (Apis genus), alder (Apis genus), hazel (Apis genus), hornbeam (Apis genus) and olive (genus Olive), cedar (Cryptomeria genus and Junipalace genus), taxonomic order of beech, asteraceae, pine, and sycamore, including sycamore (Platanus), genus genus, euphorbiaceae, strawberry genus, genus Drosophila, genus Camellia, Shiragaya Genus, cereals, rye, and sorghum generally including grasses, ragweed, mugwort, and genus genus genus generally including broadleaf herbs, and such as nettle It is. Other important inhalation allergens are house dust mites of the genus Leopard and mite, reservoir mites, e.g. those from Sayaani mite, Mite mites, and mite mites, cockroaches, small insects, and fleas, e.g. German cockroaches, black cockroaches, chironomids, And from mammals such as cats, dogs, and horses, and poison allergens include honeybees (beeps superfamily), wasps (beeps superfamily), and ants (ant superfamily) Including those resulting from puncture or biting insects such as those from the taxonomic eyes of Hymenoptera. Important inhalation allergens from fungi are generally those arising from the genera Alternaria and Cladosporium.

  In a more preferred embodiment of the invention, the allergen is “Bet v 1”, “Aln g 1”, “Cor a 1” and “Car b 1”, “Que a 1”, “Cry j 1”, “Cry j 1” j 2 ”,“ Cup a 1 ”,“ Cup s 1 ”,“ Jun a 1 ”,“ Jun a 2 ”,“ jun a 3 ”,“ Ole e 1 ”,“ Lig v 1 ”,“ Pla 1 ” ”,“ Pla a 2 ”,“ Amb a 1 ”,“ Amb a 2 ”,“ Amb t 5 ”,“ Art v 1 ”,“ Art v 2 ”,“ Par j 1 ”,“ Par j 2 ”, “Par j 3”, “Sal k 1”, “Ave e 1”, “Cyn d 1”, “Cyn d 7”, “Dac g 1”, “Fes p 1”, “Hol 1”, “Lol” p 1 and 5 ”,“ Pha a ”,“ Pas n 1 ”,“ Phl p 1 ”,“ Phl p 5 ”,“ Phl p 6 ”,“ Poa p 1 ”,“ Poa p 5 ”,“ Sec c 1 ”,“ Sec c 5 ”, “Sor h 1”, “Der f 1”, “Der f 2”, “Der p 1”, “Der p 2”, “Der p 7”, “Der m 1”, “Eur m 2”, “Gly” d 1 ”,“ Lep d 2 ”,“ Blot 1 ”,“ Tyr p 2 ”,“ Blag 1 ”,“ Blag 2 ”,“ Per a 1 ”,“ Fel d 1 ”,“ Can f 1 ” ”,“ Can f 2 ”,“ Bos d 2 ”,“ Equ c 1 ”,“ Equ c 2 ”,“ Equ c 3 ”,“ Mus m 1 ”,“ Rat n 1 ”,“ Apis m 1 ”, “Api m 2”, “Ves v 1”, “Ve” s v 2 ”,“ Ves v 5 ”,“ Dol m 1 ”,“ Dil m 2 ”,“ Dol m 5 ”,“ Pol a 1 ”,“ Pol a 2 ”,“ Pol a 5 ”,“ Sol i ” 1 ”,“ Sol i 2 ”,“ Sol i 3 ”and“ Sol i 4 ”,“ Alt a 1 ”,“ Cla h 1 ”,“ Asp f 1 ”,“ Bos d 4 ”,“ Mal d 1 ” , “Gly m 1”, “Gly m 2”, “Gly m 3”, “Ara h 1”, “Ara h 2”, “Ara h 3”, “Ara h 4”, “Ara h 5”, or Mixed hybrids from any of these “molecular breeding”.

In the most preferred embodiment of the invention, the allergen is a pollen allergen or a dust mite allergen or a ragweed allergen or a cedar pollen or a cat allergen or a birch allergen.
In yet another embodiment of the invention, the rapidly dispersible solid dosage form is either from the same allergen source or from a different allergen source, eg, herb group 1 and herd group 5 allergens from different mite and grass species, respectively. Or tick group 1 and group 2 allergens, weed antigens such as low and high size ragweed allergens, different fungal allergens such as Alternaria and Cladosporium, birch, hazel, hornbeam, oak and alder It contains at least two different types of allergens from food allergens such as fresh tree allergens, peanuts, soy and milk allergens.

The allergen incorporated into the rapidly dispersing solid dosage form can be in the form of an extract, a purified allergen, a modified allergen, a recombinant allergen, or a mutant of the recombinant allergen. An allergen extract can naturally contain one or more isoforms of the same allergen, whereas a recombinant allergen generally corresponds to only one isoform of an allergen. In a preferred embodiment, the allergen is in the form of an extract. In another preferred embodiment, the allergen is a recombinant allergen. In another preferred embodiment, the allergen is a natural low IgE binding mutant or a recombinant low IgE binding mutant.
Allergens can be present in equimolar amounts, and the allergen ratio present can preferably vary up to 1:20.
In yet another embodiment of the invention, the low IgE binding allergen is an allergen according to WO 99/47680, WO 02/40676, or WO 03 / 096869A2.

Dosage Form The dosage form of the present invention is preferably produced by lyophilization.
Preferably, the pH is adjusted prior to solidifying the allergen and matrix, including the solution, to avoid denaturation and precipitation of the allergen and to ensure a stable product. The optimum pH for different allergen solutions is that over almost the entire pH range, as is its isoelectric point (pl). Mixtures of allergens such as extracts are also optimal for solubility and stability as judged by factors such as the concentration of individual allergens in the extract. Therefore, a feasible range of pH determined individually for the formulation according to the invention can be expected. The optimum pH for the allergen in question is determined by performing accelerated stability tests on formulations of different pH. Such test designs are well known to those skilled in the art of formulating allergen vaccines.
Preferably, the dosing solution containing the allergen extract should be adjusted to a pH of 3.5-10, more preferably 4-9, most preferably 6-9.

