JP5572110B2 - Liquid formulations for prevention and treatment of mucosal diseases and disorders - Google Patents

Description

FIELD OF THE INVENTION The present invention relates to compositions and methods for the production of stable, viscous, mucoadhesive liquid formulations and mucoadhesive gel formulations, and coating mucosal skin surfaces (particularly the oral cavity) for ulcers Of these compositions for preventing and / or treating mucosal diseases and disorders, including sexual, inflammatory and / or erosive (especially mucositis induced by chemotherapy and / or radiation therapy) Regarding use. Liquid dosage forms are sufficiently mobile to coat a wide range of mucosal surfaces, but also have mucoadhesive and viscous properties to provide long-term retention on mucosal surfaces. The liquid composition can be used without pharmaceutically active known compounds. One or more pharmaceutically active compounds can be included in the formulation to provide additional benefits in the topical treatment of mucosal diseases and disorders.

BACKGROUND OF THE INVENTION The mucosa provides a protective layer on the surface of several body cavities such as the oral cavity, nasal cavity, gastrointestinal tract and airways, vagina, and bladder. The cells in these membranes or the glands adjacent to these membranes secrete mucus, liquid, or gel, which consists mainly of water, lipids, inorganic salts, and mucin glycoproteins, which are below ( underlying) Helps to form a protective barrier to block the passage of harmful substances into the tissue. There are several diseases and disorders of these mucosal surfaces that can lead to severe pain, irritation, erythema and / or ulceration. Examples of such diseases in the oral cavity include aphthous ulcers, bullous pemphigoid, oral lichen planus, and oral mucosa contact dermatitis. Many other ulcerative mucocutaneous diseases are known. There are also painful ulcerative disorders of the mucosal surface that result in deleterious side effects in certain treatments such as chemotherapy and radiation therapy. Mucositis is an adverse side effect that affects the oral cavity of patients undergoing treatment for many conditions, including cancer, AIDS, and patients undergoing bone marrow transplantation therapy.

Overview of Oral Mucositis Oral mucositis is a significant problem in patients receiving chemotherapy or radiation therapy. The estimated amount of oral mucositis in cancer treatment ranges from 40% of patients receiving standard chemotherapy to 76% of bone marrow transplant patients. Virtually all patients receiving head and neck radiation therapy develop oral complications. Mucositis is not only painful but also limits proper nutrition and may reduce the patient's willingness to continue treatment. More severe mucositis with extensive ulceration may require expensive hospitalization with parenteral nutrition and anesthetics. Mucositis reduces quality of life and can lead to serious clinical complications. Healthy oral mucosa serves to remove microorganisms and provides a chemical barrier that limits the penetration of many compounds into the epithelium. A damaged mucosal surface increases the risk of secondary infection and may even prove to be a focus of systemic infection. Mucositis may result in the need to reduce doses in subsequent chemotherapy cycles or to delay radiation therapy, which can ultimately affect the patient's response to treatment.

  Oral cells usually regenerate rapidly with a 7 to 14 day cycle. Both chemotherapy and radiation therapy interfere with cellular mitosis and reduce the ability to regenerate the oral mucosa. Cancer chemotherapeutic agents that produce direct stomatotoxicity include alkylating agents, antimetabolites, natural products, and other synthetic agents such as hydroxyurea and procarbazine hydrochloride. Typical sequelae of these cytotoxic agents include epithelial hyperplasia, collagen and gland degeneration, and epithelial dysplasia. Mucositis is an inevitable side effect of radiation. The severity of mucositis depends on the type of ionizing radiation, the volume of the irradiated tissue, the daily dose, and the accumulated dose. As mucositis becomes more severe, pseudomembrane and ulceration occur. Insufficient nutrition further interferes with mucosal regeneration by reducing cell migration and regeneration.

  Direct oral toxicity is usually seen 5-7 days after administration of chemotherapy or radiation therapy. In nonmyelosuppressed patients, oral lesions heal within 2 to 3 weeks. The mucosa, which is not keratinized at all, is most affected. The most common sites include the mucosa of the lips, buccal and soft palate, as well as the floor of the mouth and the front of the tongue. Clinically, mucositis presents a number of complex symptoms. It begins with asymptomatic redness and erythema and progresses through an isolated white highly peelable patch that is slightly painful to contact pressure. Following these, a continuous pseudo membranous lesion with large and sharp pain develops with associated dysphagia and reduced oral intake. Histopathologically, retinal edema is noted, with vascular changes indicative of intimal thickening (with concomitant reduction in vessel wall lumen size and destruction of elastic and muscle fibers) Is done. The loss of epithelial cells to the basement membrane exposes the underlying connective tissue stroma (with its associated innervation), which contributes to increased pain as mucosal lesions expand. Oral infections that can be attributed to bacterial, viral, or fungal organisms can further exacerbate mucositis and lead to systemic infection. If the patient has both severe mucositis and thrombocytopenia, oral bleeding that can be very difficult to treat can occur.

The mucositis grading sysytem allows physicians to determine the severity of mucositis, both in terms of pain and in terms of the ability of the patient to maintain adequate nutrition so that the treatment strategy can be properly established. Can be evaluated. There are many different rating systems, most of which are based on two or more clinical parameters, including erythema, pain, and feeding problems. An example of a common rating system is that proposed by the US National Cancer Institute, which uses a numbering scale of 0-4. Grade 0 means the absence of mucositis; in grade 1, the patient has painless ulcers, erythema, or soreness; in grade 2, the patient has painful erythema, Has edema, or ulcer, but is able to eat; in grade 3, the patient has painful erythema, edema, or ulcer, and cannot eat; and in grade 4, the patient has Requires parenteral or enteral assistance.
(Source: DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright (Copyright) 1997 Lippincott-Raven Publishers (Non-patent Document 1))

