KR20080071184A - Orally absorbed pharmaceutical formulation and method of administration - Google Patents

Abstract

A pharmaceutical formulation for absorption through oral mucosae comprising an effective amount of (a) a pharmaceutical agent in mixed micellar form, (b) at least one micelle-forming compound selected from the group comprising an alkali metal alkyl sulfate and a polyoxyethylene sorbitan monooleate, (c) a block copolymer of polyoxyethylene and polyoxypropylene, (d) at least one additional micelle-forming compound, and (e) a suitable solvent. The invention also provides a metered dose dispenser (aerosol or non-aerosol) containing the present formulation and a method of administering insulin using the metered dose dispenser comprising administering split doses of a formulation containing insulin before and after each meal.

Description

ORALY ABSORBED PHARMACEUTICAL FORMULATION AND METHOD OF ADMINISTRATION

The present invention provides a pharmaceutical formulation effective for delivering a pharmaceutical formulation through an oral membrane (e.g., buccal and pharyngeal mucosa) and a method of administering the pharmaceutical formulation, and the pharmaceutical formulation. A metered dose dispenser is included.

Relatively little progress has been made in the years of reaching safe and effective formulations for pharmaceutical preparations, particularly large molecular pharmaceutical preparations such as peptides and proteins. Barriers to developing oral formulations include poor endogenous permeability, enzymatic degradation by lumenal and cellular enzymes, rapid removal, and chemical instability in the GI tract. . Pharmaceutical attempts to address this barrier, which have been successful with conventional small organic drug molecules, have not been readily transformed into effective macromolecular formulations.

Various routes of administration other than injection have been developed for very large molecular drugs, with little or no success. Mouth and nasal passages were of particular interest. The ability of molecules to cross the oral mucosa has been shown to be related to molecular size, lipid solubility and peptide protein ionization. Molecules below 1000 Daltons have been shown to quickly cross the oral mucosa. As molecular size increases, the permeability of the molecule rapidly decreases. Lipid soluble compounds have better permeability than non-lipid soluble molecules. Maximum absorption occurs when the molecule is neutralized or unionized in electrical charge. Thus, charged molecules represent the greatest challenge for absorption through the oral mucosa.

Most protein drug molecules are very large molecules whose molecular weight exceeds 5500 Daltons. In addition to being huge, these molecules typically have very poor lipid solubility and are not readily absorbed through the oral mucosa or lung mucosa. Materials that facilitate the absorption or transport of large molecules (defined herein to mean> 1000 Daltons) through the biofilm are referred to in the art as "enhancers" or "absorption aids." To mention. These compounds generally include chelators, bile salts, fatty acids, synthetic hydrophilic and hydrophobic compounds, and biodegradable polymer compounds. Many enhancers lack a satisfactory stability profile with regard to irritation, reduced barrier function, and damage to the mucociliary elimination protection mechanism.

Some enhancers, especially those associated with bile salts and some protein solubilizers, have a very bitter and unpleasant taste. This makes their use almost impossible for daily human intake. Some attempts to address the taste issues associated with bile salt-based delivery systems include patches for buccal mucosa, bilayer tablets, controlled release tablets, the use of protease inhibitors, and various polymer matrices. However, these techniques will fail to deliver large molecule drugs at the desired therapeutic concentration. In addition, film patch dispensers cause severe tissue damage in the mouth.

Other attempts to deliver large molecules via the oral, nasal, rectal, and vaginal routes using a single bile acid or enhancer in combination with protease inhibitors and biodegradable polymeric materials similarly achieve therapeutic levels of the drug of interest. Often fail. Single enhancers often fail to loosen tight cell binding in the oral, nasal, rectal and vaginal cavity for the time required to allow the passage of drug molecules through the mucosa without further degradation. This problem makes the use of many systems impractical.

Thus, there is a need for therapeutic formulations useful for oral applications, particularly for oral applications including large molecule pharmaceutical formulations. There is also a need for a method of use of the formulation.

[Summary of invention]

The present invention relates to (a) large molecule pharmaceutical preparations in mixed micellar form, (b) trihydroxyoxocholanyl glycine or salts thereof, (c) glycerin, and (d) This need is addressed by providing a pharmaceutical formulation for absorption through the oral mucosa, comprising an effective amount of a suitable solvent.

In this formulation, trihydroxyoxocollanyl glycine, salts thereof, and glycerin are micelle-forming compounds. Preferably, the salt of trihydroxyoxocollanyl glycine is sodium glycolate.

The pharmaceutical formulation further comprises block copolymers of alkali metal alkyl sulfates, polyoxyethylene and polyoxypropylene, monooleate, polyoxyethylene ether, polyglycerin, lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber Extracts, oleic acid, linoleic acid, linolenic acid, monoolein, monolaurate, borage oil, evening primrose oil, menthol, lysine, polylysine, triolein, polydocanol alkyl Ethers, kenodeoxycholate, deoxycholate, alkali metal salicylates (eg sodium salicylate), pharmaceutically acceptable edetates (eg disodium edate), and their pharmaceutically acceptable And at least one additional micelle-forming compound selected from the group comprising salts and analogs.

In another embodiment, the at least one additional micelle-forming compound is a block copolymer of alkali metal alkyl sulfates, polyoxyethylene and polyoxypropylene, monooleate, polyoxyethylene ether, lecithin, oleic acid, polyglycerine, kenode Oxycholate, deoxycholate, lactic acid and their pharmaceutically acceptable salts and analogs.

In one embodiment, the micelle-forming compound comprises (i) at least one alkali metal alkyl sulphate and polyoxyethylene sorbitan monooleate, and (ii) a block copolymer of polyoxyethylene and polyoxypropylene. .

The monooleate is preferably polyoxyethylene sorbitan monooleate, and more preferably (x) -sorbitan mono-9-octadecenoate poly (oxy-1,2-ethanediyl) monooleate ( For example, a surfactant, also known as polysorbate 80, sold under the trademark TWIN 80).

The micelle-forming compound comprising trihydroxyoxocolalanyl glycine, their salts, and glycerin, when present, comprises from about 0.001 to 20 wt./wt.%, about 0.001 to 10 wt./wt.% of the total formulation, At a concentration of about 0.001 to 5 wt / wt.%, About 0.001 to 2 wt./wt.%, about 0.001 to 1 wt./wt.%, or about 0.001 to 0.15 wt./wt.%, respectively.

