Title:  Solid solution beadlet

United States Patent:  6,692,767

Issued:  February 17, 2004

Inventors:  Burnside; Beth A. (Silver Spring, MD); McGuinness; Charlotte M. (Bethesda, MD); Rudnic; Edward M. (North Potomac, MD); Couch; Richard A. (Bethesda, MD); Guo; Xiaodi (Derwood, MD); Tustian; Alexander K. (Bothell, WA)

Assignee:  Shire Laboratories Inc. (Rockville, MD)

Appl. No.:  156464

Filed:  September 18, 1998

Abstract

Disclosed is a beadlet comprising (i) a hydrophobic long chain fatty acid or ester material; (ii) a surfactant; and (iii) a therapeutic agent which in admixture form a solid solution at room temperature. The hydrophobic material preferably has a melting point of about 40 to about 100^oC., and is most preferably glyceryl behenate. The surfactant is preferably a polyglycolyzed glyceride, polyoxyethylene sorbate, ethylene or propylene block copolymer or combinations thereof, and is most preferably polyoxyethylene 20 sorbitan monolaurate.

SUMMARY OF THE INVENTION

In accordance with an aspect of the present invention, there is provided a composition including at least one therapeutic agent and a pharmaceutically acceptable carrier in the form of a solid beadlet wherein the beadlet includes a acceptable carrier in the form of a solid beadlet wherein the beadlet includes a combination of at least one hydrophobic long chain fatty acid or fatty acid ester and at least one surfactant. The hydrophobic long chain fatty acid or ester thereof and surfactant are present in the beadlet as a solid solution. The therapeutic agent is dispersed in the solid beadlet and is present in the composition in a therapeutically effective amount, with such amount generally being at least 0.001%, by weight, of the composition.

The hydrophobic long chain fatty acid or ester thereof is generally present in an amount of at least 20% with such material in most cases being present in an amount no greater than 97%, by weight.

The beadlet(s) generally has a particle size that does not exceed 1000 microns. In most cases, the particle size is at least 50 microns. In one embodiment, the particle size does not exceed 500 microns. In another embodiment, the particle size is from 100 to 350 microns.

In a preferred embodiment, the surfactant is one that is liquid at room temperature in that a liquid surfactant in the composition of the invention provides for improved drug delivery.

The surfactant may comprise at least 3% of the core beadlet formulation and in many cases exceeds 10% of the core beadlet formulation all by weight.

The beadlet is preferably in the form of a solid solution wherein the therapeutic agent is dissolved in the hydrophobic material.

In one aspect, the invention provides a solid solution beadlet (used synonymously with granule or particle) comprising (i) at least about 20% by weight of a hydrophobic long chain fatty acid or ester material; (ii) from about 3% to about 40% by weight of a surfactant; and (iii) from about 1% to about 70% by weight of a therapeutic agent, which in admixture form a solid solution at room temperature.

The long chain acids used as an acid or ester generally include at least 12 carbon atoms and generally do not include more than 22 carbon atoms. The acids may be saturated or unsaturated and generally are aliphatic long chain acids. When used as an ester, the ester is preferably a glycerol ester. The ester may be a mono-, di or tri-ester of glycerol.

The hydrophobic material is preferably oleic acid, gadoleic acid, eurcic acid, linoleic acid, linolenic acid, ricinoleic acid, riachidonic acid, glycerol esters of the foregoing acids, or glycerol behenate.

The hydrophobic material preferably has a melting point of from about 40 to about 150^oC., and is most preferably glyceryl behenate (e.g. Compritol.TM. from Gattefosse Inc., France). The surfactant is preferably selected from the group consisting of polyglycolyzed glycerides, polyoxyethylene sorbates, ethylene or propylene block copolymers or combinations thereof, and is most preferably polyoxyethylene 20 sorbitan monolaurate or Labrasol.RTM., a polyglycolized glyceride (Gattefosse, France). The beadlet can further include sodium C₉ -C₃₀ alkyl sulfate or citric acid. The beadlet can also contain a glidant (such as fumed silicon dioxide) to improve tabletting properties. Typically preferred therapeutic agents include acyclovir, acyclovir and at least one additional antiviral agent, dihydroergotamine or methylphenidate.

In another preferred embodiment the beadlets are coated with an immediate release coating, such as Opadry.RTM.I (hydropropylmethylcellulose, i.e., HPMC) and Opadry.RTM.-II (HPMC, maltodextrin and propyleneglycol) from Colorcon, Inc. (West Point, Pa.) or Aquateric.RTM. (cellulose acetate phthalate enteric polymer) from FMC, Inc. (Philadelphia, Pa.).