Current methods for prevention and treatment of mucositis Despite the importance of the problem, there are currently no well-established procedures and formulations for prevention and treatment of mucositis. As a result, there is no standardized approach and many institutions have adopted treatment therapies with little or no data based on data supporting safety and efficacy. There are even disagreements about whether good oral hygiene is beneficial (eg Dodd MJ, Miaskowski C, Shiba GH, Dibble SL, Greenspan D, MacPhail L, Paul SM, Larson P, Risk factors for chemotherapy-induced oral mucositis : dental appliances, oral hygiene, previous oral lesions, and history of smoking, Cancer Invest 1999; 17 (4): 278-84 (non-patent document 2) and Cheng KK, Molassiotis A, Chang AM, Wai WC, Cheung SS. Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in pediatric cancer patients, Eur J Cancer 2001 Nov; 37 (16): 2056-6 (non-patent document 3)). Typically, good oral hygiene is recommended and supplemented by formulations that are formulated locally and used primarily to provide prophylaxis. Thus, patients may be required to use ice, saline rinse, bicarbonate rinse, or a rinse containing an antimicrobial preparation such as acyclovir or chlorhexidine (Fulton JS, Middleton GJ, McPhail IT, Management of oral complications, Semin Oncol Nurs 2002 Feb; 18 (1): 28-35 (non-patent document 4)). Commonly used therapies to treat mucositis and its associated pain include lidocaine or local anesthetics such as Dyclone, Maalox, or Mylanta, diphenhydramine (Benadryl), nystatin, or sucralfate. These agents are used alone or in various combinations with the above drugs processed into mouthwashes. Other drugs that are not commonly used include Kaopectate, allopurinol, vitamin E, β-carotene, Kamillosan solution, aspirin, antiprostaglandins, prostaglandins, silver nitrate, and antibiotics. Oral anesthetics and sometimes parenteral anesthetics are used to reduce pain (DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright (1997) Lippincott-Raven Publishers) 1)). Recent investigations of current treatment options and research clinical trials have shown that most drugs and options do not show any benefit in the prevention and / or treatment of mucositis (Worthington HV, Clarkson JE , Eden OB, Interventions for treating oral mucositis for patients with cancer receiving treatment, Cochrane Database Syst Rev 2002; (1): CD001973 (Non-Patent Document 5); Demarosi F, Bez C, Carrassi A., Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 2002 May; 51 (5): 173-86 (non-patent document 6)).

  Many researches have been evaluated in clinical trials for the prevention and treatment of mucositis by recent studies (Sonis ST, Fey KG, Oral Complications of Cancer Therapy, Oncology 2002, 16: 680-695). An overview of these drugs is provided, and "no effective approved treatment exists for mucositis" and that the experimental drugs currently in clinical trials benefit future patients. It is concluded that there is no definitive evidence to provide. While ongoing trials provide a better understanding of the pathogenesis of mucositis, it may take some time before this knowledge can be translated into an effective new treatment. On the other hand, the main approach is based on theory, and it is expected that it may take several years before a rationale drug design can be applied based on a better understanding of the etiology.

Current approaches can be categorized as “analgesics, cytoprotectants, anti-inflammatory agents, antibacterials, and cytokines” (Plevova P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: A review. Oral Oncol 35: 453-470, 1999 (non-patent document 8); Sonis ST, Fey EG, Oral Complications of Cancer Therapy, Oncology 2002, 16: 680-695 (non-patent document 7)). Examples of each type are as follows.
i) Analgesics: saline and bicarbonate rinses, sucralfate suspensions and topical analgesics (eg, viscous lidocaine, dichronin, diphenhydramine, and loperamide).
ii) Cytoprotective agents: ice pieces, allopurinol, glutamine, pentoxifylline, ethiol, and antioxidants such as vitamin C and vitamin E.
iii) Anti-inflammatory agents: benzydamine, indomethacin, and amlexanox.
iv) Antibacterial agents: chlorhexidine, povidone iodine, protegrin IB-367.
v) Cytokines: keratinocyte growth factor, transforming growth factor-β3, and interleukin-11, and colony-stimulating factors G-CSF and GM-CSF.

  Magnesium hydroxide (eg, Milk of Magnesia), Kaopectate (Pharmacia & Upjohn, Columbus, OH), OraRinse (Carrington Laboratories), GelClair (Sinclair Pharmaceuticals), and aluminum hydroxide gel (Amphojel; Wyeth-Ayerst, Topical coatings such as Philadelphia, PA may provide some symptomatic relief of lesions associated with mucositis (JB Epstein, AW Chow, Oral complications associated with immunosuppression and cancer therapies, Infectious Disease Clinics of North America 1999, 13 (4), 901-923 (Non-Patent Document 9)).

  Temporary palliation provides temporary relief, but none of the above treatments has been proven in the prevention or treatment of mucositis, with the exception of the possibility of using ice chips during 5-FU treatment. Provide no benefits. Thus, there remains a major unmet medical need for the development of products that provide clinically proven benefits for the prevention and / or treatment of mucositis.

DeVita: Cancer: Principles and Practice of Oncology, 5th ed., Copyright (Copyright) 1997 Lippincott-Raven Publishers Dodd MJ, Miaskowski C, Shiba GH, Dibble SL, Greenspan D, MacPhail L, Paul SM, Larson P, Risk factors for chemotherapy-induced oral mucositis: dental appliances, oral hygiene, previous oral lesions, and history of smoking, Cancer Invest 1999; 17 (4): 278-84 Cheng KK, Molassiotis A, Chang AM, Wai WC, Cheung SS.Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in pediatric cancer patients, Eur J Cancer 2001 Nov; 37 (16): 2056-6 Fulton JS, Middleton GJ, McPhail IT, Management of oral complications, Semin Oncol Nurs 2002 Feb; 18 (1): 28-35 Worthington HV, Clarkson JE, Eden OB, Interventions for treating oral mucositis for patients with cancer receiving treatment, Cochrane Database Syst Rev 2002; (1): CD001973 Demarosi F, Bez C, Carrassi A., Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 2002 May; 51 (5): 173- 86 Sonis ST, Fey KG, Oral Complications of Cancer Therapy, Oncology 2002, 16: 680-695 Plevova P: Prevention and treatment of chemotherapy- and radiotherapy-induced oral mucositis: A review. Oral Oncol 35: 453-470, 1999 JB Epstein, AW Chow, Oral complications associated with immunosuppression and cancer therapies, Infectious Disease Clinics of North America, 1999, 13 (4), 901-923

  The object of the present invention is to provide viscous and mucoadhesive liquid formulations and mucoadhesive gel formulations used for the prevention and treatment of mucocutaneous disorders. The formulation can be used with or without one or more active agents. Although these formulations are particularly beneficial in diseases and conditions that require treatment on a wide range of mucosal surfaces, the formulations can also be used in treating small areas of mucosal surfaces.