  Furthermore, it is known in the art that ionic strength can be a parameter that affects the stability of a lyophilized solid dosage form, primarily through the effects of the lyophilization process. It is also known to affect precipitation at high ionic strength. Therefore, the optimum value should be established by taking measurements known to those skilled in the art. Preferably, the ionic strength of the 10 ug / m extract is 1-1500 μS / cm, more preferably 300-800 μS / cm, most preferably about 500 μS / cm, and for matrices and allergen-containing systems, The strength is preferably 1 to 2000 μS / cm, more preferably 500 to 1500 μS / cm.

Classic incremental dose desensitization, which increases the dose of allergen in the form of a rapidly dispersible solid dosage form to a certain maximum, alleviates allergic symptoms. The preferred titer of the unit dosage of the dosage form is 150 to 1000000 SQ-u / dosage form, more preferably the titer is 500 to 500000 SQ-u / dosage form, more preferably the titer is 1000 to 250,000 SQ-u / A dosage form, more preferably 1500-125000 SQ-u / dosage form, most preferably 1500-75000 SQ-u / dosage form.
In another embodiment of the invention, the dosage form is a repeated single dose, preferably in the range of 1500-75000 SQ-u / dosage form.

In yet another embodiment of the invention, the allergen dosage form dissolved in saliva is not swallowed until 3 minutes after administration, for example, to contact for a time sufficient to absorb across the mucosa in the mouth.
In yet another preferred embodiment, the allergen dosage form is not diluted in the oral cavity by not taking up fluid water until, for example, after 5 minutes.
The rapidly dispersible solid dosage form according to the present invention is manufactured as described in US Pat. No. 5,729,958 and US Pat. No. 5,343,762 and packaged in disposable single dose blister packs. Can do. Examples of suitable blister packs are all-aluminum blister packs, blister packs made of polymers such as polypropylene, PVC blister packs, and aluminum made of PVC / PVdC laminates and laminated to calendered kraft paper, for example. A sealed blister pack, “Aclar®”, or “Triplex®”.

In one embodiment of the present invention, a rapid dispersion dosage form is manufactured and packaged in an aluminum sealed blister pack made of PVC / PVdC laminate and laminated to calendered kraft paper. In another embodiment of this, the blister pack is enclosed in an appropriately sized aluminum sachet made of aluminum laminated to calendered kraft paper.
In yet another embodiment, the rapid dispersion dosage form is packaged in an aluminum sealed blister pack formed of aluminum and laminated to calendered kraft paper.
In yet another embodiment, the rapid dispersion dosage form is packaged in a multi-layer blister pack formed, for example, of a five-layer aluminum laminate and sealed with aluminum laminated to calendered kraft paper.
In yet another embodiment, the rapid dispersion dosage form is packaged in a blister pack formed of an aluminum laminate and sealed with aluminum laminated to calendered kraft paper so that the child can use this blister pack, eg, child safety packaging. Make it difficult to open.

  Non-compressed rapidly dispersible solid dosage forms are usually characterized by low mechanical strength compared to compressed tablets due to their inherent properties such as being uncompressed dosage forms. This will release allergen-containing residual particles when removed from the blister pocket and while the patient handles the dosage form. In most cases this is not important or is mainly only superficially important. However, this is particularly detrimental when the active ingredient is an allergen, since low-dose allergens can induce allergic reactions, i.e. sensitization, in ingested humans. Exposure is usually in the range of 10 μg / year for the major allergen protein accumulated, for example for pollen allergens or dust mite allergens, which is reasonable to sensitize or cause symptoms. is there.

When handling solid dosage forms, allergens can come into contact with target organs such as the respiratory tract or eyes and trigger allergic human reactions. One of the dosage forms can contain an amount of allergen that is sufficient to expose a human being over a year or more, depending on the nature of the exposure. Conjunctival allergen challenge can also be used to induce ocular symptoms in allergic patients. Based on such challenge studies, it can be estimated how much allergen extract is needed to induce conjunctival symptoms. In the population of patients with pollen-induced hay fever, the lowest dose of pollen extract that causes conjunctival symptoms is proposed to be 3000 SQ-U / ml × 0.05 ml = 150 SQ-U (median) (SR Durham, By SM Walker, EM Varga, MR Jacobson, F. O'Brien, W. Noble, S. J. Till, Q. A. Hamid, K. and T. Nouri-Aria. “Long-term clinical efficacy of pollen immunotherapy”, “N. Engt. J. Med.”, 341 (7), 468-475, 1999).
That is, in one embodiment of the dosage form of the present invention, less than 500 SQ-U, more preferably less than 250 SQ-U, and most preferably less than 150 SQ-U is released from each solid dosage form during hand handling.

To ensure that allergens, including residues from solid dosage forms, are never released to the environment when the blister pack is opened, make the dosage form as brittle as possible without compromising allergen release of the dosage form after oral administration. It is important to.
In a preferred embodiment of the present invention, the residual content of blister pack dust after removal of the dosage form does not exceed 2% of the total allergen content, more preferably 0.5% of the total allergen content of the solid dosage form. More preferably, it does not exceed 0.2% of the total allergen content of the solid dosage form, and most preferably it does not exceed 0.1% of the total allergen content of the solid dosage form.

  Usually, the friability test of compressed tablets is performed according to the European Pharmacopoeia P. Performed as specified in 2.9.7 and United States Pharmacopeia USP <1216>, weight loss is assessed as a parameter of the intact dosage form. Thus, the intactness of current dosage forms can be assessed by visual inspection and tablet weight measurement when such methods are performed. Alternatively, due to the low weight of the dosage form according to the invention, the weighing can be replaced by an immunoassay specific for the allergen in question.