Although not required, the pharmaceutical formulation may further comprise an effective amount of at least one stabilizer and / or preservative (eg, phenolic compound, sodium benzoate). Each of these components, when present, is from about 0.01 to 10 wt./wt.%, or from about 0.1 to 7 wt./wt.%, from about 0.1 to 5 wt / wt.%, Or from about 0.1 to 3 It may be present at a concentration of wt./wt.%.

In addition, one or more inorganic salts, antioxidants, protease inhibitors, and isotonic agents may be added to provide the necessary or required properties. The choice of these ingredients and their concentrations in such formulations will depend on the pharmaceutical formulation employed and are within the expertise of those skilled in the art.

The pharmaceutical preparations are present in the form of micelles mixed in the formulation. The micelle size is at least 7, 8, 9, 10, or 11 microns (μm). Preferably, the micelle size is 50, 40, 30, 15, or 11 microns or less. Particles of this size have been shown to result in a reduction in the deposition of the pharmaceutical agent in the lungs and effective absorption by the oral membranes. Thus, absorption of the pharmaceutical agent occurs maximally through the intraoral (eg buccal and pharyngeal) mucosa.

A further aspect of the present invention is to provide a metered dose dispenser (aerosol or non-aerosol) comprising a pharmaceutical formulation. Preferably, the dispenser is an aerosol dispenser further comprising a pharmaceutically acceptable propellant, wherein the propellant is a liquid under pressure in the dispenser.

According to a further aspect, the present invention provides a method of administering a pharmaceutical formulation of the invention comprising spraying the pharmaceutical formulation into the mouth of a patient using the metered dose dispenser.

When the pharmaceutical agent is insulin, the method may further comprise spraying the pharmaceutical formulation into the oral cavity of the patient at intervals throughout the day to maintain blood glucose levels within the usual range. This method is performed by adding administration of insulin or insulin analogs as part of baseline therapy. Preferably, the formulations are administered immediately before and after breakfast, lunch, dinner and snack, respectively. The amount of insulin administered immediately before and after each meal is more than 14, 20, 26, 30 or 40 units, less than 110 or 85 units.

The formulations may also be administered in between meals for fine adjustment of glycemic levels. The amount of insulin administered between meals is more than 14, 20, or 30 units, less than 80 or 60 units.

The amount and specific schedule of insulin administered per dose will depend on the requirements of the patient, as can be determined through blood glucose monitoring.

The present invention satisfies the need for an easy and convenient means for regulating postprandial glucose levels (ie, blood glucose levels at one and two hours after a meal). Formulations according to the invention, administered before and after a meal, produce a pharmacokinetic profile that indicates normalization of postprandial glucose levels. There is data that elevated postprandial glucose levels are associated with an increased risk for cardiovascular disease. Thus, control of postprandial glucose levels is expected to bring health benefits.

These and other aspects and advantages of the invention will be apparent from the following detailed description and the appended claims.

The invention is illustrated in more detail by the following non-limiting figures.

1 is a front isometric view of a metered dose aerosol dispenser that can be used to deliver a formulation according to the present invention.

2 is a side view of a metering valve assembly and aerosol can for a metered dose aerosol dispenser.

3 is a cross-sectional view of the metering valve for a metered dose aerosol dispenser, aerosol can, and actuator, showing the stopped state of the metering valve.

4 is a cross-sectional view of the metering valve, aerosol can, and actuator for a metered dose aerosol dispenser, with the metering valve open.

FIG. 5 shows the pharmacokinetic / pharmacodynamic (PK / PD) profiles of the formulations according to the invention when given in single versus discrete doses near meals, and also to compare the bioavailability of the formulations with injected insulin. This is a graph plotting mean blood glucose levels as a function of time.

FIG. 6 is a graph plotting average blood glucose concentration as a function of time for comparing bioavailability of formulations according to another embodiment of the invention with injected insulin.

FIG. 7 shows the pharmacokinetic / pharmacodynamic (PK / PD) profile of a formulation according to another embodiment of the invention when given in single versus discrete doses near a meal, and also shows the bioavailability of the formulation with injected insulin. For comparison, a graph plotting average blood glucose levels as a function of time.

Detailed Description of the Invention

As used herein, the term "comprising" means "including without limitation." Thus, formulations or groups containing many integers may also include additional integers not specifically mentioned. As used herein, the term "consisting essentially of" means that the inclusion of the mentioned integers and the additional integers does not substantially affect the basic and novel properties of the present invention. A basic and novel feature of the present invention is the absorption of the pharmaceutical formulations of the present invention into the bloodstream of the patient through the oral mucosa (eg, buccal, pharynx, tongue, sublingual, and palatal mucosa).

Pharmaceutical formulations of the present invention include an "effective amount" of the pharmaceutical formulation. As used herein, the term “effective amount” means the amount of pharmaceutical agent required to achieve the desired result, such as the intended treatment or prevention of the disorder, or to achieve control of the physiological condition of the patient. do. Thus the amount can be understood to have a therapeutic and / or prophylactic effect in the patient.

As used herein, the term "patient" means a member of the animal kingdom, including but not limited to humans. It will be appreciated that the effective amount may vary depending upon the particular pharmaceutical agent used, the severity and nature of the disorder being treated, and the patient being treated. Determination of what constitutes an effective amount is within the skill of one in the art based on the general guidelines provided herein.

For absorption through the oral membranes, it is often desirable to increase, such as by doubling or tripled the dosage of a pharmaceutical formulation normally required via administration or injection through the gastrointestinal tract. In formulations containing insulin as a pharmaceutical preparation, the amount of insulin administered per dose can be increased up to 10 times because the bioavailability of the sprayed insulin is much lower.

Typically, formulations of the present invention comprise about 0.001-20 wt./wt.%, about 0.1-15 wt./wt.%, about 0.1-10 wt./wt.%, about 0.1-5 wt. will contain the pharmaceutical formulation at a concentration of /wt.%, or about 0.1 to 1 wt./wt.%.

As used herein, the term "pharmaceutical agent" includes a broad spectrum of agents, and may include agents used for both human and veterinary applications, including but not limited to treatment and research. have. The term broadly encompasses proteins, peptides, hormones, vaccines and drugs.

The term "macromolecular" or "large molecule" means a pharmaceutical formulation having a molecular weight greater than about 1000 Daltons, although larger molecules may also be considered, preferably the macromolecules of the present invention Pharmaceutical formulations have a molecular weight of about 2000 to 2,000,000 daltons. As used herein, "dalton" means 1/12 of the nuclear mass of carbon-12 (ie, 1.657 x 10 ^-24 grams, also known as "atomic mass unit").