  In order to effectively treat mucocutaneous disorders, it is preferred that the lesion is in contact with the liquid or gel mucoadhesive preparation for the period necessary to obtain benefits. To confer such benefits, the present invention provides mucoadhesive, viscous liquid formulations and mucoadhesive gel formulations that may or may not include one or more pharmaceutically active ingredients. Describe. The liquid can be easily applied to the affected area of the mucosa by methods known in the art, while the liquid or gel remains in contact with the lesion for an extended period of time due to high viscosity and mucoadhesiveness. Conceivable. The formulations of the invention can be applied to treat mucocutaneous skin lesions in various body compartments including, but not limited to, oral cavity, nasal cavity, esophagus, rectum, bladder, and vagina.

  The present invention includes compositions for the treatment and prevention of mucocutaneous disorders. In certain embodiments, this composition of the invention comprises an amount of mucoadhesive effective to coat the mucocutaneous area being treated and is also therapeutic for mucocutaneous disorders or Contains prophylactically active drugs. In important embodiments, the mucoadhesive agent is at a viscosity-inducing concentration. In another aspect of the invention, mucosal drug delivery compositions that can be used in the treatment or prevention of mucocutaneous disorders are described. The composition includes an amount of mucoadhesive agent, viscosity inducer, and therapeutic or prophylactic agent for mucocutaneous disorders that forms an effective coating in the mucocutaneous area being treated. In certain embodiments, the mucoadhesive agent of the present invention may be a natural or synthetic, linear or cross-linked polymer. This mucoadhesive agent is, for example, linear or cross-linked polyacrylic acid, carboxymethylcellulose, hydroxyalkylcellulose, polyvinylpyrrolidone sulfate dextran, dermatan sulfate, water-soluble vinyl polymer, guar gum, xanthan gum, tragacanth gum, and pectin Or it can be chitosan. In the compositions of the present invention, the mucoadhesive agent is typically at a concentration between about 0.1 w / w% and about 3.0 w / w%. In a preferred embodiment, the mucoadhesive agent of the present invention is optionally directly derived from linear polyacrylate and / or polymethacrylate and / or acrylate and methacrylate monomers in addition to the crosslinked polyacrylic acid hydrogel. Includes chain copolymers. There are many viscosity inducers that can be used, including agar, bentonite, glycerin, providone, kaolin, tragacanth, sodium alginate, and cross-linked polyacrylic acid. The compositions of the present invention preferably have a pH between about 6.5 and about 9.5.

  The mucocutaneous disorders that can be treated by the methods and compositions of the present invention are as follows: mucositis, Behcet's disease, aphthous ulcer, bullous pemphigoid, chemical cystitis, radiation cystitis Erythema multiforme, esophagitis, interstitial cystitis, lichen planus, pemphigus, radiation proctitis, or ulcerative colitis.

  An important aspect of the present invention includes a method for the prevention or treatment of mucocutaneous disorders. The method involves the identification of a patient having a mucocutaneous disorder or having the possibility of developing disease. Next, in this method, a formulation comprising an amount of mucoadhesive agent effective for preventing or treating mucocutaneous disorders is administered to the patient. Of course, the formulation may and often includes a viscosity inducer and / or a viscosity increasing concentration of mucoadhesive agent. The mucocutaneous disorders that can be treated by this method are as described above. If it has a pseudoplastic behavior that reduces the viscosity upon application (so that the liquid can more easily cover the mucosa) and increases the viscosity of the liquid when present on the mucosal skin area, The liquid formulations of the present invention are often more useful. In terms of treatment length, this will vary with severity and type of disorder. It is sought that alleviation of mucocutaneous damage is apparent to everyone who is treating the patient and the treatment continues until recovery is apparent. Depending on the situation, this can take hours to days to weeks. Preferred mucoadhesive agents for this method are as described above. The same applies to the viscosity inducer.

FIG. 1 shows an in vitro model that has been developed to show increased delivery of active pharmaceutical ingredients to mucosal surfaces. FIG. 1a shows an in vitro model developed to show increased delivery of active pharmaceutical ingredients to mucosal surfaces. 1 shows that the apparatus described in FIG. 1 is attached to the LC pump 2-3 using a 10/31 "ferrule and a large diameter HPLC tube. FIG. 3 shows the results of amlexanox delivery of three different formulations when tested using the device shown in FIGS. FIG. 3a shows the results of amlexanox delivery of three different formulations when tested using the device shown in FIGS. The comparison results of the formulations described in Example 7 are summarized.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS The present invention describes formulations for the prevention and treatment of mucosal disorders in humans and animals. While the liquid or gel formulations of the present invention are ideally suited for treating diseases and disorders affecting a wide range of mucosal surfaces, they also treat discrete and localized lesions, especially in the oral cavity. It also provides an opportunity to do. Mucosal membranes that can be treated by the compositions described in this patent include, but are not limited to, the oral cavity, nasal cavity, gastrointestinal and respiratory tract, vagina, and intramucosal mucosa. Inflammatory, erosive and / or ulcerative diseases that can be treated by topical application of the compositions described in this patent include aphthous ulcers, Behcet's syndrome, bullous pemphigoid, chemical or radiation-induced bladder Inflammation, erythema multiforme, esophagitis, interstitial cystitis, mucositis, oral lichen planus, pemphigus, and radiation proctitis include, but are not limited to. In conditions such as aphthous ulcers, chemical or radiation-induced cystitis, mucositis, and radiation proctitis (e.g., by progenitors in the case of aphthous ulcers and in the treatment of cancer, chemotherapy and / or If the occurrence of an inflammatory, erosive, and / or ulcerous condition (or by initiation of radiation therapy) can be predicted, the composition of the present invention may be applied prior to lesion formation or at the beginning of the treatment to produce inflammatory The development of erosive, and / or ulcerative lesions can be prevented or delayed. The mucosal protective agent may be a mucoadhesive agent alone, but if the pharmaceutical agent is present for selective delivery to a mucosal target, it is a viscous mucoadhesive liquid or mucoadhesive agent. Gels are particularly preferred.