Another embodiment provides pharmaceutical compositions of a plurality of coated or uncoated single phase solid solution beadlets in a pharmaceutically acceptable carrier. The composition can be, for example, in the form of a tablet (optionally coated, such as with an enteric coating), buccal tablet, sublingual tablet, capsule or other oral dose delivery forms.

The oral delivery form can also be coated, if desired, with various protective coating materials or with materials that control the rate or location of release in the patient. This can be done by known methods using such known materials.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The delivery system of the invention can be used to provide rapid controlled release of any of a broad variety of therapeutically active agents. Examples include the following: cough suppressants, such as dextromethorphan hydrobromide and codeine; antibiotics such as cephalosporin; antihistamines such as chlorpheniramine maleate, brompheniramine maleate, loratidine, astemizole, diclofenac sodium and terfenadine; decongestants such as pseudoephedrine and phenylephrine; antihypertensives such as ACE-inhibitors, verapamil, nifedipine, propanolol, metoprolol, metoprolol succinate, metoprolol fumarate, metoprolol, methylphenadate, tartarate; agents to treat attention deficit disorder/hyperactivity such as methylphenadate, d and/or 1 isomers of methylphenadate, amphetamines, d and/or 1 isomers of amphetamines, and combinations of amphetamines; calcium channel blockers such as verapamil, diltiazam, nifedipine, nimodipine, felodipine, nicardipine, isradipine and amlodipine; antidiabetic agents such as glipizide and ibromectin; proton pump inhibitors such as omeprazole; anti-convulsants and anti-epileptics such as valproate sodium, clonazepam, gabapetin, and topiramate; anti-depressives such as buspirone, fluoxeline, 5-hydroxytryptamine receptor agonist and antagonist; anti-migraines such as sumatreptan and dihydroergotamine; antipsychotics such as resperidone; antiemetics such as ondansetron; anti-heartburns such as cisapride; H2 receptor antagonists such as cimetidine, ranitidine, famotidine, nizatidine; carbamazepine; beta adrenergic receptor blockers; anti-Parkinson agents such as selegiline, carbidopa/levodopa, pergolide, bromocriptine, amantadine, trihexyphenidyl HCl; antiviral agents including antiherpesvirus agents such as acyclovir, famciclovir, valcyclovir, foscamet, ganciclovir; antiretroviral agents such as didanosine, stavudine, zalcitabine, zidovudine; and others such as amantadine, interferon alpha, ribavirin, rimantadine; anti Alzheimer's agents such as galantamine; and other therapeutic agents such as cimetidine, propiomazine, phenytoin, tacrine, propiazam, proplazam; vinca alkaloid.

Also contemplated are other therapeutic polypeptides and proteins, including fragments, analogs and mimetics thereof, and prodrugs which possess the same therapeutic activity, to at least a therapeutically useful extent, such as vasopressin, desmopressin, LHRH, luprolide, buserelin, calcitonin, insulin, parathyroid hormone, growth hormone(s) and erythropoietin. Further, examples include cyclosporin, angiotensin I, II and III, encephalins, enkephalins and their analogs, ACTH, antiinflammatory peptides I, II, III, bradykinin, cholecystikinin (CCK) fragments 26-33 and 30-33, pre/pro CCK (V-9-M), .beta.-endorphin, dinorphin, leucokinin, leutinizing hormone releasing hormone (LHRH), neurokinins (e.g. neurokinin A), somatostatin, substance P, thyroid releasing hormone (TRH), vasopressin, fibrinogen receptor antagonists (arginine-glycine-aspartic acid containing peptides) which are platelet aggregation antagonists or inhibitors, growth hormone releasing peptides (GHRP), insulin, LH-RH releasers and inhibitors, endothelins, glutamate or kainic acid neuro-excitation or neuro-toxicity inhibitors, GPIIb/IIIa receptor blockers such as the prodrug orbofiban, atrial natreutetic factor, gastrin, cytoprotectives, MSH modulators, or elastase or growth factors and cytokines, renin inhibitors, and HIV protease inhibitors.

Therapeutic agents can also include immunoactive agents selected from peptides, proteins, glycopolysaccharides and glycoproteins and fragments and analogs thereof, which possess the ability to suppress or eliminate immune responses thereto. Active analogs include compounds which have at least 90% structural homology to the proteins or to the active fragments. As such, the term includes, without limitations, any combination of their polypeptide domains or fragments possessing the ability to eliminate or suppress immune responses to the protein upon oral administration such as is used for replacement therapy. Examples of polypeptides include hormones, such as insulin; polypeptides to supplement a deficiency in production of a physiologically important polypeptide, such as hematologic regulatory factor; or cell or tissue preparations such as allogeneic or xenogeneic tissue or cells.