Preferred pharmaceutical agents include insulin, heparin, low molecular weight heparin (molecular weight less than about 5000 Daltons), hirulog, hirugen, hirudin, interferon, cytokines, mono and polyclonal antibodies , Immunoglobin, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonin, glucagon-like peptides (GLP-1), large molecule antibiotics (ie greater than about 1000 Daltons), protein-based thrombolytic compounds, platelets Large molecule drugs of various sizes, including inhibitors, DNA, RNA, gene therapeutics, antisense oligonucleotides, opioids, narcotics, hypnotics, steroids and analgesics.

Hormones that may be included in the formulation include, but are not limited to, thyroids, androgens, estrogens, prostaglandins, somatotropin, gonadotropins, erythropoietin, interferons, steroids, and cytokines. Cytokines are small proteins with the properties of locally acting hormones, including but not limited to various forms of interleukin (IL) and various forms of transforming growth factor (TGP), fibroblast growth factor (FGF), and insulin- Growth factors, including like growth factor (IGF).

Vaccines that can be used in the formulations according to the invention include vaccines against bacterial and viral vaccines such as hepatitis, influenza, tuberculosis, canary rash, chicken pox, measles, mumps, rubella, pneumonia, BCG, HIV and AIDS; Bacterial toxoids include, but are not limited to, diphtheria, tetanus, Pseudomonas sp., And Mycobacterium tuberculosis. Examples of drugs, more specifically cardiovascular or thrombolytic agents, include heparin, hyrugen, hirulose and hirudin. The pharmaceutical preparations included in the present invention further include monoclonal antibodies, polyclonal antibodies and immunoglobins. It is not limited to these lists.

Pharmaceutical preparations that can be used in the present invention are insulin, very large molecules. As used herein, "Insulin" refers to insulin extracted from naturally extracted human insulin, bovine, porcine or other mammalian sources, recombinantly produced human, bovine, porcine or other mammalian insulin, insulin analogues, insulin Derivatives, and any mixtures of these insulin products. The term further includes insulin polypeptides in substantially purified form or in commercially available forms to which additional excipients are added. Various forms of insulin are widely available commercially. An "insulin analogue" includes any of the insulins defined above, wherein one or more amino acids in the polypeptide chain are replaced with another amino acid, wherein one or more amino acids are deleted, or one or more amino acids are added herein. do. By "derivative" of insulin is meant insulin or an analog thereof in which at least one organic substituent is associated with one or more amino acids in the insulin chain.

As mentioned above, the pharmaceutical preparations are in the form of mixed micelles in the pharmaceutical formulation of the present invention. As will be appreciated by those skilled in the art, micelles may have a polar hydrophobic portion of the molecule extending outwards and conversely a non-polar hydrophobic portion extending inwards, or a hydrophilic-affinity of a micelle-forming compound. It is a colloidal aggregate of amphiphilic molecules inverted depending on the lipid balance and the type of pharmaceutical agent and solvent used. As described below, various combinations of micelle forming compounds are used to achieve the formulations of the present invention. Thanks to both their enhanced absorption capacity and size, the presence of micelles is believed to greatly assist in the absorption of pharmaceutical agents. In addition, encapsulating the pharmaceutical formulation in micelles protects the formulation from rapid degradation in harsh environments.

As used herein, the term “mixed micelle” includes (a) at least two different types of micelles each formed using one or more micelle-forming compounds; Or (b) one type of micelle formed of at least two micelle-forming compounds. For example, the formulations of the present invention may comprise a mixture of at least two different types of micelles: micelles formed between the pharmaceutical formulation and sodium glycocholate and micelles formed between the pharmaceutical formulation and glycerin. However, each micelle may also comprise micelles formed from these two or more micelle-forming compounds. The mixed micelles of the present invention tend to be smaller than the pores of the membrane in the oral cavity. Therefore, the mixed very small size micelles of the present invention are believed to assist the effective encapsulation of the encapsulated pharmaceutical agent through the intraoral mucosa. Thus, the formulations of the present invention often provide an increase in the bioavailability of the active drug as compared to pharmaceutical agents known in the art.

The shape of the micelles can vary, for example, prolate, oblate, or spherical, spherical micelles being the most common.

As mentioned above, the formulations are block copolymers of alkali metal alkyl sulfates, polyoxyethylene and polyoxypropylene, monooleate, polyoxyethylene ether, polyglycerin, lecithin, hyaluronic acid, glycolic acid, lactic acid, chamomile extract, Cucumber extract, oleic acid, linoleic acid, linolenic acid, monoolein, monolaurate, borage oil, evening primrose oil, menthol, lysine, polylysine, triolein, polydocanool Alkyl ethers, kenodeoxycholate, deoxycholate, alkali metal salicylates (eg sodium salicylate), pharmaceutically acceptable edetates (eg disodium edate), and their pharmaceutically acceptable It may further comprise at least one additional micelle-forming compound selected from the group comprising salts and analogs thereof.

If no compatibility problem occurs, any alkali metal alkyl sulphate may be used in the formulation of the present invention. Preferably, alkyl is C8 to C22 alkyl, more preferably lauryl (C12). Any alkali metal can be used, with sodium being preferred.

Particularly preferred block copolymers are those having the formula:

HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H

Where a = 12 and b = 20. This compound is marketed under the trademark PLURONIC L44 by BASF of Mount Olive New Jersey.

Other suitable block copolymers that can be used are those with a = 12 to 101 and b = 20 to 56. For example, useful block copolymers available from BASF include the trademarks PLURONIC F68 (where a = 80; b = 27), PLURONIC F87 (here a = 64; b = 37), PLURONIC F108 (where a = 141 b = 44 ), And PLURONIC F127 (where a = 101 b = 56).

The lecithin may be saturated or unsaturated, and is preferably selected from the group consisting of phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, and lysolecithin.

Preferred salts of hyaluronic acid are alkali metal hyaluronates, in particular sodium hyaluronate, alkaline earth hyaluronate, and aluminum hyaluronate. When using hyaluronic acid or their pharmaceutically acceptable salts in the formulations of the invention, concentrations between about 0.001 and 5 wt./wt.% Of the total formulation are preferred, and more preferably about 3.5 wt./wt.% Is less than.