  As will be described later in the Examples section, a viscous liquid, which is one of the viscous and mucoadhesive formulations of the present invention, composed entirely of pharmaceutically acceptable excipients, is Proven amazing results. This study examined the extent of mucositis in patients undergoing radiation therapy for head and neck cancer. Mucous membranes for patients rinsed 6 times a day with one of the viscous mucoadhesive solutions of the present invention during a period of radiation therapy (6-7 weeks) with or without concombinant chemotherapy The mean and median flame score was much lower than the score for patients who did not use this rinse.

  Furthermore, the mucoadhesive liquid / gel formulations of the present invention, which are also composed entirely of pharmaceutically acceptable excipients, have shown surprising results in a radiation-induced mucositis hamster model.

  There is currently no perfect explanation of why the viscous mucoadhesive liquids and gels of the present invention without known pharmaceutically active ingredients offer such benefits to patients. The following are conceived and realistic possibilities, but the present invention should not be regarded as limited to any one of these possibilities.

  Viscous mucoadhesive solutions provide a layer on the mucosal surface for an extended period of time, which can have beneficial effects (eg humidification or barrier effects), thereby causing damage to the mucosal surface caused by the disease Or wounds derived from ionizing radiation and / or chemotherapeutic agents. Thus, any aqueous formulation formulated with non-toxic, non-irritating excipients to provide a liquid or gel (both viscous and mucoadhesive) suffers from mucosal diseases or disorders It is assumed that it is expected to provide benefits.

  It is known that polyanionic carbohydrate polymers and oligomers can have beneficial effects in the treatment of mucosal disorders. For example, pentosan polysulfate and hyaluronic acid are known to provide benefits to patients with interstital cystitis (Morales A, et al, Treatment of refractory interstitial cystitis, Int Urogynecol J Pelvic Floor Dysfunct 1996; 7 (4): 215-20). It is very likely that other polyanionic and polycationic compounds of natural origin or synthetic, whether carbohydrates or not, can provide benefits in the prevention and treatment of mucosal disorders as well. Linear and partially crosslinked polyanionic polymers are included in formulations used in products that have demonstrated benefits in the mucositis clinical trials described in the Examples.

  Other ingredients of the formulation (benzyl alcohol, citric acid, glycerin, polysorbate 60, and saccharin) used in clinical trials, alone or in combination with each other and / or other excipients of the formulation, Can have a positive effect. Other preservatives, wetting agents, emulsifiers, antioxidants, antibacterial agents, solubilizers, and other excipients, known in the art, in pharmaceutical liquid product formulations are either single or combined. It may also provide or increase beneficial properties on the mucosal surface when formulated to provide a viscous, mucoadhesive solution.

  Other components of the liquid / gel formulation used in the mucositis hamster model (phenoxyethanol, glycine, glycerol, ethanol) alone or in combination with each other and / or other excipients of the formulation are beneficial effects Can be included. Other preservatives, wetting agents, emulsifiers, antioxidants, antibacterial agents, solubilizers, and other excipients known in the art, in the formulation of gel-like pharmaceutical products Can also provide or enhance beneficial properties to mucosal surfaces when formulated to provide mucoadhesive gels.

  Viscous, mucoadhesive formulations for prevention and treatment of mucosal diseases and disorders can be further formulated with one or more compounds known to be pharmaceutically active. The addition of additional pharmaceutically active compounds could provide greater benefits to patients undergoing prevention and treatment of mucosal damage. Examples of pharmaceutically active compounds that can be incorporated into the viscous, mucoadhesive solutions of the present invention are described later in this section.

  Aqueous solutions of pharmaceutically active compounds are known in the art as convenient drug delivery formulations. Such formulations are most useful for oral delivery when the solution is swallowed, and the drug is provided to the stomach and gastrointestinal tract in a form suitable for rapid absorption. Aqueous solutions are also used to deliver drugs to mucosal tissue. In general, aqueous solutions used for drug delivery tend to be non-viscous and non-mucosal. This property is undesirable for oral delivery because the amount of drug retained in the oral cavity and esophagus is minimized while the amount of drug delivered to the stomach and gastrointestinal tract is maximized. . One preferred drug for the treatment of mucocutaneous disorders is amlexanox.

  For topical treatment of the mucosa, aqueous solutions of pharmaceutically active compounds offer advantages over other dosage forms in that a wide range of mucosa can be easily covered with the solution, which is treated. It is advantageous if the region to be processed is not a single discrete region. Also, aqueous solutions of pharmaceutically active compounds and simple application methods can be used to treat mucosa that is not easily accessible. However, non-mucosal, non-viscous formulations are not ideal for drug delivery to mucosal surfaces. For example, such a solution is rapidly removed from the area being treated, as liquid flows from the application site under the influence of gravity and / or mucous natural secretions carry the solution from the application site. It is thought.

  The present invention includes the finding that neither high viscosity nor high mucoadhesive properties alone give ideal properties. Viscous but non-mucosal liquid is not retained in place on the mucosal surface. Instead, non-mucosal solutions are easily lost from the application site, for example under the influence of gravity and / or by natural movement of the membrane and surrounding structures and / or by the flow of natural secretions it is conceivable that. In a mucoadhesive but low viscosity aqueous liquid formulation, only a thin layer of liquid adjacent to the mucosa may be held in place, but most of the liquid is removed from the application site under the influence of gravity. It can flow rapidly and / or be easily removed by natural mucosal secretions. In mucoadhesive and viscous liquid formulations, the liquid is thought to adhere to the mucosa, while the high viscosity of the liquid is thought to reduce the rate of removal of most liquids from the application site. In some cases, particularly when no pharmaceutical agent is required, effective treatment may be provided by low viscosity and mucoadhesiveness. The mucoadhesive agent may itself be a viscosity inducing factor and thus serve two purposes. The term “viscous induction” means an increase in the aqueous mucoadhesive layer that adheres to the mucosal area.

  For most liquids, the viscosity remains constant over a wide range of shear rates. This phenomenon is known as Newtonian viscosity, and a liquid exhibiting this characteristic is called a Newtonian liquid. A liquid whose viscosity varies with shear rate is called non-Newtonian. There are several known non-Newton profiles. One of these profiles is called pseudoplastic, and liquids that fall into this category show a decrease in viscosity with increasing shear rate. Preferred formulations of the present invention are pseudoplastic and exhibit a decrease in viscosity at low shear rates. Pseudoplasticity is due to the fact that the application of shear forces (eg swishing the liquid in the mouth) reduces the viscosity, thereby allowing the liquid to flow and more easily coat the mucosal surface. Benefit from the application of the formulations of the present invention. Once the shear forces are interrupted, the viscosity of the liquid required for long-term adhesion to the mucosal surface (along with mucoadhesiveness) increases.