The use of a modified friability test has been found to be a useful tool for assessing which compositions are most stable with respect to fastness and mechanical strength. In one embodiment, the friability of the solid dosage form, measured as the amount of allergen released, is 500 SQ-U / solid in any suitable friability test that exerts sufficient external force on the composition being tested. Less than a dosage form, more preferably less than 250 SQ-U / solid dosage form, most preferably less than 150 SQ-U / solid dosage form. In a more preferred embodiment, the friability, measured as the amount of allergen released in a friability test conducted according to the pharmacopoeia, is less than 500 SQ-U / solid dosage form, more preferably 250 SQ-U / solid agent. Less than form, most preferably less than 150 SQ-U / solid dosage form. In a further preferred embodiment, the friability measured as the amount of allergen released is the following steps:
a) placing the individual units of the solid dosage form contained in a sealed blister pack unit into equipment suitable for friability measurement;
b) moving it at an appropriate speed for an appropriate time;
c) removing the sealed solid dosage form unit;
d) opening the sealed solid dosage form unit and dispensing the unit contents into a container / filling the rapidly dispersing dosage form unit and all the residue into the container;
e) removing the solid dosage unit from the container and leaving all free residue in the container;
f) performing an allergen-specific assay on said residue to determine the allergen content in said residue; and g) optionally said percent allergen content in said residue of the total allergen content of the solid dosage unit. Calculating the stage,
Is less than 500 SQ-U / solid dosage form, more preferably less than 250 SQ-U / solid dosage form, and most preferably less than 150 SQ-U / solid dosage form.

In a preferred embodiment of the friability test method, the unit is rotated 100 rpm at 251 rpm and the allergen content is determined by ELISA assay.
Furthermore, the oral dosage form preferably has an attractive appearance. Accordingly, as part of quality control, it is preferred that the rapidly dispersible solid dosage form according to the present invention be visually inspected for parameters such as color, shape, irregularity, and defects.
In order to ensure optimal patient compliance, it is preferred that the patient feel comfortable when the dosage form is broken into the mouth. Accordingly, the dosage form is preferably also tested for mouth feel.

Allergens can reproduce the response pattern experienced by patients when given the same dose because allergic humans have a major impact on the body, i.e., even a small amount can trigger a response. It is preferred that the allergen content be homogeneous during treatment so that it is possible. Preferably, the variation in the allergen content of the units within the blister pack is within ± 10%, preferably within ± 7%, most preferably within ± 5% compared to the dose setting.
The blister pack can include any conceivable number of rapidly dispersing solid dosage forms. In a preferred embodiment, the blister pack comprises 1-100 solid dosage forms, more preferably 5-35 solid dosage forms. The blister pack can be further packaged in a suitable container according to any particular dosing regime required to desensitize the patient.

  Furthermore, the present invention provides a step of preparing an aqueous dosage solution of a pharmaceutically active substance and maltodextrin and optionally one or more other matrix forming agents and suitable excipients, and this solution in the recesses of the multilayer laminate blister sheet. The method of producing a rapidly dispersible incompressible solid dosage form according to claim 1 comprising introducing and freezing and lyophilizing the loaded sheet using standard conditions of storage temperature and pressure in the chamber.

  Furthermore, the present invention includes 1) producing a rapidly dispersible uncompressed solid allergen vaccine dosage form, 2) a) placing the solid dosage form contained in a sealed blister pack unit into an instrument suitable for friability measurement, b) moving it at an appropriate speed for an appropriate time, c) removing the sealed solid dosage form unit, d) opening the sealed solid dosage form unit and dispensing the unit into a container / rapid dispersion Placing the dosage unit into the container; e) removing the solid dosage unit from the container and leaving a free residue in the container; f) performing an immunochemical allergen-specific assay on the residue; Determining the amount of allergen content in the residue, g) calculating the percent allergen content in the residue as compared to the total allergen content of the solid dosage unit, and h) the dosage form The key to low brittleness Measuring the friability of the dosage form as described above in an assay comprising determining whether or not the condition is satisfied; and 3) repeating steps 1) and 2) until the requirements for the dosage form are met. It relates to a method for obtaining a rapidly dispersible uncompressed allergen vaccine solid dosage form suitable for administration to the mucosa.

Treatment The rapidly dispersible solid dosage form according to the present invention can be prepared by a sublimation process according to the process disclosed in US Pat. No. 4,371,516. Thus, the solidified solution of allergen and matrix forming excipient will undergo sublimation. The sublimation step is preferably performed by freeze-drying the solution. The solution is contained in a blister pack recess during the lyophilization step to produce a solid form of any desired shape. The blister pack can be cooled using liquid nitrogen or solid carbon dioxide. After the freezing step, the frozen solution in the blister pack is depressurized and heat is added as needed to help sublimate the solvent.

  There are several signs and symptoms of clinical allergies, which may vary depending on the sensitized individual and the allergy suffering. Symptoms such as edema, pruritus, and tears and runny nose (rhinitis conjunctivitis) and skin conditions such as wheezing, coughing, upper and lower respiratory tract symptoms such as respiratory insufficiency, eczema, hives, and pruritus are common . Other symptoms such as fatigue are also experienced. Symptomatic therapy aims at reducing or affecting the severity of symptoms or reducing other drugs given in parallel. Symptomatic drugs include antihistamines such as H1 and H2 receptor antagonists, nasal and systemic corticosteroids, nonsteroidal anti-inflammatory drugs, and nasal decongestants such as adrenergic receptor antagonists. It is another object of the present invention to reduce the need for treatment and alleviation of one or more allergic symptoms or other medications.