For the delivery of pharmaceutical preparations of the invention, in particular very large molecules such as insulin, the use of three or more micelle-forming compounds is preferred, as compared to when only one or two micelle-forming compounds are used. This is because a cumulative effect is achieved in which the amount of pharmaceutical agent that can be delivered is greatly increased. The use of three or more micelle-forming compounds also improves the stability of the pharmaceutical formulation formulation.

Particularly suitable micelle-forming compound combinations are i) block copolymers of polyoxyethylene and polyoxypropylene, glycerin, sodium glycocholate, and sodium lauryl sulfate; ii) polyoxyethylene ether, glycerin, sodium glycocholate, and sodium lauryl sulfate; iii) glycerin, sodium glycocholate and polyoxyethylene sorbitan monooleate; iv) glycerin, sodium glycocholate, sodium lauryl sulfate and oleic acid; v) kenodeoxycholate, sodium glycocholate, sodium lauryl sulfate, and glycerin; vi) deoxycholate, sodium glycocholate, sodium lauryl sulfate, and glycerin; vii) glycerin, sodium glycocholate, sodium lauryl sulfate, deoxycholate, and lactic acid; vii) glycerin, sodium lauryl sulfate and sodium glycocholate; And viii) each of glycerin and sodium glycocholate.

It will be understood that some micelle-forming compounds are generally described as fatty acids, bile acids, or salts thereof. The best micelle-forming compound for use may vary depending on the pharmaceutical formulation used and can be readily determined by one skilled in the art. In general, bile salts are particularly suitable for use with hydrophilic drugs, and fatty acid salts are particularly suitable for use with lipophilic drugs. Because the present invention uses relatively low concentrations of bile salts, the toxicity issues associated with the use of such salts are minimized if this is unavoidable.

The components of the formulations of the invention described above are contained in a suitable solvent. As used herein, the term "suitable solvent" means any solvent that can be dissolved in the components of the present invention, does not cause compatibility problems, and can be administered to a patient. Any suitable aqueous or non-aqueous solvent may be used, such as water and alcohol solutions (eg ethanol). Alcohol should be used at a concentration that will avoid precipitation of the components of the formulations of the present invention. Sufficient solvent must be added so that the sum of all components in the formulation of the invention is 100 wt./wt.%, I.e. the solvent is in an appropriate amount (q.s.). Typically, a portion of the solvent will be used initially to solubilize the pharmaceutical formulation prior to the addition of the micelle-forming compound. Embodiments of pharmaceutical formulations comprising insulin employ an aqueous solvent. The pH of the solution is typically in the range of 5-8, 6-8, or 7-8. If necessary, hydrochloric acid or sodium hydroxide may be used to adjust the pH of the formulation.

Formulations of the present invention optionally include stabilizers and / or preservatives (eg, sodium benzoate and phenolic compounds). Phenolic compounds are particularly suitable for this purpose because they not only stabilize the formulation, but also protect against bacterial growth. Phenolic compounds are also believed to aid in the absorption of pharmaceutical agents. Phenolic compound will be understood to mean a compound having at least one hydroxy group attached directly to the benzene ring. Preferred phenolic compounds according to the invention include phenol, o-cresol, m-cresol, and p-cresol, with phenol and m-cresol being most preferred.

Formulations of the present invention may further comprise one or more of the following: inorganic salts, antioxidants, protease inhibitors, and isotonic agents. The amount of any of these optional components for use in the formulations of the present invention can be determined by one skilled in the art. Those skilled in the art will appreciate that non-therapeutic amounts of colorants, flavoring agents and other compounds may be included in the formulation. Common flavoring agents are menthol, sorbitol, and fruit flavors. When menthol is used as one of the micelle-forming compounds, it will also give a flavor to the composition.

In formulations comprising insulin, an inorganic salt may be added so that open channels in the GI tract provide additional stimulation to release insulin into the body. Non-limiting examples of inorganic salts are the sodium, potassium, calcium and zinc salts, in particular sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate. In use, inorganic salts are typically at a concentration of about 0.001 to 10 wt./wt.% Of the total formulation.

Those skilled in the art will recognize that for many pharmaceutical formulations, although optional, it is common to add at least one antioxidant to prevent degradation and oxidation of the pharmaceutically active ingredient. Antioxidants can be selected from the group consisting of tocopherol, deteroxime mesylate, methyl parabens, ethyl parabens, ascorbic acid, and mixtures thereof, and other antioxidants known in the pharmaceutical art. Preferred antioxidant is tocopherol. Parabens will also impart shelf life to the formulation. In use, the antioxidant is typically at a concentration of about 0.001 to about 10 wt./wt.% Of the total formulation.

Protease inhibitors function to inhibit degradation of pharmaceutical agents by the action of proteolytic enzymes. In use, the protease inhibitor is preferably at a concentration of about 0.1 to about 3 wt./wt.% Of the total formulation. Any substance that can inhibit proteolytic activity and has no compatibility problem can be used. Examples include, but are not limited to, bacitracin and bacitracin derivatives such as bacitracin methylene dissalicylate, soybean trypsin, and aprotinin. Bacitracin and its derivatives are preferably used at a concentration of 1.5 to 2 wt./wt.% of the total formulation, while soybean trypsin and aprotinin are preferably used at about 1 to 2 wt./wt. Used in concentrations of%.

Isotonic agents, such as glycerin or dibasic sodium phosphate, may also be added after formation of the mixed micellar formulation. Isotonic agents function to preserve micelles in solution. When glycerin is used as a micelle-forming compound, it may function as an isotonic agent. If dibasic sodium phosphate is used, it may also function to inhibit bacterial growth.

Formulations of the present invention may be stored at room temperature or at low temperatures (ie, about 2-8 ° C.). It is desirable to store proteinaceous drugs at low temperatures in order to prevent degradation of the drug and to prolong its shelf life.

Therefore, the present invention provides new novel pharmaceutical formulations in which the pharmaceutical formulation is encapsulated in mixed micelles formed by a combination of micelle-forming compounds. The formulation can be delivered through an oral membrane, such as the pharynx, sublingual and buccal mucosa. The pharyngeal mucosa is the upper part of the throat located inside the posterior end of the oral cavity, i.e. under the soft palate and above the larynx, the sublingual mucosa comprises the membranes of the anterior side of the palate and tongue and the buccal mucosa to be. The pharynx, sublingual and buccal mucosa are very vascular, permeable, and allow for rapid absorption and excellent bioavailability of many drugs. Compared with the gastrointestinal tract and other tissues, the oral environment has low enzymatic activity and neutral pH, which allows for longer and effective life of the drug in vivo. The pharynx, sublingual, tongue, palate and buccal mucosa are referred to herein as "oral mucosae" throughout.