Therapeutic agents can also include immunoactive agents that can suppress or eliminate an immune response against allergens, particularly in cases of hypersensitivity caused by allergens, e.g. Type IV cell-mediated (delayed type) hypersensitivity. Also included are vaccines, especially those yielding mucosal immunity.

Therapeutic agents can also include those intended to be locally active in the gastrointestinal tract, such as therapeutics intended to treat Inflammatory Bowel Disease or Krohn's Disease, including corticosteroids such as beclomethasome dipropionate, budesonide, flunisolide, cromolyn, and nedocromil sodium.

Several methods are known in the art for the formation of beadlet/granule particles, both in uncoated and coated forms. The experiments reported in the Examples set forth below were performed using three of these methods: (i) a spray congealing method; (ii) a hot-melt method; and (iii) a spray-melt method. Each can be scaled in accordance with the stage of development.

The spray-congealing method begins with melting a typical pharmaceutically acceptible long chain alkyl-based wax that has a melting point of greater than or equal to about 55^oC. Examples include stearic acid wax, glyceryl fatty acid esters (e.g. Compritol.RTM. brand), glyceryl monostearate or lauric acid wax. The melted wax is then mixed in a suitable mixing vessel, with the active pharmaceutical agent (usually 50-100 microns) and all other components of the beadlet composition, except for flow aids as described below. The mixture is sprayed into a spray-congeal tower or fluid bed processor. A flow of cool air is passed through the tower to solidify the beadlets. After the solidified beadlet has been formed, flow aids are added to prevent beadlet sticking, i.e. to make the beadlet surfaces more slippery, resulting in finished uncoated beadlets prepared by this method.

The hot-melt method is performed in a fluid bed, which takes the form of a vertical cylinder resting in a bowl-shaped base (one such device used in the Examples is the Wurster inserted in a Glatt GPCG5 fluid bed). The side walls of the cylinders have a number of spray nozzle entry ports along their length. A dry powder particulate mixture of the beadlet components, except for the wax and lubricant(s), is placed in the bowl and a metered flow of air is introduced into the cylinder. This raises the powder particles into the cylinder forcing a controlled flow pattern of the powder particles within at least one portion of the height of the cylinder. Then, melted wax and lubricant are introduced through some of these same nozzles, particularly the upper nozzles in an embodiment called the "top spray" method. The lower nozzles continue to introduce cool air from below to effect solidification of beadlets containing the powder, wax and lubricant components. The "top spray" method is used in several of the Examples presented herein.

The spray-melt method is also performed in a fluid bed. Solid ingredients (including wax that is solid at room temperature) i.e. not including liquid surfactants or solubilizing agents, are placed in a suitably configured fluid bed. Liquid surfactants, mixtures thereof and/or solubilizing agents are then sprayed onto the solid ingredients already in the fluid bed. This results in particles which are actually separate but attached drug, wax and surfactant components. These separate-component particles are heated sufficiently to soften the wax, resulting in homogeneous particles which are then cooled to result in solidified beadlets. Several formulations in the Examples were prepared this way.

The composition or preparation of the invention can further include a surfactant, or a mixture of two or more surfactants. A surfactant is an amphiphilic molecule consisting of a hydrophobic tail and a hydrophilic head. These molecules possess distinct regions of both hydrophilic and hydrophobic character. The hydrophobic tail can be a hydrocarbon or fluorocarbon chain of 8 to 18 carbon atoms. They are long chain molecules such as, for example, soaps or detergents. Surfactants accumulate at the hydrophilic/hydrophobic (water/oil) interface and lower the surface tension at the interface. One effect of a reduced surface tension is the stabilization of the emulsions. This is because molecules with both polar and non-polar groups become oriented such that the hydrocarbon tail embeds itself into the hydrophobic phase and the hydrophilic head protrudes into the hydrophilic phase. Where the hydrophobic composition or other component of the preparation includes a surface-active agent, such as a surfactant, it is usually present in amounts of about 3% to 50.0% weight/weight of the beadlet or granule composition with a preferred range of 3% to 10% (w/w). Preferred surfactants include, for example, the Tween (polyoxyethylene sorbate) family of surfactants (ICI, Wilmington, Del.), the Span (sorbitan long chain carboxylic acid esters) family of surfactants (ICI), the Pluronic (ethylene or propylene oxide block copolymers) family of surfactants (BASF, Parsippany, N.J.), the Labrasol, Labrafil and Labrafac (each polyglycolyzed glycerides) families of surfactants (GatteFosse, St. Priest, France), sorbitan esters of oleate, stearate, laurate or other long chain carboxylic acids, poloxamers (polyethylene-polypropylene glycol block copolymers), other sorbitan or sucrose long chain carboxylic acid esters, mono and diglycerides, PEG derivatives of caprylic/capric acid triglycerides and mixtures thereof. Representative preferred surfactants are poloymer 124, a poly-glycolized glyceride, sorbitan laurate, polyoxyethlyene (20) sorbitan monooleate.

Coating of the beadlets formed by any of the above methods is achieved as follows. An aqueous solution of an "immediate release" coating is formed and sprayed onto the beadlets substantially immediately after they have been formed, using the same apparatus and same nozzles by which the beadlets were formed. A list (non-limiting) of release coating materials and suppliers is provided in Table 1 below. At this point, more flow aid may be introduced briefly. The beadlets are then discharged to a blender (such as a Patterson-Kelly V-blender).

Major fluid bed processors and suppliers include Aeromatic and Multiprocessor series (Niro Inc., Columbia, Md. 21045); GPCG series (Glatt Air Techniques, Inc., Ramsey, N.J. 07446); Vector fluid bed series (Vector Corporation, Marion, Iowa 52302); and Kugel Coater series (Huttlin, Coating-Technik GmbH, Steinen, Germany).

The beadlets can be incorporated into hard gelatin capsules, either with additional excipients, or alone. Typical excipients to be added to a capsule formulation include, but are not limited to: fillers such as microcrystalline cellulose, soy polysaccharides, calcium phosphate dihydrate, calcium sulfate, lactose, sucrose, sorbitol, or any other inert filler. In addition, there can be flow aids such as fumed silicon dioxide, silica gel, magnesium stearate, calcium stearate or any other material imparting flow to powders. Because of their hydrophobic nature, the particles should not need a lubricant, but one can be added if necessary by using polyethylene glycol, leucine, glyceryl behenate, magnesium stearate or calcium stearate.

The beadlets can also be incorporated into a tablet, in particular by incorporation into a tablet matrix, which rapidly disperses the particles after ingestion. In order to incorporate these particles into such a tablet, a filler/binder must be added to a tablet that can accept the particles, but will not allow their destruction during the tableting process. Materials that are suitable for this purpose include, but are not limited to, microcrystalline cellulose (Avicel), soy polysaccharide (Emcosoy), pregelatinized starches (STARCH 1500, National 1551), and polyethylene glycols (Carbowax). The materials should be present in the range of 5-75% (w/w), with a preferred range of 25-50% (w/w).

In addition, disintegrants are added in order to disperse the particles once the tablet is ingested. Suitable disintegrants include, but are not limited to: cross-linked sodium carboxymethyl cellulose (Ac-Di-Sol), sodium starch glycolate (Explotab, Primojel), and cross-linked polyvinylpolypyrrolidone (Plasdone-XL) These materials should be present in the range of 3-15% (w/W), with a preferred range of 5-10% (w/w).

Lubricants are also added to assure proper tableting, and these can include, but are not limited to: magnesium stearate, calcium stearate, stearic acid, polyethylene glycol, leucine, glyceryl behanate, and hydrogenated vegetable oil. These lubricants should be present in amounts from 0.1-10% (w/w), with a preferred range of 0.3-3.0% (w/w).

Tablets are formed, for example, as follows. The particles are introduced into a blender along with Avicel, disintegrants and lubricant, mixed for a set number of minutes to provide a homogeneous blend which is then put in the hopper of a tablet press with which tablets are compressed. The compression force used is adequate to form a tablet; however, not sufficient to fracture the beads or coatings.

The tablets can also be coated with conventional coatings known for a variety of effects, e.g. enteric, immediate or sustained release.

Caco-2 Cell Monolayer Testing of Drug Transport

We have used a cell culture based model to test formulations to improve intestinal adsorption of poorly adsorbed drugs. This allows testing of transport through intestinal epithelium without the influence of gastric hydrolysis or enzyme degradation in the GI tract, blood, or liver. It further allows simultaneous testing of multiple different formulations.

The Caco-2 cell line is derived from human colon cancer cells. They are epithelial-type cells that differentiate, in culture, into cell monolayers that are extremely similar to normal fetal intestinal epithelium. Intestinal epithelium is the cell type that lines the intestine. It has very specific adsorptive and barrier properties to allow absorption of nutrients but prevent passage of most of the intestinal contents. Two important characteristics of intestinal epithelium are the brush border, which forms the luminal surface of the epithelium, and the tight junctions, which are impenetrable fusions between cells. The brush border is important because it produces the enzymes and specialized membrane structures that allow cells to selectively absorb important nutrients such as glucose; tight junctions are important because they form continuous connection between cells and allow the epithelium to exclude unwanted molecules. Caco-2 cells, as used in our assays, display both of these characteristics.

Caco-2 colon carcinoma cells were obtained from the American Tissue Culture Collection (Rockville, Md.) and maintained in culture in high glucose DMEM with 10% fetal calf serum, plus pen/strep, at 37^oC., in 5% CO₂. Cells are subcultured roughly every 5-7 days, 1:3 in T75 flasks, or when cells are 80-90% confluent, as determined by visual inspection. Caco-2 cells are adherent and are disassociated from the surface of the flask by incubation at room temperature with 0.25% trypsin in Hank's balanced salt solution (HBSS) without calcium or magnesium. Caco-2 cells are contact inhibited and when they become confluent, begin to differentiate and lose the capacity to undergo mitosis. To maintain a consistent genotype, it is important to avoid selecting for a subset of cells that is not differentiated. This is done by subculturing working stocks of cells before they differentiate. Initial experiments establish the time course of differentiation.

Transport studies use differentiated cells, which are cells that have acquired many of the characteristics of normal intestinal epithelium including a brush border and barrier properties. Transport experiments use 2.45 cm Transwell cell culture inserts with 3.0 .mu.m pores (Costar, Boston, Mass.). These are plastic inserts for tissue culture wells, which allow a distinct apical and basal compartment only connected by small pores on the growing surface. Cells are seeded on the upper surface of the insert at 3x10⁵ cells per well and media changed every day. Media was changed in the lower compartments by lifting insert with a sterile forceps. The upper compartment holds 1.5 ml, and the lower 2.6 ml. Tissue culture reagents can be purchased from GIBCO-Life Technologies (Gaithersburg, Md.) or Biofluids (Rockville, Md.).

Transport studies usually include polyethylene glycol (PEG) 4000 as a large, nonreactive, reference molecule, which would not permeate normal epithelium, and the following test peptides, which have a range of molecular weights and hydrophilicitys: thyrotrophin releasing hormone (TRH) (MW=362.15), DAGO-enkephalin (MW=513.26) and [ARG8-] vasopressin (MW=1083.41). Glucose transport is also measured using ³ H and ¹⁴ C labeled D- and L- glucose. Unlabeled peptides can be purchased from Peninsula Laboratories, Belmont, Calif. Tritium-labeled peptides and glucose and ¹⁴ C-PEG can be purchased from NEN-DuPont, Boston, Mass., or Amersham Corp., Arlington Heights, Ill.

For transport determinations unlabeled peptides, concentration 10 mM, and labeled, concentation of 1 .mu.Ci per ml and transport enhancers, are added to HBSS plus calcium and magnesium. Transport media, containing peptide or glucose plus labeled and unlabeled PEG, is added to the upper compartment of the Transwell, where the test solution is in contact with the apical surface of the cells. Transport is measured by taking aliquots from the lower compartment, which is in contact with the basal surface of the cells. Studies are performed in a six-well tissue culture plate and Transwells are moved to a new well every twenty minutes, giving determinations for two hours. An aliquot of media is removed from the upper and lower compartments, scintillation cocktail is added (NEN DuPont) and the total radioactivity from the upper and lower compartments is calculated. Transport is calculated as percent transport per hour from top to bottom. Because in all experiments the amount of peptide in the upper compartment is large compared to the amount transported, no correction is made for loss of peptide in the upper compartment with time. Radioactivity is measured in a Wallac or Beckman scintillation counter.

Claim 1 of 23 Claims

What is claimed is:

1. A composition comprising:

at least one therapeutic agent and a solid beadlet having a size of from 50 microns to 1,000 microns, said beadlet comprising at least 20% by weight of at least one hydrophobic long chain fatty acid or glycerol ester thereof having 12 to 22 carbon atoms and at least 3.0% by weight of at least one surfactant, said at least one surfactant being a liquid at room temperature, said at least one surfactant being selected from the group consisting of ethylene or propylene oxide block copolymers, polyglycolyzed glycerides, sorbitan esters of stearate, sorbitan esters of laurate, polyethylene-polypropylene glycol block copolymers, sucrose long chain carboxylic acid esters, sucrose monoglycerides, sucrose diglycerides, sorbitan monoglycerides, sorbitan diglycerides. PEG derivatives of caprylic/capric acid triglycerides, and mixtures thereof, and said therapeutic agent being dispersed in said beadlet.

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