That is, the present invention relates to a method for preventing or treating a disease comprising the step of administering an effective amount of a dosage form according to the present invention to the oral mucosa.
More particularly, the present invention relates to a method for preventing or treating allergy or alleviating allergic symptoms, comprising administering to the oral mucosa an effective amount of an allergen vaccine dosage form according to the present invention.
The invention also relates to a pharmaceutically active substance for the preparation of a rapidly dispersible uncompressed solid dosage form according to the invention.
More particularly, the present invention relates to an allergen for producing a rapidly dispersible uncompressed allergen vaccine solid dosage form according to the present invention.

Furthermore, the present invention relates to a rapidly dispersible uncompressed solid dosage form according to the present invention for preventing or treating oral mucosa.
More particularly, the present invention relates to a rapidly dispersible uncompressed allergen vaccine solid dosage form according to the present invention for preventing or treating allergy to oral mucosa or reducing allergic symptoms.
The invention also relates to the use of a pharmaceutically active substance for the preparation of a rapidly dispersed or uncompressed solid dosage form according to claim 1 for preventing or treating oral mucosa.
More particularly, the present invention relates to the use of an allergen to produce a rapidly disperse or uncompressed allergen vaccine solid dosage form according to claim 1 for preventing or treating allergy to oral mucosa or reducing allergic symptoms. About.

  Sublingual immunotherapy can be viewed as a method of producing mucosal vaccination that causes resistance. The oral mucosa is rich in dendritic cells with a strong potential to present antigen. Dendritic cells are thought to process allergens and then migrate to local lymph nodes where they display peptides from allergens to allergen-specific T cells. During sublingual immunotherapy, this dendritic cell-T cell interaction is believed to induce T cells with regulatory potential or to increase the ratio of allergen-specific Th1 cells to allergen-specific Th2 cells. Several immune parameters monitored during allergy vaccination can each be used alone or in combination as an appropriate marker for the effectiveness or efficiency of treatment. These include systemic and mucosal antibody responses, such as specific IgA, IgG, and IgE antibodies and cytokine levels in blood or mucosal secretions, such as INF gamma, IL-2, IL-4, IL-5. , IL-10, IL-12, and TNF alpha and regulatory T cells, Th1 cells, TH2 cells, CD8 cells, other T cell subsets or B cell or NK cell activity, chemotaxis, proliferation, signals Cell surface markers such as transmission, cytokine production and other reactions, and CD (membrane protein group) markers such as CD4, CD8, CD23, CD25, CD62L, CLA, beta 7, CCR9, CD69, CD45RO, CCR3, CXCR5 Phenotype, effector cell functions such as the total histamine content of basophils, and eosinophils, basophils in blood, tissues and secretions, Includes the number of lymphocytes, monocytes, and release of eosinophils, basophils, lymphocytes, monocyte inclusions, cytokine production, activation, chemotaxis, proliferation, signaling, and other responses .

  In a preferred embodiment, the dosage form according to the invention is characterized in that it can find one or more of the following immunological changes. That is, an increase in allergen-specific IgG response, an increase in allergen-specific IgA response, a decrease in allergen-specific IgE response, and almost no local side-reactions; Reduced specific effector response and induction of regulatory T cells with regulatory potential, increased ratio of allergen-specific Th1 cells to allergen-specific Th2 cells, induction of other cells with regulatory potential, and reduced allergen-specific Th2 response It is.

  Allergies are also known diseases for animals, particularly livestock and pets. They are known in the art to develop allergies to many allergen sources including grass, house dust mites, and parasites. It is known that the spread of blood-sucking animals, or blood-sucking insects, causes a hypersensitivity reaction called flea allergic dermatitis (FAD). In a preferred embodiment of the present invention, allergens for animal vaccines include parasites such as ectoparasites (eg fleas, ticks, mosquitoes, flies), parasitic helminth toxins (canine filamentous worms such as dilofilaria, or And allergens derived from or migrated from house dust mites, such as Oncocelca. More preferred are salivary allergens from the flea genus, for example fleas such as dog fleas and cat fleas, ticks such as Ixodes and Kirara ticks, soft mites such as genus Mite, and small insects such as Nukaka.

The Peyer's patch containing microcapsules is a collection of lymph nodules located on the walls of the small intestine, large intestine, and appendix, and is important for body defense against the attachment and permeation of infectious substances and other substances that are foreign to the body It is an important part. Peyer's patches are also known as collecting lymph nodes. Similar collecting lymph nodes can be found in the respiratory tract, rectum, nasal cavity, oral cavity, pharynx, urogenital tract, large intestine, and other mucosal tissues of the body. The tissue described above can generally be referred to as mucosa-associated lymphoid tissue (MALT).
Pharmaceutically active substances of appropriate size and appropriate physicochemical properties have been shown to be effectively taken up by Peyer's patches and MALT.

  Thus, an additional aspect of the invention relates to a dosage form in which at least a portion of the active agent is present in the form of a microcapsule embedded in a matrix, the microcapsule comprising a first encapsulant and the active agent. Without being bound by theory, some active substances in certain allergens can achieve the intended therapeutic effect with microcapsules that can be taken up by MLT or elicited through MALT. It is considered. In a preferred embodiment of the invention, the active substance is present in the matrix both in the form of microcapsules and in the form of molecules in direct contact with the matrix. In this embodiment, the active agent is taken up and / or induced by two different mechanisms: a mechanism via MALT and a mechanism by immune system stimulation induced by free allergens, and the active agent is It is believed that a better therapeutic effect can be obtained compared to the case where it is formulated by either a capsule or a direct combination with a matrix.