Absorption of pharmaceutical agents through the oral mucosa can be achieved by avoiding the first pass-through effect of drug degradation and hepatic metabolism in adverse gastrointestinal environments, easy and convenient access to the membrane site; And a pain free form of administration (as compared to administration by subcutaneous injection).

Preferably, the formulations of the present invention are delivered via an aerosol or non-aerosol dispenser that enables delivery of the correct amount of medicament in each application. The aerosol dispenser is filled with a pharmaceutically acceptable propellant. Such dispensers are known for pulmonary drug delivery for some drugs (eg, asthma drugs). Non-aerosol dispensers include spray pumps and drop dispensers.

One of the advantages of using a metered dose aerosol dispenser is that the potential for contamination is minimized because the dispenser is self-contained. In addition, propellants provide improved penetration and absorption of the mixed micellar formulations of the present invention. These include C ₁ to C ₂ dialkyl ethers, butanes, fluorocarbon propellants, hydrogen-containing fluorocarbon propellants, chlorofluorocarbon propellants, hydrogen-containing chlorofluorocarbon propellants, other non-CFCs and CFCs Propellants, and mixtures thereof. Examples of suitable propellants include tetrafluoroethane (eg, HFA 134a which is 1,1,1,2 tetrafluoroethane), heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane , Dimethyl ether and diethyl ether.

The propellant is a liquid under pressure, causing the pharmaceutical formulation to be sprayed with a fine spray from a metered dose aerosol dispenser. The dispenser preferably has a metered dose valve having an associated metering chamber of at least about 10, 50, 250, 540 or 570 μl and of a size of about 660 or 630 μl or less. In embodiments comprising insulin, the valve preferably has a size of about 540-660 μl, but the size may be as small as 50 μl.

The amount of propellant added to the metered dose aerosol dispenser will depend on a number of factors including the size of the pressurized container and the amount of pharmaceutical formulation contained therein. The amount of propellant is chosen to provide administration of an appropriate amount of pharmaceutical agent per actuation, while avoiding undesirable consequences such as foaming. In one embodiment where the pharmaceutical formulation is insulin, the amount of pharmaceutical formulation is 50, 67, 71, 77, or 83 parts per 1000 parts of the total composition (ie, pharmaceutical formulation plus propellant) in the container. Preferably, the amount of pharmaceutical formulation is 91 parts or less per 1000 parts of total composition in the container.

The amount of pharmaceutical agent released per dispenser or drive of the dispenser depends on a number of factors including the amount and nature of the pharmaceutical formulation in the container, the amount and nature of the propellant in the container, the size of the container and the size of the metering valve of the dispenser. So it will be different.

Formulations of the present invention may be prepared by mixing micelle-forming compounds and optionally stabilizers and other additives with pharmaceutical agents in a suitable solvent. The compounds may be added in one step or sequentially. If added sequentially, they can be added in any order solubility problems do not occur. Mixed micelles will be formed from virtually any form of mixing of the components, but vigorous mixing is preferred to provide micelles of about 7 to 11 microns in size. The vigorous mixing can be carried out using a high speed stirrer such as a magnetic stirrer, a propeller stirrer or a sonicator.

In one embodiment, Solution III, a pharmaceutical formulation comprising insulin, is prepared by making two solutions, Solutions I and II, and then mixing them together with a solvent according to the following protocol.

Preparation of Solution I

Solution I, a large insulin solution containing 200 units of insulin, was prepared as follows. The absolute amount of each component in solutions I, II and III can be calculated based on the final batch size of solution III. Note that the amount of insulin units per mg of commercial insulin differs from commercial insulin products, which are generally about 25.3 to 28.3 units per mg of insulin. Knowledge of the number of units per mg can be readily determined from the product specification.

Step-1

10 ± 5 w / w% injection water is added to an appropriately sized beaker with a magnetic stir bar.

↓

Step-2

Slowly drop 5M NaOH into the beaker until the target pH of 12.5 is reached.

↓

Step-3

200 units of synthetic human insulin crystals (prepared using rDNA) were added.

↓

Step-4

Stir the solution and avoid vortex until the insulin is completely dissolved (the pH of the solution should be 7-8)

↓

Step-5

If necessary, adjust pH with 5M NaOH or 7M HCl until solution pH reaches 7-8.

solution II Manufacture

Solution II is an aqueous solution of micelle-forming compound to be added to Solution I.

Step-1

50 ± 5 w / w% water for injection is added to an appropriately sized beaker with a magnetic stir bar.

↓

Step-2

Slowly add 0.25 w / w% glycerin to the beaker with continuous slow stirring.

↓

Step-3

Add 0.06 w / w% sodium glycocholate and continue stirring until dissolved.

↓

Step-4

Add 0.02 w / w% sodium lauryl sulfate and continue stirring until dissolved.

↓

Step-5

2.00 w / w% of a block copolymer of polyoxyethylene and polyoxypropylene having the following formula was added and stirring was continued until dissolved:

HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H

Where a = 12 and b = 20 (sold under the trademark PLURONIC L44 by BASF).

Preparation of Insulin Formulation (Solution) III )

Solution III is a pharmaceutical formulation according to one embodiment of the invention. It is prepared as follows.

Step-1

Add solution I and solution II.

↓

Step-2

↓

Check the pH of the solution and, if necessary, until the pH of the solution is between 7 and 8

Adjust pH with 5M NaOH or 7M HCl.

↓

Step-3

Fill with water for injection to final batch size (Q. S.).

↓

Step-4

Transfer the solution to a storage beaker and stir the solution for about 5 minutes. Store at 2-8 ° C.

solution III Metered dose aerosol comprising dispenser

According to one aspect, the invention also provides a metered dose aerosol dispenser comprising a formulation according to the invention (eg solution III).

In one embodiment, the present invention employs the metered dose aerosol dispenser shown in FIGS. The metered dose aerosol dispenser 10 includes an actuator 12, a 28 ml aluminum aerosol can 14, and a metering valve 16. 2 ml of solution III is introduced into the aerosol can 14 according to known methods. Can 14 is then also filled with about 27.06 g of HFA-134a propellant in a known manner.