  The formulations of the present invention are viscous, free-flowing liquids or fluid gels, which are Newtonian or pseudoplastic. The ability to flow freely or freely diffuse is advantageous for easily coating selected areas or a wide range of affected mucosa and for coating mucosa that cannot be easily touched by mere application. It is. The solution of the present invention is considered to have a viscosity in the range of 100 cP to 20,000 cP at zero shear.

  The stable, viscous and mucoadhesive liquid formulations of the present invention can be applied to the mucosa to deliver pharmaceutically active compounds to the mucosa for the prevention and / or treatment of mucosal disorders or diseases. The liquid can be applied, for example, to the following mucosal surfaces: oral cavity, nasal cavity, gastrointestinal and respiratory tract, vagina, and / or bladder. The formulations of the present invention can also be applied to other mucous membranes for the prevention and treatment of disorders and diseases. A number of methods known in the art can be used for delivery of liquid to the body compartment.

  For the treatment of oral disorders and diseases, the stable, viscous and mucoadhesive liquid formulations of the present invention may be ingested by the mouth and by a crushing action or when the patient is slow on the head It may be distributed throughout the oral cavity by incorporating slow circulating movement. Excess solution may be swallowed or released. For the treatment of oral disorders and diseases, the stable mucoadhesive gel formulation of the present invention may be taken by mouth and by mouth movement and / or by swab or similar means. You may distribute to the whole. Excess gel may be swallowed or released.

  For the treatment of esophageal disorders and diseases, the stable and mucoadhesive liquid and gel formulations of the present invention can be swallowed with minimal contact with the oral cavity or by gavage or into the throat Can be administered by spraying a liquid.

  For the treatment of nasal disorders and diseases, the stable and mucoadhesive liquid and gel formulations of the present invention can be delivered as droplets or by spraying the liquid into the nose.

  For the treatment of bladder disorders and diseases, the stable, mucoadhesive liquid or gel formulations of the present invention can be delivered by intravesical administration.

  For the treatment of rectal and lower gastrointestinal disorders and diseases, the stable, mucoadhesive liquid or gel formulations of the present invention can be administered by catheter or enema.

  Other methods for applying the stable, viscous, mucoadhesive liquid formulations and stable, mucoadhesive gel formulations of the present invention to mucosal tissue are known to those skilled in the art.

  For topical treatment of the mucosa, pharmaceutically active compounds that can be formulated with the stable and mucoadhesive liquid and gel formulations of the present invention include one or more of the following types of drugs, alone or Can be included in combination: antiallergic compounds, anti-inflammatory analgesics, steroidal and non-steroidal anti-inflammatory agents, antioxidant compounds, analgesics, antihistamines, local anesthetics, bactericides and disinfectants, vasoconstrictors, hemostasis Agents, antibiotics, keratolytic agents, cauterizing agents, antiviral agents, growth factors, food supplements, and other potential agents for the treatment of mucositis. Other types of pharmaceutically active agents may also be formulated with the stable mucoadhesive liquid and gel formulations of the present invention.

  Examples of anti-inflammatory analgesics include acetaminophen, methyl salicylate, monoglycolic salicylate, aspirin, mefenamic acid, flufenamic acid, indomethacin, diclofenac, alclofenac, diclofenac sodium, ibuprofen, ketoprofen, naproxen, pranoprofen, fenoprofen, Sulindac, fenclofenac, clidanac, flurbiprofen, fentiazak, bufexamac, piroxicam, phenylbutazone, oxyphenbutazone, clofesone, pentazocine, mepyrizole, thiaramide hydrochloride and the like.

  Examples of steroidal anti-inflammatory agents include hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, hydrocortisone acetate, prednisolone acetate, methylprednisolone acetate, dexamethasone acetate, betamethasone, betamethasone valerate, flumethasone, fluorometholone, dimethasone And beclomethasone propionate.

  Examples of antioxidant compounds include ascorbic acid, dehydroascorbic acid, α-tocopherol, glutathione, β-carotene, azelastine, N-acetyl-L-cysteine, allopurinol, flavonoids and the like.

  Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine, chlorpheniramine hydrochloride, chlorpheniramine maleate, istipendyl hydrochloride, tripelenamine hydrochloride, promethazine hydrochloride, and methodirazine hydrochloride.

  Examples of local anesthetics include dibucaine hydrochloride, dibucaine, lidocaine hydrochloride, lidocaine, benzocaine, p-butylaminobenzoic acid 2- (diethylamino) ethyl ester, procaine hydrochloride, tetracaine, tetracaine hydrochloride, chloroprocaine hydrochloride, hydrochloric acid Examples include oxyprocaine, mepivacaine, cocaine hydrochloride, piperocaine hydrochloride, dichronin, and dichronin hydrochloride.

  Examples of disinfectants and disinfectants include phenoxyethanol, triclosan, thimerosal, phenol, thymol, benzalkonium chloride, benzethonium chloride, chlorhexidine, povidone iodide, cetylpyridinium chloride, eugenol, trimethylammonium bromide and the like.

  Examples of the vasoconstrictor include naphazoline nitrate, tetrahydrazoline hydrochloride, oxymetazoline hydrochloride, phenylephrine hydrochloride, tramazoline hydrochloride, and the like.

  Examples of hemostatic agents include thrombin, phytonadione, protamine sulfate, aminocaproic acid, tranexamic acid, carbazochrome, carbaxochrome sodium sulfanate, rutin, hesperidin and the like.

  Examples of antibiotics include penicillin, methicillin, oxacillin, cephalothin, cephaloridine, erythromycin, lincomycin, tetracycline, chlortetracycline, oxytetracycline, metacycline, chloramphenicol, kanamycin, streptomycin, gentamicin, bacitracin, cycloserine, and Clindamycin is mentioned.

  Examples of keratolytic agents include salicylic acid, podophore, podolifox, and cantharidin. Examples of caustic agents include chloroacetic acid and silver nitrate.