In addition to enhancing the therapeutic effect, the use of microcapsules has the advantage of protecting the pharmaceutically active substance from degradation during both the production and storage of the dosage form and in the course of administering the active substance to the patient. . This is particularly important when the active substance is an allergen, as described in more detail elsewhere herein. It is known to protect sensitive bioactive substances from degradation using microencapsulation. In general, bioactive substances are encapsulated in any of several protective wall materials that are usually polymeric in nature. The encapsulated drug can be coated with a single wall of polymeric material (microcapsules) and can be homogeneously dispersed within the polymer matrix (microspheres). (Hereafter, the term microcapsule means both microcapsules and microspheres, and the terms “encapsulation” and “microencapsulation” should be interpreted accordingly.) Amount of substance in microcapsules Can be varied as needed from a trace amount of the microcapsule composition to as much as 95% or more. The diameter of the microcapsule is preferably less than 20 μm, more preferably less than 15 μm, still more preferably less than 10 μm, and most preferably 1 to 10 μm.
Furthermore, the use of microcapsules has the advantage that the active substance is prevented from being released from the dosage form. This is particularly important when the active substance is an allergen, as will be explained in more detail elsewhere herein.

  The encapsulant can be any biodegradable material, preferably a polymeric agent. Preferably, the first encapsulant is poly-lactide, poly-lactide-poly (ethylene glycol), poly (DL-lactide-co-glycolide), poly (glycolide), copolyoxalate, polycaprolactone, poly Selected from the group consisting of (lactide-co-caprolactone), poly (ester amides, polyorthoesters and poly (8-hydroxybutyric acid), and polyanhydrides, most preferably poly (DL-lactide-co-glycolide) Other examples of encapsulants are poly (butyl-2-cyanoacrylate), poly (3-hydroxybutyrate), and poly (FA: polyanhydride copolymer of fumaric acid and sebacic acid). SA) In addition, suitable encapsulants for use in accordance with the present invention include gelatin, dextrin. Animal or plant proteins such as soybean, wheat and psyllium seed proteins, gums such as acacia, guar, agar, and xanthan, polysaccharides, starches and modified starches and alginate, carboxymethylcellulose, carrageenans, Included are those derived from dextran, pectin, synthetic polymers such as polyvinylpyrrolidone, and polypeptide / protein or polysaccharide conjugates such as gelatin-acacia conjugates. One or more encapsulants are used, preferably the encapsulant is selected to render the microparticles hydrophobic, which are more easily taken up by MALT or via MALT. It is thought to lead the effect.

  In one preferred embodiment of the invention, the microcapsule-containing dosage form is formulated as a tablet, ie a cohesive dosage form unit. In another preferred embodiment, the microparticle-containing dosage form is formulated as a granular composition suitable for preparing a granular composition, eg, a compressed tablet. A dosage form of the invention in which the pharmaceutically active substance is present in direct combination with a matrix forming agent can also be formulated as a granular composition suitable for preparing a granular composition, eg, a compressed tablet.

The invention further relates to a compressed tablet comprising the granule composition of the invention.
Furthermore, the present invention relates to an aqueous administration solution for preparing a rapidly dispersed solid composition suitable for the oral mucosal administration of a pharmaceutically active substance, the administration solution comprising (a) a dextrose equivalent (DE) of 1-20. A first matrix-forming agent in the form of maltodextrin, and (b) a microcapsule comprising a first encapsulation matrix-forming agent and an active substance.

  Finally, the present invention comprises the steps of preparing a microcapsule comprising a first encapsulated matrix-forming agent and a pharmaceutically active substance, a microcapsule and maltodextrin and optionally one or more other matrix-forming agents and a suitable loading. Preparing a dosage form according to the present invention comprising: preparing an aqueous dosage solution of the dosage form; spray-freezing the dosage solution to produce primary granules, and lyophilizing the primary granules to produce secondary granules. On how to do.

Definitions The term "maltodextrin" is dextrose equivalent (DE) is meant partially hydrolyzed starch is from 1 to 20.
The term “rapidly dispersed dosage form” is used in the oral cavity for less than about 90 seconds, preferably for less than 60 seconds, preferably for less than 30 seconds, more preferably for less than 20 seconds, even more preferably for less than 10 seconds, even more preferably. It means a dosage form that degrades in less than 5 seconds, most preferably in the oral cavity in less than about 2 seconds.

The term “stable” means a dosage form in which the loss of allergen content of at least one major allergen is less than 50% of the initial content according to the method described in Example 1.
The term “low friability” means the amount of residual material that is lost from a dosage form when subjected to external forces. The solid dosage form comprises a residual material loss of less than 500 SQ-unit / solid dosage form of the total allergen content of the dose, more preferably less than 250 SQ-unit / solid dosage form, most preferably less than 150 SQ-U / solid dosage form In some cases, it is friable and fast enough to be transported, stored and handled. In the present invention, the friability can be measured by the method according to the present invention, or by a modified method according to the “European Pharmacopoeia”.

The term “uncompressed” refers to a solid dosage form made by removing liquid from a solidification system comprising a matrix forming agent, an active ingredient, and other suitable ingredients to form an allergen-containing solid matrix.
The term “solid dosage form” means a dosage form such as a tablet or granule composition that is neither liquid nor powder when administered to the oral cavity.
The “tensile strength σ” is calculated by the following formula.
σ = 3Wax9.8 Nmm−2 / 2d2b
Where w = peak load to break (kgF), a = distance between supports, d = thickness of rapidly dispersing solid dosage form (mm), and b = diameter of rapidly dispersing solid dosage form (mm) It is.

“Peak load to break” means that the unit breaks in a three-point bending test using an appropriate instrument (eg “CT5”, Engineering Systems, 1 Roach Coat, Radford Bridge Road, Nottingham, NG81NA). It means the peak force required for.
The term “oral mucosal” means a dosage form that is placed under the tongue or at any other site in the oral cavity where the active ingredient contacts the oral cavity of the patient or the mucous membrane of the pharynx.
The term “monosaccharide” means any organic molecule containing 6 carbons, whether cyclic or in the form of a linear molecule. The term “disaccharide” means any saccharide including any combination of two monosaccharides. The term “trisaccharide” means any saccharide including any combination of three monosaccharides.