The aerosol can 14 is best shown in FIGS. 2-4. The aerosol can 14 is preferably cylindrical with an open end 18. The opening end 18 is configured to have a size that matches the ferrule (described below) of the metering valve 16. Can 14 is aluminum in this embodiment, but stainless steel may also be used.

In connection with FIGS. 3 and 4, the metering valve 16 comprises a three-slot housing 20 with a stem 22 slidably included in the housing. Preferred materials for the three-slot housing 20 and stem are polyesters, and acetal resins may also be used. The metering valve 16 is configured to be sized to fit the outer circumference of the opening end 18 of the aerosol can 14, crimped around the end 18 to secure the metering valve to the can. 24) is also included. Preferred material for ferrules is aluminum. The sealing gasket 26 imparts a seal between the open end 18 of the can and the ferrule 24. Preferred materials for sealing gaskets are Nitrile (Buna) rubbers. The metering chamber 28 in the three slot housing 20 is defined between the first stem gasket 30 and the second stem gasket. Preferred materials for the first and second stem gaskets are nitrile (bunna) rubbers. The stem comprises an upper stem and a lower stem, the upper stem having a U-shaped retention channel 34 having ends 36 and 38, and the lower stem having channels 40 and ends 42. Has The principle of retention is in a special shape at the base of the stem, which allows for the passage of the fluid under differential pressure from the aerosol can to the valve metering chamber after driving, although the fluid is aerosolized by capillary action of the retention channel Prevent return to cans (due to gravity).

The stem 22 moves between the stop (closed) position and the open position. In the rest position shown in FIG. 3, the inlet end 36 of the retention channel 34 is above the first stem gasket 30 so that the contents of the aerosol can 14 can enter the retention channel 34. . The outlet end 38 of the retention channel 34 is below the first stem gasket 30 and in the metering chamber 28. Both the inlet end 42 and the outlet end 44 of the channel 40 are outside the metering chamber 28, thereby preventing the passage of fluid from the metering chamber 28 to the channel 40. In the open position shown in FIG. 4, both the inlet end 36 and the outlet end 38 of the retention channel 34 are above the first stem gasket 30 of the metering chamber 28, whereby the aerosol can Prevent all fluid flow from 14 to metering chamber 28. At the same time, the inlet end 42 of the channel 40 is above the second stem gasket 32 and inside the metering chamber 28, thereby passing the fluid from the metering chamber 28 through the passage 40. Allow. The stem 22 is biased to the rest position of FIG. 3 by the spring 46. The metering chamber 28 in the metering valve 16 may hold a total volume of approximately 600 μl. Large molecules, such as insulin, are poorly absorbed through the epithelial membrane, are easily degraded by enzymes found in saliva, and are also relatively insoluble, requiring large dosages. Therefore, more drugs need to be delivered to the buccal cavity to compensate for this loss.

The actuator assembly 12 is best shown in FIGS. 1, 3, and 4. Actuator 12 includes a mouthpiece 50, a stem block 48, and an actuator sump 52. The actuator catcher 52 located in the stem block 48 has an inner end 54 configured to be sized to receive the lower end 56 of the valve stem 22 and an outer end 58 called a spray orifice. Include. The spray orifice of the actuator catcher 52 is configured to be sized to deliver the drug toward the buccal cavity and back of the throat. The spray orifice 58 may have a rounded shape, or may have an elliptical, rectangular or similar extended shape, thereby sending the drug to both sides of the mouth and increasing the likelihood that the drug is applied to the buccal cavity. Some preferred embodiments have a spray orifice 58 having a diameter of approximately 0.58 to 0.62 mm. The preferred configuration for the actuator catcher 52 is a substantially reduced volume of 45 mm ³ or less. More preferred actuator catchers have a volume of up to 42 mm ³ and ideally actuator actuators have a volume of up to 37 mm ³ . The sump volume given above will be sufficient to create a high pressure stream of fluid upon driving the metered dose aerosol dispenser.

The actuator 12 may also include a cap 60 that fits the actuator 12 and the aerosol can 14. The cap 60 is preferably mounted to the actuator and is slidable and removable. One method of slidably and removably mounting the cap 60 to the actuator 12 is by friction, thereby removing the cap 60 and the actuator 12 by simply pushing up on the cap 60 or Enable reattachment. Actuator 12 may also include a dust cover 68 configured to cover the mouthpiece 50.

In this embodiment, the propellant under pressure is in liquid form in the can and forms a single phase with solution III. However, in other embodiments where the ratio of pharmaceutical formulation and propellant differs, the aqueous phase may be separated from the propellant phase. In such cases, it is desirable for the user to shake the dispenser before dispensing some of the content.

When the actuator is driven, solution III with insulin can be propelled with a fine spray from the metered dose valve. In this embodiment, about 7 to 13 units of insulin (average 10 units) are released per run. This corresponds to about 0.27 mg to about 0.50 mg of insulin dispensed per run.

Further description regarding metered dose aerosol dispenser 10 and solution III is summarized in Table 1 below.

Other of the formulation Embodiment

Other embodiments of the formulations according to the invention are summarized in the table below. In these tables, POE (9) is polyoxyethylene 9 lauryl ether.

Dosing method

The invention also provides a method for administering a pharmaceutical formulation of the invention by spraying the formulation into the mouth with a metered dose dispenser (aerosol or non-aerosol). The following examples are intended to illustrate the method of the invention in detail and should not be construed as limiting the invention in any way.

Example I

A study was conducted to determine the difference in the pharmacokinetic / pharmacodynamic (PK / PD) profile of Solution IV when given in single versus discrete doses near the meal. Study with injected insulin, Humulin ™ brand insulin (recombinant human insulin sold by Eli Lilly and Company) to compare the bioavailability and glucodynamic profiles of solutions IV and V (provided in separate administration) Also done. This study relates to the following phases.

Transition phase ( transfer phase )

In this phase, the appropriate dose for each patient was determined by giving 19 patients who met the condition (i.e., meeting certain health criteria) with a varying dose of Solution IV over three days:

On the first day, patients were given 16 puffs of solution IV administered over a period of 8 minutes just before the test meal (standardized meal of liquid, Ensure Plus: 20 kCal / kg ideal body weight) and a total of 16 puffs 1 puff was administered every 30 seconds for. Glucose monitoring immediately before test meal (-30 minutes), immediately before test meal (0 minutes), and at 5, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes after breakfast test administration Done.