  Examples of antiviral agents include protease inhibitors, thymidine kinase inhibitors, sugar or glycoprotein synthesis inhibitors, structural protein synthesis inhibitors, adhesion and adsorption inhibitors, and, for example, acyclovir, penciclovir, valacyclovir, and Examples include nucleoside analogs such as ganciclovir.

  Examples of antiallergic compounds include allopatadine, astemizole, cromolyn, fenpiplan, repirinast, tranilast, trazanox and the like.

  Examples of growth factors, supplements, and other potential drugs for the treatment of mucositis include keratinocyte growth factor, granulocyte colony stimulating factor, transforming growth factor-β3, sucralfate, L-glutamine, amino acids, Examples include lysofylline, IL-15, antimicrobial peptides, and histamine.

  The amount of pharmaceutically active compound used depends on the strength of the desired treatment, but preferably the pharmaceutical ingredient is from 0.001% to 30%, and more preferably from 0.005% by weight of the formulation. It constitutes between 20% by weight.

  In addition to the preferred requirements of mucoadhesiveness and viscosity described above, for the use of the formulation for the prevention and treatment of mucosal diseases and disorders, the formulation even when subjected to high or low temperatures for a short time It is important that the liquid or gel is stable so that it can be stored at ambient temperature for months or years without physical or chemical degradation of the material. Although it is usually desirable to formulate the product without the use of any organic solvents (the presence of which can treat the mucosal lesion being treated), the incorporation of such solvents does not damage the mucosa. Liquid formulations and gel formulations containing pharmaceutically acceptable organic solvents are within the scope of the present invention, provided that they may provide the following benefits: for example, benefits as a disinfectant, or Benefits to support mucosal solvation and provide more rapid mucoadhesion, or shaping (by solvent evaporation after application to mucous membranes) to increase mucoadhesion and / or viscosity after application Benefits for agent concentration. Furthermore, it is desirable to formulate viscous, mucoadhesive solutions using only those excipients that are recognized as safe by all major pharmaceutical regulatory authorities.

  The following list provides examples of components of the stable, viscous, mucoadhesive formulations of the present invention.

  Linear or cross-linked polyanionic or polycationic polymers that may or may not be known to provide mucoadhesive properties. Such polymers include (but are not limited to) linear polyacrylic acid, cross-linked homopolymers based on acrylic acid, cross-linked copolymers based on acrylic acid, linear methacrylic acid. Includes acid homopolymers and copolymers, carboxymethylcellulose, hydroxyalkylcellulose, dextran sulfate, dermatan sulfate, and hyaluronic acid. Other mucoadhesive polymers are well known to those skilled in the art. The mucoadhesive formulation of the present invention can comprise a single mucoadhesive component or a mixture thereof. Preferred mucoadhesive polymers are cross-linked homopolymers and copolymers based on acrylic acid and methacrylic acid, especially polycarbophil polymers supplied by Carbopol and BF Goodrich, and Eudragit supplied by Rohm-Haas It is a polymer. Carbopol, Noveon AA1, and Eudragit L-100 are most preferred.

  Increased viscosity is provided by one or more of the mucoadhesive polymers described above in combination or alone with agar, bentonite, glycerin, povidone, kaolin and / or tragacanth, and sodium alginate. Most preferred is Carbopol in combination with glycerin.

  The pH of the solution is adjusted to the desired final pH with any pharmaceutically acceptable acid or base. Most preferred is sodium or potassium hydroxide, phosphoric acid, or citric acid. A final pH of 6.5 to 9.5 is preferred.

  It is desirable to include a preservative to inhibit microbial growth in the formulation during storage. Preservatives known in the art include benzyl alcohol, benzoate, phenoxyethanol, methyl paraben, and propyl paraben. Phenoxyethanol and benzyl alcohol are the most preferred preservatives.

  Wetting agents are desirable to provide a good mouth feel in oral application. Wetting agents known in the art include cholesterol, fatty acids, glycerin, lauric acid, magnesium stearate, pentaerythritol, and propylene glycol. Glycerin is preferred.

  For example, an emulsifier may be necessary to ensure complete dissolution of all excipients (especially hydrophobic components such as benzyl alcohol). Many emulsifiers are known in the art. A preferred emulsifier is polysorbate 60.

  For oral application, it may be desirable to add pharmaceutically acceptable fragrances, colorants, and / or sweeteners. Compounds such as saccharin, glycerin, simple syrup, and sorbitol are particularly useful as sweeteners. Saccharin is preferred.

  It may be desirable to include other ingredients such as pharmaceutically acceptable organic solvents, buffers, antioxidants, free radical scavengers, antibacterial agents, and / or colorants. The exact formulation and manufacturing method of the above ingredients will be apparent to those skilled in the art. Many sources, including Remington's Pharmaceutical Sciences, Mack Publishing Company Co., Easton, PA and Pharmaceutical dosage forms and drug delivery, Ansel et al, 1995, Williams and Wilkins, Malvern, PA, assist in the design and manufacture of pharmaceutical formulations. It becomes.

  The following examples are provided to demonstrate the beneficial effects of the stable and mucoadhesive liquids and gels of the present invention. Example 4 is provided to demonstrate that both mucoadhesiveness and viscosity are desirable to provide a liquid coating having extended retention properties on an artificial mucosal surface. In this in vitro model of the mucosal surface, an attempt is made to remove the liquid coating by a steady flow of artificial saliva over the “mucosal” surface. Amlexanox, a hydrophobic drug, is used as a marker for film erosion and retention (the latter by delivery of the marker across the model mucosa). This test clearly shows that the liquid requires both mucoadhesive and viscous properties for retention.

  Example 6 presents an analysis of a clinical trial of a stable, viscous, mucoadhesive rinse formulation of the present invention compared to standard treatment in patients receiving head and neck radiation therapy. This analysis shows that the stable, viscous, mucoadhesive rinse formulations of the present invention that do not contain an acceptable pharmaceutically active ingredient are compared to a similar group of patients receiving standard treatment for mucositis. Thus, surprising results have been provided to reduce the mean and median mucositis scores of these patients.

Example 8 presents the results of a study in a golden hamster in which mucositis was induced by oral radiation. Six gel formulations were tested in this model, and the severity of mucositis for each treatment group is expressed as the average number of days that animals in each group experienced mucositis with a score of 3 or higher. Score 3 represents the occurrence of ulceration, and a score above it represents more severe mucositis. The formulations tested in this study are listed in Example 7. None of the formulations contain acceptable pharmaceutically active ingredients. The results of this study clearly show the following:
a. The most effective formulation (A and B) contains a mixture of two mucoadhesive polymers, Carbopol 971 and Noveon AA1.
b. There is a general tendency for effectiveness to increase with viscosity across all systems. This provides a basis for the importance of the viscosity of liquid and gel formulations used in the treatment of mucositis.
c. Formulation B (similar to A except that Eudragit L-100 is removed) is similar to A but has slightly reduced efficacy, but small differences observed Was not statistically significant and could be explained by viscosity.
d. Formulation C is obtained by removing phenoxyethanol from Formulation B. Phenoxyethanol is a preservative with known antiseptic and bactericidal properties. Formulation C is clearly effective in reducing the severity of mucositis, but this formulation is clearly more effective when preservatives / bactericides are present.
e. Formulation D is the same as B except that the glycine buffer is replaced with a borate buffer. The viscosity of formulation D is slightly lower than that of B, which may account for some of the differences, but the data also indicate that there are benefits provided by amino acids.
f. Formulation E is the same as B except that Noveon AA1 is removed. Viscosity and mucoadhesiveness are provided only by Carbopol 971. The total concentration of cross-linked acrylate must be increased to provide a similar viscosity. The lack of effectiveness of this formulation can be attributed mainly to its low viscosity.
g. Formulation F is the same as B, except that all mucoadhesive polymers have been replaced with nonmucoadhesive thickening agents. Although the viscosity of this formulation is slightly higher than B, it still has no efficacy (compared to saline). This indicates that mucoadhesiveness is as important as effectiveness for viscosity.

Example 1 Preparation of Viscous Mucoadhesive Aqueous Composition Master Servodyne® mixer equipped with a suitable mixing device (high-lift blade rotating at 200-300 rpm) to obtain a clear solution ) Was used to formulate a viscous, mucoadhesive aqueous solution by adding Carbopol® 971P NF to the water. An aqueous potassium hydroxide solution was added with stirring to obtain a transparent gel. While stirring, an aqueous solution of potassium hydroxide, citric acid, sodium saccharin, phosphoric acid, and glycerin was added to obtain a clear solution. While stirring, a solution of benzyl alcohol and polysorbate 60 was added to obtain a clear solution. The pH was adjusted to 7.0 to 7.8 using an aqueous phosphoric acid solution. The resulting product was mixed for an additional 30 minutes.

  The formulation of the product is shown in Table 1.

Example 2 Preparation of Viscous and Mucoadhesive Aqueous Composition Containing Amlexanox The method described in Example 1 was followed to provide a viscous and mucoadhesive aqueous composition of the following formulation:

Example 3 High Performance Liquid Chromatography Assay for Amlexanox The following HPLC parameters were used in performing the assay for amlexanox.
Phenomenex, Prodigy, 5μm ODS (2), 150 mm × 4.6 mm
Mobile phase: 25% THF / 75% 10 mM phosphate buffer, pH 8.0
h. Flow rate: 1.0 mL / min
Injection dose: 10 μL
i. Detector: UV @ 244 nm

Example 4 Demonstration of drug delivery from a liquid formulation in an in vitro model of mucosal surfaces Referring to FIG. 2, the apparatus described in FIG. 1 uses an LC pump using a 10/32 "ferule and a large diameter HPLC tube. The half of one side of the polycarbonate block 7 has a reservoir 1 that provides a continuous flow of artificial saliva across the Spectra / Por4 dialysis membrane 6 and is eluted in a 10 mL container 8. Polycarbonate block The other half of 7 is connected to an LC pump 3 having a reservoir 4 of artificial saliva that constantly recirculates throughout the dialysis membrane 6.

  In a separate experiment, comparing two aqueous formulations of amlexanox that are mucoadhesive but non-viscous and viscous but non-mucoadhesive to the composition of Example 1, the optimal drug for a liquid formulation that is free to move Both properties have been shown to be necessary for delivery.

  An aqueous preparation of amlexanox (2.9 mL to 3.1 mL) was applied to an in vitro dialysis membrane, and the artificial saliva flow was started at a rate of 1.0 mL / min. mL samples were collected from reservoirs 4 and 6 and samples were assayed for amlexanox content using the HPLC assay method described in Example 3.

  The results of this test are shown in FIG. As shown in FIG. 3a, in the case of the viscous and mucoadhesive solution that is the subject of the present invention, a much smaller amount of amlexanox is washed away in the simulation of saliva flow compared to the other two formulations. As a result, in the case of the viscous and mucoadhesive solution that is the subject of the present invention, a much higher amount of amlexanox (data shows a 10-fold difference) is delivered to the membrane compared to the other two formulations. And transported to a receiver vessel.

Example 5 Stability Test The composition of Example 2 was subjected to a stability test. The clear solution was filled into a clear glass bottle and sealed with a white screw cap fitted with a Teflon liner. The bottle was divided into two groups. The first group was stored in a stability chamber set at 25 ° C./60% relative humidity, while the second group was stored at 40 ° C./75% relative humidity. 0th, 1st, 2nd, 3rd, and 6th months for physical appearance (solution transparency), package integrity, amlexanox and benzyl alcohol content, pH, and viscosity Considered the bottle. No physical or chemical changes were observed in all periods and under both conditions.

Example 6 Clinical Trials Clinical trials were conducted in patients over 18 years of age who received a histologically documented diagnosis of head and neck cancer and had a KPS of at least 60%. The patient was irradiated with a dose of at least 60 Gy over a period of 6-7 weeks in a field intended to contain at least 40% oral mucosa. Patients receiving concurrent chemotherapy were also included in the study. During the period of radiation therapy (6-7 weeks), patients were rinsed 6 times daily (5 mL each time) using the solution illustrated in Example 1. This started on the first day of radiation therapy. Objective measurement of the degree of mucositis (“Sonis scale” as described in Cancer, 1999, 85 (10) 2103-13) was performed three times a week during the study period. The following table shows the mean and median scores of patients on days 14, 28, and 39. These data were obtained in 12 subjects. Historical data (Sonis scale mucositis score for a similar patient population (17 total) undergoing similar treatment for head and neck cancer) is provided for comparison.

Example 7 Mucoadhesive gel preparation
Six gel formulations were prepared using a lightning mixer with an A-100 propeller as well. For a sample described below designated B, 354 grams of 50 mM glycine / sodium hydroxide buffer was added to a 600 ml beaker and stirred at 200 rpm. The buffer was prepared by mixing 1 liter of 0.2M aqueous glycine solution with 176 ml of 0.2N sodium hydroxide solution and 2984 ml of deionized water. 50 grams of 95% USP ethanol was then added, followed by 5 grams of glycerin. The agitation speed was increased to 300 rpm and 5 grams of Noveon AA1 was slowly added to the vortex and the speed was gradually increased to 700 rpm. This solution was homogenized for 1 hour. 50 grams of Carbopol® 971P NF was slowly added to the vortex and the speed was gradually increased to 1200 rpm. The material was mixed for an additional 30 minutes, after which 75 grams of 2N sodium hydroxide and 5 grams of phenoxyethanol were added. The resulting gel was further mixed for 30 minutes and the pH was measured and found to be 9.82. The mixing speed was reduced to 1000 rpm, and the pH was adjusted to 9.01 using 6.4 ml of 1N hydrochloric acid. The final gel product was clear and homogeneous and was transferred to a polypropylene container.

  The method described above was used to prepare gels using the following formulation.

Example 8 Hamster mucositis test
On day 0, 56 hamsters were given 40 Gy of acute radiation towards their oral mucosa. From the day before irradiation (-1 day) to the 20th day (20th day) after irradiation, the test materials (each of the preparations A to F described above) were applied locally. The grade of mucositis was recorded from day 6 until every other day thereafter until the end of the study on day 28. The effect of each treatment group on mucositis was compared to saline controls. Each animal was recorded according to the mucositis scale (0-5), where 0 indicates no mucositis, 5 indicates severe mucositis, and a score of 3 or higher indicates ulceration Is observed. The average score for each group of animals was recorded and the number of days that each group of hamsters had severe (> 3 score) mucositis was calculated. The number of hamsters with this score in the drug-treated group, which was statistically significantly less than the control, was determined by chi-square analysis to define the therapeutic effect.

  In FIG. 4, the comparison results of the preparations described in Example 7 are summarized.

Claims (17)

A pseudoplastic liquid composition for use in the treatment or prevention of oral mucosal disorders, comprising:
Free of pharmaceutically active compounds;
Having a viscosity of 100 cps to 15,000 cps;
Cross-linked polyacrylic acid, polyvinylpyrrolidone, carboxymethylcellulose, dextran sulfate, hydroxyalkylcellulose, dermatan sulfate, water-soluble vinyl polymer, chitosan, guar gum, xanthan gum, tragacanth gum, and pectin, and 0.1% by weight Containing one or more mucoadhesive agents at a concentration of from 3.0 to 3.0% by weight as a solution or suspension; and when administered to the oral mucosa,
1) When shear is applied to swish liquid in the mouth, the liquid state is maintained,
2) When the shear is interrupted, it adheres to the oral mucosa and coats the oral mucosa.
Pseudoplastic liquid composition.   2. The composition of claim 1, further comprising a viscosity inducer.   The mucoadhesive agent is at least one agent selected from the group consisting of polyvinylpyrrolidone, carboxymethylcellulose, dextran sulfate, hydroxyalkylcellulose, dermatan sulfate, water-soluble vinyl polymer, chitosan, guar gum, xanthan gum, tragacanth gum, and pectin. The composition of claim 1.   2. The composition of claim 1, wherein the one or more mucoadhesive agents are cross-linked polyacrylic acid.   2. The composition of claim 1, further comprising a preservative having antimicrobial activity.   The composition of claim 1, comprising less than 20% by weight of a pharmaceutically acceptable water-miscible organic solvent.   5. A composition according to claim 4, wherein the crosslinked polyacrylic acid is Carbopol® or polycarbophil.   5. The composition of claim 4, further comprising a viscosity inducer.   9. The composition of claim 2 or 8, wherein the viscosity inducer is a monovalent, divalent, or trivalent cation inorganic salt.   10. The composition of claim 9, wherein the salt is Na, K, Ca, Mg, Zn, or Al having a pharmaceutically acceptable chlorine, bromine, phosphoric acid, boric acid, tartaric acid, or benzoic acid counterion. object.   The viscosity-inducing agent is a pharmaceutically acceptable organic molecule comprising at least two ionizable groups or hydrogen bond groups suitable for the formation of electrostatic or hydrogen bond bridges of crosslinked polyacrylic acid, 10. A composition according to claim 2 or 9.   10. The composition of claim 2 or 9, wherein the viscosity inducer comprises at least one amino acid, peptide, diamine, alcohol, organic acid, fatty acid, polyol, polyvinyl alcohol, ethylene oxide / propylene oxide block copolymer, or surfactant. .   6. The composition of claim 5, wherein the preservative is methyl paraben, propyl paraben, benzyl alcohol, phenoxyethanol, or a mixture thereof.   2. The composition of claim 1, further comprising a pharmaceutically acceptable excipient to improve stability, mouthfeel, appearance, and flavor.   15. The composition of claim 14, wherein the excipient is a preservative, wetting agent, emulsifier, antioxidant, antibacterial agent, solubilizer, fragrance, or sweetener. Viscous and mucoadhesive pseudoplastic liquid composition for treating or preventing mucosal lesions, including:
Purified water added so that the liquid is 100% in total;
4.6% by weight of 10% potassium hydroxide;
1.50% by weight of benzyl alcohol;
0.05 wt% polysorbate 60;
0.35% by weight of Carbopol® 971P;
5.7% by weight of 0.5% phosphoric acid;
0.05% by weight citric acid;
0.40% by weight sodium saccharin; and
5.00% by weight glycerin. (I) protect mucous membranes, (ii) provide relief of symptoms, and (iii) delay the onset of signs and symptoms of mucositis including erythema and ulceration induced by chemotherapy or radiation therapy Use of a composition according to any one of claims 1 to 16 for the manufacture of a medicament for one or more selected from the group consisting of: reducing the severity thereof.

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