“Dosing solution” means a non-solid mixture of solidifying solvent, matrix-forming agent, active agent, and other optional excipients.
The term “allergen” means any natural protein or mixture of proteins that has been reported to cause allergies, ie IgE-mediated reactions, upon repeated exposure to a solid. Examples of natural allergens include pollen allergens (trees, weeds, broadleaf herbs and grass pollen allergens), mite allergens (eg, from house dust mites and storage mites), insect allergens (inhalable, saliva, and venom derived) Allergens), eg, animal allergens such as dogs, cats, horses, rats, mice etc., eg saliva, hair, and dandruff, fungal allergens, and food allergens. The allergen can be used in the form of an allergen extract, purified allergen, modified allergen, or recombinant or recombinant mutant allergen, any allergen fragment of more than 30 amino acids, or any combination thereof.

  SQ units: SQ units are determined by the “ALK-Abello A / S” “SQ Biopotency” standardization method, where 100.000 SQ units equal the standard subcutaneous maintenance dose. Usually, 1 mg of extract contains 100,000 to 1,000,000 SQ units depending on the allergen source from which it is derived and the manufacturing process used. The exact allergen amount can be determined by immunoassay, ie total major allergen content and total allergen activity. There is no internationally satisfactory standardization method in this technical field. Thus, if extracts from other sources are used, they should be standardized against the “ALK-Abello A / S” extract of procedures known to those skilled in the art. This content is Ipsen et al., “Allergen Extract”, Chapter 20, “Allergy, Principles and Practice” (S. Manning), 1993, “Mosby-Year Book”, St. Louis, “Lowenstein H.” (1980), “Arb Paul Ehrlich Inst”, 75: 122.

“Homogeneity of inclusions” shall mean the variation of the dosage unit from the prescribed dosage.
“Water content” means the residual water content in a solid dosage unit determined quantitatively using the “Karl Fischer” titration principle. The method is based on the principle that a predetermined amount of 12 will be converted to an equivalent amount of water (European Pharmacopoeia 2.5.12).

“Water activity aw” as used herein is effective water in a sample. Water activity measurements are performed using methods known to those skilled in the art, for example, using cold mirror dew point technology, relative humidity at a sensor that changes electrical resistance or capacitance, or a lithium chloride electrode.
aw can be calculated by the following equation.
aw = p / ps = ERH (%) / 100
Where p = water vapor partial pressure at the product surface, ps = water vapor partial pressure over pure water at saturation pressure or product temperature, and ERH = equilibrium relative humidity.

Abbreviation:
API: Active protein raw material ELISA: Enzyme-linked immunosorbent assay DDT: Dithiothreitol HRP: Horseradish peroxidase LIA: “Magic Lite” specific IgE assay LITE reagent: Fluorescent label anti-gE
PMP: Paramagnetic particles SDS-PAGE: Sodium dodecyl sulfate polyacrylamide gel electrophoresis TMB: Tetramethylbenzidine

Example 1
A grass pollen extract was prepared by the method described in Grass Extract Ipsen and Lowensten (1983), “Jour. Allergy. Clin. Immunol.”, 72: 2, pages 150-159. In low size grasses, the pollen was extracted with ammonium bicarbonate for 20 hours at 5 ° C. The particulate material was removed by centrifugation and the supernatant was dialyzed against water (3 times) and stored in a cold place until reconstitution.
Solid formulation :
Manufacturing process :
1. Add MQ water to a beaker equipped with a magnetic stir bar.
2. If present, add mannitol and sorbitol and dissolve with stirring.
3. If present, add maltodextrin and PEG and dissolve with stirring.
4). If present, add allergen extract.
5. If allergen is present, the pH is adjusted to pH = 7-8 using hydrochloric acid (2N) or sodium hydroxide (2N).
6). Add 250 μl of the solution to a pre-formed blister pack. The solution is charged at ambient temperature conditions.
7). After charging, the filled blister pack is frozen at -80 ° C. The unit is lyophilized using standard conditions of storage temperature and chamber pressure.

Brief description of the analysis method :
Visual inspection: For example, color, shape, irregularity, and defects were visually inspected for all the unit bodies to confirm that the appearance was acceptable.
Degradation: Tests were performed as described in the current “European Pharmacopoeia” or current “USP”.
Water content: Residual water was determined using the “Karl Fischer” titration principle. The method quantitatively determines the water content in the sample based on the principle that a predetermined amount of 12 is converted to an equal amount of H ₂ O.
composition

  It has been shown that it is possible to produce lyophilized solid dosage forms using various contents of mannitol, maltodextrin, allergen extract with or without sorbitol. All dosage form decomposition times were 1 second.

(Example 2)

  It has been shown that lyophilized solid dosage forms can be produced using various contents of mannitol, maltodextrin, and / or sorbitol.

(Example 3)

  It has been shown that it is possible to produce lyophilized solid dosage forms with various contents of mannitol and / or maltodextrin and / or sorbitol and / or PEG. The degradation time of the dosage form containing mannitol, maltodextrin, and sorbitol was 3 seconds.

Example 4

  It has been shown that it is possible to produce lyophilized solid dosage forms with various contents of mannitol and / or maltodextrin and / or sorbitol and / or PEG. The degradation time of the dosage form containing mannitol, maltodextrin, and sorbitol was 3 seconds.