On the second day of this phase, patients were given a single dose of 13 puffs of Solution IV administered over a time period of 6.5 minutes just prior to the test meal and 1 puff every 30 seconds. Glucose levels were monitored as the day before.

On the third day of this phase, patients were given a single dose of 10 puffs of Solution IV administered over a 5 minute time period just prior to the test meal, with 1 puff every 30 seconds. Glucose levels were monitored as the day before.

None of the patients who were administered 16 puffs and had glucose levels of 200 mg / dL or three consecutive levels higher than 180 mg / dL at any time participated in the Crossover Treatment Phase.

Crossover Treatment phase

In this phase, the 19 patients were exposed to each of the following four treatment regimens on another day:

Humulin ™ brand insulin (injected insulin)

Single solution IV-pre-meal

Solution IV separate dosing-1/2 pre and post meal

Solution V separate dosing-1/2 pre and post meal

Each treatment regimen was administered over 24 hours.

Single dose regimens involve administering 16 puffs of Solution V over 8 minutes, with 1 puff every 30 seconds. The first puff was timed so that the last puff was received 30 seconds before the test meal.

Regarding the separate dosing regimen for Solution IV, Solution IV was administered 4 minutes prior to meal for the first 1/2 dose (1 puff every 30 seconds, between the last puff and the test meal, for a total of 8 puffs). Every 30 seconds). Immediately after the standardized meal, the patients were given two sips of water and given a second 1/2 dose (8 puffs every 30 seconds) starting approximately 2 minutes after the meal was completed.

Regarding the separate dosing regimen for Solution V, Solution V was administered 4 minutes prior to meal for the first 1/2 dose (1 puff every 30 seconds, for the entire 8 puffs, between the last puff and the test meal). Every 30 seconds). Immediately after completing a standardized meal, the patient is given two sips of water and given a second 1/2 dose (1 puff every 30 seconds for a total of 8 puffs) beginning about 5 minutes after the meal is completed. did.

Each of the puffs of Solution IV contained, on average, about 50 units of insulin.

Each of the puffs of Solution V contained about 25 units of insulin on average.

For comparison, five units of Humulin ™ brand insulin were injected 15 minutes before meals to 19 patients in the same group on different days.

During the crossover treatment phase, patients consumed three standardized meals (standardized meal of liquid, Ensure Plus: 20 kCal / kg ideal body weight) in each of the treatment periods. The standardized meal was consumed in four equal amounts over 30 minutes.

During each treatment period, the breakfast test dose -30 minutes, immediately before the breakfast test dose (0 minutes), and 5, 15, 30, 45, 60, 90, 120, 150, 180, 210, And blood samples were extracted at 240 minutes. Glucose and insulin levels were measured for each blood sample.

Average blood glucose levels for each group were plotted in the graph shown in FIG. 5. In this graph, the blue line represents Solution IV provided as a separate dose, the green line represents Solution V provided as a separate dose, the orange line represents Solution IV provided as a single dose, and the black line (circular point) is used for injection. Humulin brand insulin provided by.

As can be seen in this figure, solutions IV and V are effective in regulating blood glucose levels, and separate administration of solution IV showed slightly better results than single administration of solution IV.

Example II

A 12-day study was conducted to compare the efficacy of injected insulin with Solution III and to evaluate the stability and tolerability of Solution III. The study compared the effect of blood glucose levels of Solution III administered intranasally with the metered dose aerosol dispenser described above with the effect of blood glucose levels of injected insulin. Fructosamine, a parameter of protein glycosylation, was determined as part of a panel of safe monitoring.

Ten patients with type 1 diabetes, whose glucose levels were below 140 mg / dL and one hour postprandial glucose levels below 200 mg / dL during two consecutive fasts, participated in this study.

During the 12-day study period, patients received conventional baseline glargine insulin treatment (2/3 in the morning and 1/3 in the evening).

On the first three days, each patient received three meals each: a routine of Humulin ™ brand insulin (recombinant human insulin sold by Eli Lilly and Company) by injection 30 minutes prior to breakfast, lunch, and dinner. Phosphorus administration. The amount of insulin injected differed from patient to patient based on 0.1 unit of insulin per kilogram of body weight. Patients were also allowed mid-morning and mid-afternoon snacks and had the option of administering up to 4 units at the snack time. Patients who chose dosing treatment at snack time recorded the snack time dose on a personal diary card.

On days 4-12, each patient received 5-8 puffs of solution III, before and after each meal (breakfast, lunch, dinner), based on their recommended dosage (as determined by previous experiments). . Solution III was administered buccally using the metered dose aerosol dispenser described above. If the measured glucose value exceeded 100 mg / dL between 30 and 60 minutes after the last meal, an additional single dose following each meal was allowed for immediate administration up to 4 puffs. Thus, the total maximum dose of Solution III for each meal was 20 puffs (or up to 60 puffs per day).

In addition to three meals a day, patients were allowed snacks in the morning and afternoon. Patients were administered up to 5 puffs (eg 2 puffs before snacks and 2 or 3 puffs after snack) at snack time in divided doses.

Each of the puffs of Solution III contained, on average, about 10 units of insulin.

On all 12 days, blood samples were extracted 30 minutes before breakfast and 4 hours after breakfast. A standardized meal (Ensure Plus: 4.8 kCal / kg ideal body weight) was fed for breakfast at 8 am (0 min). Blood samples were extracted at breakfast -30 minutes, immediately before breakfast (0 minutes), and at 5, 15, 30, 45, 60, 90, 120, 150, 180, 210, and 240 minutes after breakfast. Peripheral glucose concentrations were measured twice by Roche Accu-Check system. Two measurements of glycated hemoglobin (HbAl _{c- II} ) and fructosamine were obtained using locale commercial analysis.

The study protocol required preprandial glucose levels to be less than 100 mg / dL. Thus, adjustment of blood glucose levels in the morning and afternoon was done using conventional snacks, additional subcutaneous injections of Humulin ™ brand insulin or puffs of Solution III, as described above.

The mean blood glucose concentration from this study was plotted in the graph shown in FIG. 6. In this figure, the dark lines represent the mean blood glucose concentrations for 10 patients as a function of time, averaged over the first 3 days, with insulin administered between them. The red line represents the mean blood glucose concentration for 10 patients as a function of time, averaged over 4 to 12 days, during which Solution III was administered using the metered dose aerosol dispenser described above.

6 shows that injected insulin and Solution III of the Humulin ™ brand induce similar glucodynamic responses. Solution III provided adequate glycemic control as assessed by the individual daily-glycemic curve, in particular normal preprandial glycemia. Determination of protein void glycosylation showed a trend towards lower values after the 12-day study period. This suggests that solution III is safe for long term use.

Example III

When provided in single versus discrete doses near a meal, similar to that described in Example I to determine the difference in the pharmacokinetic / pharmacodynamic (PK / PD) profile of solution XIV (described in Table 6 above) The study was conducted. To compare the bioavailability and glucodynamic profiles of solution XIV, the study was also conducted with injected insulin, Humulin ™ brand insulin (recombinantly produced human insulin sold by Eli Lilly and Company). In this study, 19 patients described in Example I and the same protocol were adopted.

The results are plotted in the graph shown in FIG. This figure shows that Solution XIV produces better glucodynamic profiles when administered in separate doses than the profile produced by the administration of a single dose of Solution XIV before each meal. In addition, the study found that administering solution XlV in separate doses resulted in lower postprandial glucose levels than levels achieved through the administration of a single dose of insulin injected before each meal or a single dose of solution XlV. It indicates coming. High postprandial blood glucose levels have been identified as a risk factor for cardiovascular disease, and adopting separate dosing regimens may serve to minimize this risk.

While specific embodiments of the invention have been described above for the sake of detailed description, it will be apparent to those skilled in the art that various modifications may be made to the description of the invention without departing from the invention defined in the appended claims.

Claims (23)

A pharmaceutical formulation for absorption through the oral mucosa, comprising an effective amount of (a) a pharmaceutical preparation in mixed micellar form, (b) an alkali metal alkyl sulphate and polyoxyethylene sorbitan monooleate At least one micelle-forming compound selected from the group comprising: (c) block copolymers of polyoxyethylene and polyoxypropylene, (d) trihydroxyoxocollanyl glycine and salts thereof, glycerin, poly Glycerin, Lecithin, Hyaluronic Acid, Glycolic Acid, Lactic Acid, Chamomile Extract, Cucumber Extract, Oleic Acid, Linoleic Acid, Linolenic Acid, Monoolein, Monooleate, Monolaurate, Borage Oil ) Evening primrose oil, menthol, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ether, polydocanol alkyl ether, kenodeoxycholate, deoxycholate, At least one additional micelle-forming compound selected from the group comprising kali metal salicylates, pharmaceutically acceptable edetates, and pharmaceutically acceptable salts and analogs thereof, and (e) suitable solvents Pharmaceutical formulations. The pharmaceutical formulation according to claim 1, wherein the salt of trihydroxyoxocolalanyl glycine is sodium glycocholate. The pharmaceutical according to claim 1 or 2, wherein the polyoxyethylene sorbitan monooleate is (x) -sorbitan mono-9-octadecenoate poly (oxy-l, 2-ethanediyl) monooleate Formulation. The pharmaceutical formulation according to any one of claims 1 to 3, wherein the alkali metal alkyl sulfate is sodium lauryl sulfate. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the block copolymer of polyoxyethylene and polyoxypropylene has the following formula. HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H Where a = 12 and b = 20. The method according to claim 1, wherein the at least one additional micelle-forming compound is sodium glycocholate, glycerin, lecithin, oleic acid, monooleate, polyglycerine, polyoxyethylene ether, kenodeoxycholate, des. Pharmaceutical formulations selected from the group comprising oxycholate, lactic acid and their pharmaceutically acceptable salts and analogs. The pharmaceutical formulation of claim 1, wherein the at least one additional micelle-forming compound is selected from the group comprising sodium glycocholate, glycerin, and polyoxyethylene ether. The pharmaceutical formulation of claim 1 comprising glycerin, sodium glycocholate, sodium lauryl sulfate, and a convex copolymer of polyoxyethylene and polyoxypropylene having the formula: HO (C ₂ H ₄ O) _a (C ₃ H ₆ O) _b (C ₂ H ₄ O) _a H Where a = 12 and b = 20. The pharmaceutical formulation of claim 1, wherein the micelle-forming compound is present at a concentration of about 0.001 to 20 wt./wt.%, Respectively. 10. The pharmaceutical formulation of claim 9, wherein the convex copolymer of polyoxyethylene and polyoxypropylene is present at a concentration of about 0.001 to 3 wt./wt.%. The pharmaceutical formulation of claim 9, wherein the micelle-forming compound is present at a concentration of about 0.001 to 1 wt./wt.%, Respectively. The pharmaceutical formulation of claim 1, wherein the micelle size of the pharmaceutical formulation is at least about 7 microns (μm). The pharmaceutical formulation of claim 1, wherein the micelle size of the pharmaceutical formulation is about 11 microns (μm) or less. The method according to any one of claims 1 to 13, wherein the pharmaceutical formulation is insulin, heparin, low molecular weight heparin (molecular weight less than about 5000 daltons), hirulog, hirugen, hirudin , Interferon, cytokines, monoclonal and polyclonal antibodies, immunoglobins, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonin, glucagon-like peptides (GLP-1), large molecule antibiotics (ie Greater than about 1000 Daltons), protein-based thrombolytic compounds, platelet inhibitors, DNA, RNA, gene therapy, antisense oligonucleotides, opioids, drugs, hypnotics, steroids and analgesics Pharmaceutical formulation. The pharmaceutical formulation of claim 14, wherein the pharmaceutical formulation is insulin. The pharmaceutical formulation of claim 15, wherein said insulin is present at a concentration of about 0.1 to 12 wt./wt.%. The pharmaceutical formulation of claim 16, wherein the insulin is present at a concentration of about 0.1 to 1 wt./wt.%. A metered dose non-aerosol dispenser comprising the pharmaceutical formulation of any one of claims 1 to 17. A metered dose aerosol dispenser comprising the pharmaceutical formulation of any one of claims 1 to 17 and a pharmaceutically acceptable propellant. The method of administration of the pharmaceutical formulation of claim 1, comprising spraying the pharmaceutical formulation into the oral cavity of the patient. The method of claim 20, wherein the pharmaceutical formulation of the pharmaceutical formulation is insulin and about 35 to 104 units of insulin are sprayed before and after each meal. 22. The method of claim 20 or 21, further comprising spraying about 14 to about 65 units of insulin into the oral cavity before and after the snack. 22. The method of any one of claims 19-21, wherein the pharmaceutical formulation is sprayed intobetween meals.

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