(Example 5)
This example has a matrix consisting of maltodextrin, mannitol, and sorbitol, the preparation of a granular composition of granules such that the matrix contains microencapsulated allergen (MEA), and compressed tablets from this granular composition And the preparation.
Material Encapsulant: “Poly-D, L-lactide-glycolide (DL-PLG)” (60/40) with a molecular weight of 40,000 g / mol obtained from Birmingham Polymers, USA
Active substance: “Phl p” extract in MEA particles Mannitol: “Ph.Eur. <559>”, number 281048, obtained from “Unikem”
Sorbitol: “Ph. Eur. <435>”, number 340927, obtained from “Nomeco”
Maltodextrin: “NF 18” obtained from “Cerestar”, CPUR01915 (18DE) type talc powder: “Ph.Eur. <438>” obtained from “Unikem”, number 297911
Magnesium stearate: “Ph.Eur. <229>”, number 280560, available from “Unikem”

Test method for compressed tablets
The crushable tablet is placed horizontally on the support so as to contact the first vertical plate. A piston with a second vertical plate at the distal end, with the two plates arranged in parallel, is moved into contact with the tablet and the pressure applied when the tablet is crushed is measured in N.
Fragility Weigh and weigh 20 tablets, then place in a cylinder with internal ribs. The cylinder rotates for a selected time at 25 rpm and is removed from the cylinder and dusted and weighed. The difference between the first and last weight is calculated as a percentage and represents friability.

Preparation of MEA Homogenization “DL-PLG” is dissolved in ethyl acetate (30 w / w%) and the allergen extract is dissolved in water (13 w / w%). The two solutions are mixed and homogenized to form an oil / water two-phase emulsion.
2. Emulsification of oil / water emulsion in aqueous medium The oil / water emulsion is mixed with a 2 w / w% aqueous solution of PVA, saturated with ethyl acetate and adjusted to pH = 6.8 using sodium phosphate and hydrochloric acid. Buffer and emulsify to form a water / oil / water emulsion. The water / oil / water emulsion is passed through the emulsion screen of the emulsifying device to form MEA-microcapsules.
3. Extraction of ethyl acetate / PVA Extract ethyl acetate and PVA to cure the MEA-microcapsules. During the first 10 minutes of extraction, the temperature is maintained at 22 ° C and then lowered to 12 ° C.
4). Concentration by centrifugation The suspension formed in step 3 is centrifuged.
5. Resuspension and spray drying After centrifugation, the microcapsules are resuspended in water (1800 ml / 25 g) and spray dried to form the finished microcapsules.

Preparation of Granule Composition MEA is suspended in distilled water, mannitol, maltodextrin and sorbitol are added and the suspension is stirred. When the resulting mixture is sprayed into a chamber filled with liquid nitrogen, the droplets now freeze immediately. During spray freezing, portions of the droplets will freeze with respect to each other, and thus the frozen particle composition will optionally undergo crushing. The crushed ice particles are stirred and freeze-dried, and then again, the finished granules are obtained.
Tablet Preparation Tablets were produced using a “Complex II” tablet forming device.
composition

result

  Several microcapsule-containing granule compositions and different composition compressed tablets were prepared. All compressed tablets disintegrate rapidly, which means that the granule composition is easily dispersible. As is apparent from the results in the table above, the dispersion of MEA, granule composition, and tablet particle size after dissolution was almost similar in all cases. That is, it can be concluded that by using the microcapsule-matrix system of the present invention, it is possible to prepare a granular composition that can be used to prepare a compressed tablet in which the microcapsules remain intact. Further, as is apparent from the results of the crushability and friability, the matrix composed of mannitol, maltodextrin, and sorbitol is strong, and is strong enough to resist compression when it is made into tablets.

Claims (42)

A non-compressed rapidly dispersible solid dosage form suitable for buccal administration of a pharmaceutically active substance,
(A) a first matrix-forming agent in the form of maltodextrin having 1-20 dextrose equivalents (DE);
(B) a second matrix forming agent in the form of sorbitol;
(C) the active substance;
A dosage form characterized by comprising:   The dosage form of claim 1, comprising one or more additional matrix forming agents.   3. Dosage form according to claim 1 or 2, characterized in that the further matrix-forming agent is a monosaccharide, disaccharide or trisaccharide.   4. Dosage form according to any one of claims 1 to 3, characterized in that the further matrix-forming agent is mannitol.   The dosage form according to any one of claims 1 to 4, further comprising polyethylene glycol (PEG).   The maltodextrin is present in an amount of 3-40% (w / w), preferably 10-35 (w / w), more preferably 15-25% (w / w) of the administration solution. The dosage form according to any one of claims 1 to 5, wherein:   Sorbitol is in an amount of 0.01 to 10% (w / w), preferably 0.05 to 5% (w / w), more preferably 0.1 to 2% (w / w) of the administered solution. The dosage form according to any one of claims 1 to 6, wherein the dosage form is present in an amount of.   Mannitol is present in an amount of 1-20% (w / w), preferably 2-10% (w / w), more preferably 3-6 (w / w) of the dosing solution. 7. A dosage form according to any one of claims 4 to 6, characterized in that   PEG is present in an amount of 1-20% (w / w), preferably 2-15% (w / w), more preferably 3-10% (w / w) of the dosing solution. The dosage form according to any one of claims 5 to 8, wherein:   10. A dosage form according to any one of claims 1 to 9, further comprising one or more additional excipients.   The excipients are adjuvants, antacids, diluents, activators, mucoadhesives, flavoring agents, taste masking agents, preservatives, antioxidants, surfactants, thickeners, colorants, pH 11. The dosage form of claim 10, wherein the dosage form is selected from the group consisting of conditioning agents and sweeteners.   The dosage form according to any one of claims 1 to 11, wherein the active substance is an allergen.   13. The dosage form of claim 12, wherein the allergen is selected from the group consisting of a tree pollen allergen, a grass pollen allergen, a mite allergen, an insect allergen, a poison allergen, an animal hair and fuchsia allergen, and a food allergen. .   14. Dosage form according to claim 12 or 13, characterized in that the allergen is in the form of an extract, a purified allergen, a modified allergen or a recombinant allergen or a mutation of a recombinant allergen, or a combination thereof.   The dosage form according to claim 13 or 14, wherein the allergen is grass pollen.   The dosage form according to claim 13 or 14, wherein the allergen is a dust mite.   15. Dosage form according to any one of the preceding claims, comprising at least two different allergens.   18. Dosage form according to any one of claims 1 to 17, characterized in that the titer is 150 to 1000000 SQ-u / dosage form.   The variation in the allergen content of the unit bodies in the blister pack is ± 10%, preferably ± 7%, most preferably ± 5% compared to the set dose. 19. The dosage form according to any one of 18.   20. The dosage form according to any one of claims 1 to 19, wherein the dosage form is for sublingual administration.   Decomposes in the oral cavity in less than about 90 seconds, preferably less than 60 seconds, preferably less than 30 seconds, more preferably less than 20 seconds, even more preferably less than 10 seconds, even more preferably less than 5 seconds, most preferably in the oral cavity 21. A dosage form according to any one of the preceding claims, wherein the dosage form degrades preferably in less than about 2 seconds.   22. Dosage form according to any one of the preceding claims, characterized in that it is sufficiently strong to be removed from a blister pack without releasing any residue around it.   23. Less than 500 SQ-U of allergens, more preferably less than 250 SQ-U of allergens, most preferably less than 150 SQ-U of allergens are released from each solid dose during manual handling. The dosage form described.   The friability, measured as the amount of allergen released, is less than 500 SQ-U / solid dosage form, more preferably less than 250 SQ-U / solid dosage form, most preferably 150 SQ-U / in a suitable friability test. 24. A dosage form according to any one of claims 1 to 23, wherein the dosage form is less than a solid dosage form. The friability is
a) placing one unit of a solid dosage form contained in a sealed blister pack unit into a device suitable for reproducible friability measurement;
b) moving it at an appropriate speed for an appropriate time;
c) removing the sealed solid dosage form unit;
d) opening the sealed solid dosage form unit to place the unit in a container and placing the rapid dispersion dosage unit into the container;
e) removing the solid dosage unit from the container leaving any free residue in the container;
f) performing an allergen specific assay on the residue and measuring the allergen content in the residue;
g) optionally calculating a percentage of the allergen content in the residue compared to the total allergen content of the solid dosage unit;
25. A dosage form according to claim 24, wherein the dosage form is measured by an assay comprising:   The dosage form of claim 1, wherein at least a portion of the active substance is present in the form of a first encapsulant and a microcapsule containing the active substance embedded in the matrix.   26. The dosage form of claim 25, wherein the first encapsulant is poly (DL-lactide-co-glycolide).   28. A dosage form according to any one of claims 1 to 27, which is in the form of a granule composition suitable for preparing compressed tablets.   A blister pack containing a number of solid dosage forms according to any one of claims 1 to 28.   A method for preventing or treating a disease, comprising the step of orally administering an effective amount of the dosage form according to any one of claims 1 to 27.   28. A method for preventing or treating allergy or alleviating allergic symptoms, comprising the step of orally mucosally administering an effective amount of the allergen vaccine dosage form according to any one of claims 1 to 27.   Use of a pharmaceutically active substance for the preparation of a rapidly dispersible uncompressed solid dosage form according to claim 1.   Use of an allergen for the preparation of a rapidly dispersible uncompressed allergen vaccine solid dosage form according to claim 1.   A rapidly dispersible uncompressed solid dosage form according to claim 1 for preventing or treating oral mucosa.   A rapidly dispersible uncompressed allergen vaccine solid dosage form according to claim 1 for preventing or treating allergies in the oral mucosa or for alleviating allergic symptoms.   Use of a pharmaceutically active substance for the preparation of a rapidly dispersed or uncompressed solid dosage form according to claim 1 for the prevention or treatment of oral mucosa.   Use of an allergen for the preparation of a rapidly disperse or uncompressed allergen vaccine solid dosage form according to claim 1 for preventing or treating allergies or reducing allergic symptoms. A method of producing a rapidly dispersible incompressible solid dosage form according to claim 1 comprising:
Preparing an aqueous dosage solution of a pharmaceutically active substance and maltodextrin, optionally with one or more additional matrix forming agents and suitable excipients;
Introducing the solution into the recesses of the multilayer laminate blister sheet;
Freezing and lyophilizing the loaded sheet using standard conditions of storage temperature and champ pressure;
A method comprising the steps of: A method of obtaining a rapidly dispersible uncompressed allergen vaccine solid dosage form suitable for oral mucosal administration,
1) producing a rapidly dispersible uncompressed solid allergen vaccine dosage form;
2) a) placing the solid dosage form contained in a sealed blister pack unit into an instrument suitable for friability measurement;
b) moving it at an appropriate speed for an appropriate time;
c) removing the sealed solid dosage form unit;
d) opening the sealed solid dosage form unit to place the unit in a container and placing the rapid dispersion dosage unit into the container;
e) removing the solid dosage unit from the container leaving any free residue in the container;
f) performing an immunochemical allergen specific assay on said residue to detect the allergen content in said residue;
g) calculating a percentage of the allergen content in the residue compared to the total allergen content of the solid dosage form unit; and h) whether the dosage form meets the requirements for low friability. Detection stage,
Measuring the friability of the dosage form with an assay comprising:
3) repeating 1) and 2) until the requirements for the dosage form are satisfied;
A method comprising the steps of:   A compressed tablet comprising the granule composition according to claim 28. An aqueous dosing solution for preparing a rapidly dispersible solid composition suitable for oral mucosal administration of a pharmaceutically active substance, comprising:
(A) a first matrix-forming agent in the form of maltodextrin having 1-20 dextrose equivalents (DE);
(B) a microcapsule comprising a first encapsulation matrix-forming agent and an active substance;
A solution characterized by comprising. A method for preparing a dosage form according to claim 28, comprising:
Preparing a microcapsule comprising a first encapsulation matrix-forming agent and a pharmaceutically active substance;
Preparing an aqueous dosage solution of said microcapsules and maltodextrin, optionally with one or more further matrix forming agents and suitable excipients;
Spray freezing the dosing solution to produce primary granules;
Lyophilizing the primary granules to produce secondary granules;
A method comprising the steps of: