WO2000076480A9 - Pharmaceutical materials and methods for their preparation and use - Google Patents

Pharmaceutical materials and methods for their preparation and use

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Publication number
WO2000076480A9
WO2000076480A9 PCT/US2000/016140 US0016140W WO0076480A9 WO 2000076480 A9 WO2000076480 A9 WO 2000076480A9 US 0016140 W US0016140 W US 0016140W WO 0076480 A9 WO0076480 A9 WO 0076480A9
Authority
WO
WIPO (PCT)
Prior art keywords
phase
crystals
active pharmaceutical
pharmaceutical ingredient
crystal
Prior art date
Application number
PCT/US2000/016140
Other languages
French (fr)
Other versions
WO2000076480A2 (en
WO2000076480A3 (en
Inventor
Jerry Lewis
Jean A Chmielewski
Bart E Kahr
Original Assignee
Lilly Co Eli
Jerry Lewis
Jean A Chmielewski
Bart E Kahr
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Lilly Co Eli, Jerry Lewis, Jean A Chmielewski, Bart E Kahr filed Critical Lilly Co Eli
Priority to EP00939811A priority Critical patent/EP1189599A2/en
Priority to US10/018,043 priority patent/US7001892B1/en
Priority to AU54836/00A priority patent/AU5483600A/en
Publication of WO2000076480A2 publication Critical patent/WO2000076480A2/en
Publication of WO2000076480A3 publication Critical patent/WO2000076480A3/en
Publication of WO2000076480A9 publication Critical patent/WO2000076480A9/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to pharmaceutical formulations involving the inclusion of an active pharmaceutical ingredient ("API") in a pharmaceutically- acceptable single crystal matrix. More particularly, the crystals contain growth- sector specific, oriented inclusions of active pharmaceutical ingredients which are isolated.
  • the active pharmaceutical ingredients have higher stability and shelf-life, and can be delivered in conventional dosage forms.
  • This invention has general application to active pharmaceutical ingredients, and in one aspect has particular application to biopharmaceuticals.
  • biopharmaceuticals is used to refer to a subset of API's which are polymeric in nature, including for example, proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids. Description of the Prior Art:
  • compositions which are capable of maintaining the quality and efficacy of the API during storage and delivery.
  • the loss of potency of an API is a critical concern in assuring that viable, effective drugs are delivered to patients. It is similarly desirable to have formulations which do not require special packaging or handling. Further, it remains a constant goal to provide active pharmaceutical ingredients in a form which facilitates their use by the consumer, such as through convenient dosage forms.
  • the present invention addresses these and other issues concerning pharmaceutical compositions and formulations.
  • biopharmaceuticals Although not limited to biopharmaceuticals, the usefulness of the present invention is well exemplified with respect to biopharmaceuticals, many of which demonstrate the problems encountered in prior-art approaches. Ensuring long-term stability and maintaining activity of biopharmaceuticals is a prevalent concern.
  • the chemical complexity and conformational fragility of protein drugs make them highly susceptible to both physical and chemical instabilities and threaten their emergence into the marketplace. Denaturation, adsorption with container walls, aggregation, and precipitation can result from non-covalent interactions between a drug and its environment. Insulin, for instance, has been shown to adsorb onto the surfaces of glass and plastic containers, and to have interactions at air-water interfaces, leading to denaturation, aggregation and precipitation.
  • HGH human growth hormone
  • glucagon in solution has been shown to readily gel or aggregate when subjected to mechanical stress.
  • researchers have distinguished nine major reaction mechanisms by which proteins degrade, including hydrolysis, imide formation, deamidation, isomerization, racemization, diketopiperazine formation, oxidation, disulfide exchange, and photodecomposition. The rates of these deleterious processes depend in large measure on the protein and its environment.
  • the primary chemical degradation products of glucagon include oxidation of Met (27), deamidation of Gin (24), and acid-catalyzed hydrolysis at Asp (9), Asp (15) and Asp (21). HGH undergoes chemical decomposition via oxidation at Met (14) and deamidation at Asn (149).
  • biopharmaceuticals One technique used in formulating biopharmaceuticals has been lyophilization of the biopharmaceutical solution in the presence of excipients, buffers and/or bulking agents.
  • lyophilized preparations must typically be stored under refrigeration, a requirement which is neither technically nor economically feasible in many markets and inhibits flexibility of patient use.
  • formulations of many biopharmaceuticals which would permit their storage at ambient temperatures. This would permit more rapid development of products, increasing flexibility in shipping, storing and carrying the drug products, and allowing introduction and use of such products in markets where refrigeration is too costly.
  • the increased stabilization of biopharmaceuticals would naturally improve the general use of the biopharmaceuticals where shelf life is an important consideration, whether or not refrigeration or other concerns are at issue.
  • aqueous solution containing a biopharmaceutical with a limited amount of excipient(s) is frozen and then dried under vacuum to produce solids of sufficient stability for storage and distribution.
  • Excipients are added to prevent blow out of the product, to provide stability during lyophilization and/or dissolution, and to enhance compatibility for parenteral use.
  • Various excipients used with lyophilization have included salts, metal ions, polyalcohols, surfactants, reducing agents, chelating agents, other proteins, amino acids, fatty acids, and phospholipids.
  • excipients include mannitol, alanine, glycine, sorbitol, lactose, arginine, and maltose.
  • the results obtained with such excipients have usually been inconsistent.
  • Most lyophilized biopharmaceuticals are amo ⁇ hous powders that have no specific structure, and as a result, the amount and location of the inco ⁇ orated biopharmaceutical varies widely for the product particles. Also, they are typically readily dissolved, rendering them unsuitable for use as a sustained-release material. Further, there is no isolation of the pharmaceutical molecules from the environment or one another, leaving them susceptible to degradation by various mechanisms. Studies have shown that lyophilization of excipients can typically damage proteins rather than protect them.
  • Crystallized pharmaceuticals have been used in some instances, but there have been inherent limitations. Some API's , e.g. insulin, can be crystallized themselves, and are useful in that form for administration to patients. However, the majority of biopharmaceuticals either do not crystallize or the crystallization is very difficult, particularly on a commercial scale. Further, crystallization procedures are limited to the use of pharmaceutically-acceptable ingredients and process conditions that do not adversely affect the active pharmaceutical ingredient, thus further constraining the ability to obtain desired microcrystalline suspensions.
  • United States Patent No. 5,075,291 describes a process for preparing a uniformly-dispersed, pharmaceutically-active material in a crystalline sugar alcohol matrix.
  • this process requires the addition of the API into a molten sugar alcohol with considerable mechanical agitation.
  • Many API's and virtually all biopharmaceuticals would not be stable in the extreme temperature of 110°C and the physical stresses of a high-shear vortex mixer used for agitation.
  • the present invention does not require these extremes of temperature and physical agitation.
  • the process of the present invention slowly includes the API into the growing crystal lattice in specific growth sectors, instead of homogeneous mixing and entrapping of the active pharmaceutical ingredient in a viscous melt.
  • the present invention relates to pharmaceutical compositions comprising single crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation.
  • the crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the API's to a patient.
  • the crystals may be coated or combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing dosage amounts of the API's.
  • the crystals are prepared as depot formulations which may be administered, as by subcutaneous injection or implantation, to provide a long-term payout or sustained release of the active pharmaceutical ingredient.
  • the present invention further provides methods for preparing the crystals and for storing and administering the active pharmaceutical ingredient either in crystal form or upon reconstitution to a solution.
  • Another object of the present invention is to provide pharmaceutical delivery units including an amount of single crystals sufficient to provide a dosage amount of the included active pharmaceutical ingredient.
  • the pharmaceutical delivery units include a quantity of crystals sufficient to provide a prolonged payout of the active pharmaceutical ingredient.
  • the crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants including excipients, diluents and carriers.
  • a further object of the present invention is to provide methods for preparing compositions comprising single crystals with growth-sector specific inclusions of API's.
  • Figure 1 is a photomicrograph illustrating fluorescence of a single crystal of green fluorescent protein in ⁇ -lactose monohydrate (1.8 (h) x 0.8 (w) x 0.5 (d) mm 3 ) with an idealized representation of habit.
  • the sides of the crystal in the photomicrograph are bright due to internal reflection.
  • Figure 2 is a graph of the fluorescence decay of the green fluorescent protein at 333°K in several environments: mixed crystal in ⁇ -lactose monohydrate (triangle), saturated lactose solution (square), and lyophilized ⁇ -lactose monohydrate (diamond).
  • the present invention utilizes single-crystal matrix inclusion of active pharmaceutical ingredients ("API's”) to achieve advantageous storage and delivery of the API's.
  • API's active pharmaceutical ingredients
  • This invention has application to a wide range of API's to provide enhanced stability and/or delivery of the active pharmaceutical ingredients.
  • the invention is particularly advantageous in providing greater stability over time and in providing alternative delivery and sustained release formulations to patients .
  • the small molecule host crystals comprise a crystal lattice component which includes the API's in an oriented, growth-sector specific manner.
  • the crystals and included API's are prepared to be pharmaceutically acceptable and pure, thereby being useful for administration to patients to be treated with the API's.
  • the term "pharmaceutically-acceptable" refers to sufficient quality to meet regulatory and compendial requirements for administration to humans and/or animals.
  • the crystals provide a regular, predictable inclusion of the guest active pharmaceutical ingredient, and the crystals can consequently be used for obtaining a predetermined amount of the active pharmaceutical ingredient for delivery to a patient.
  • the host crystal gradually dissolves upon contact with body tissue or fluids, and is therefore useful as a system for delivery of the active pharmaceutical ingredient into the body.
  • the crystals and included active pharmaceutical ingredient may be reconstituted into a solution for administration to a patient.
  • the active pharmaceutical ingredient molecules are generally isolated from one another and are insulated from the environment by the host crystal. This leads to reduced susceptibility of the API to degradation, and therefore enhanced stability and shelf-life. Also, the use of appropriate host crystal compounds, or selected dosage forms, permits the design of quick, delayed, or sustained-release formulations for delivery of the active pharmaceutical ingredient. Sustained- release formulations are particularly advantageous for treatment of chronic conditions as they provide a consistent amount of drug delivery over a long period of time to improve ease of use and patient compliance in administering the API.
  • the crystals preferentially inco ⁇ orate the active pharmaceutical ingredient on certain faces, thereby providing a growth-sector specific inclusion and orientation to the API's.
  • growth-sector specific inclusion and orientation refers to the fact that the API molecules are included primarily at certain faces of the crystal matrix.
  • the growth-sector specific inclusion and orientation can be determined by one skilled in the art, as demonstrated in the examples herein, by fluorescence microscopy and anisotropy measurements, single crystal deso ⁇ tion mass spectrometry, and autoradiography of 14 C-labeled material. In one embodiment, at least about
  • 0.001% (on weight/weight (w/w) basis) of the pharmaceutical is included within specific faces of the crystal matrix, and in another embodiment at least about 0.1% (w/w) and up to about 10%.
  • the crystal parameters including the particular crystal lattice component for a given API, the concentration of API, the use of crystal adjuvants, and the crystallization conditions, are selected to achieve the growth-sector specific inclusion and orientation of the API within the crystals.
  • the method of the present invention broadly involves the including of the active pharmaceutical ingredient into the single crystal matrix formed from a pharmaceutically-acceptable crystal lattice component.
  • the term "included” in the crystals refers to the active pharmaceutical ingredient being chemically adsorbed within the crystal lattice as the crystal is formed.
  • This inclusion of the active pharmaceutical ingredient molecules is distinguished from crystallization of the API molecules with one another, and from simple and random entrapment of the API molecules by the formed crystal.
  • the crystal product of the present invention is ordered, in contrast to the amo ⁇ hous material produced by other approaches.
  • the API is inco ⁇ orated in the crystal in relation to its degree of affinity for the crystal lattice molecules.
  • the crystal lattice component is therefore selected to be both chemically and physically compatible with the API such that the API is received by the crystal during formation, and remains stable and efficacious while within the crystal and upon release therefrom.
  • the including of the active pharmaceutical ingredient involves combining the crystal lattice component, the active pharmaceutical ingredient and a pharmaceutically-acceptable adjuvant in a liquid state.
  • the crystal lattice component is then crystallized under pharmaceutically-acceptable conditions to form the inventive crystals.
  • one method uses spiking of the API into a saturated or supersaturated solution of the crystal lattice component in a suitable organic and/or aqueous solvent system.
  • the saturated or supersaturated solution of the crystal lattice component may be spiked into the API solution.
  • Other components may also be added to the solution, including compounds which facilitate or modify crystal growth or which are desired for inco ⁇ oration in the final formulation.
  • the solution may be seeded using any of a variety of conventional techniques.
  • the solution is allowed to evaporate and/or equilibrate to cooler conditions for growth of the crystals.
  • the crystals are then grown as the solvent is slowly evaporated away and or the solution is cooled, with the evaporation and temperature gradient conditions being selected dependent on such factors as the solvent system and the desired crystal size.
  • the crystals containing the active pharmaceutical ingredient are harvested from the remaining solution and are preferably washed to remove surface contamination. This procedure yields crystals which include the active pharmaceutical ingredient at a predictable concentration and facial orientation.
  • crystals are grown under pharmaceutically-acceptable conditions.
  • pharmaceutically-acceptable conditions refers to the use of crystal and API compounds which are pharmaceutically-pure, and for which such pharmaceutical purity is maintained in the final crystals.
  • the crystal and API compounds are pharmaceutically pure, or have pharmaceutical purity, if they are of sufficient purity to be suitable for administration under applicable FDA or other administrative regulations regarding purity.
  • pharmaceutically-acceptable conditions further refers to the use of crystallization conditions through which the API compounds retain pharmaceutical efficacy in the final crystals and upon subsequent administration to patients.
  • the present invention readily allows the inclusion of API's by affinity with the small host molecules in the growing crystal lattice. This overcomes many of the limitations associated with previous approaches.
  • the processing involved with preparing the present crystals does not expose the API's to harsh conditions, thereby substantially reducing or avoiding the possible degradation or disruption of the structural aspects of the API which could occur with prior art techniques.
  • the inventive crystals have an added advantage in that they do not interfere with normal analytical methodologies used for characterizing the pharmaceutical product.
  • the small host molecules can be easily separated on the basis of molecular size, which is not the case for prior art techniques which use polymers that interfere with analytical methodologies.
  • the API molecules are inco ⁇ orated into the host crystals typically at rates of at least about 0.001% (w/w), preferably at least about 0.1%, and more preferably about 1% to about 10% (w/w). Alternatively, the API molecules are included at rates of at least about 0.01%, and as much as at least about 1% (w/w).
  • the limited molar concentration of the active pharmaceutical ingredient in the host crystals means that the active pharmaceutical ingredient molecules are generally isolated from one another in the crystals. Isolation of the API molecules is particularly advantageous for those molecules, such as certain biopharmaceuticals, which could otherwise react with one another (e.g., by polymerization) or the surrounding environment. The degree of isolation can be verified by those skilled in the art using atomic force microscopy or reaction fluorescence energy techniques.
  • the present invention has a particular application to guest-host systems in which the guest API molecules are reactive with one another, but in which these molecules are sufficiently isolated from one another in the crystals as to substantially prevent such interaction. Consequently, the invention provides containment of the API molecules in the solid state crystals and provides for the API to be comformationally stable.
  • the method preferably involves preparing a mixture of crystals of substantially uniform size. This may include processing of the harvested crystals, such as by grinding or milling, to reduce the crystals to a substantially uniform size. Greater uniformity can be achieved by sorting the processed crystals, such as by sieving.
  • a preferred method further includes obtaining crystals which have a substantially uniform concentration of pharmaceuticals, for example, about 1% (w/w) of pharmaceuticals, that do not vary between crystals by more than 10 percent.
  • the method of the present invention may further include formulating the crystals into pharmaceutical preparations.
  • the collected crystals may optionally be coated with a suitable composition.
  • Coated or uncoated crystals may be blended with one or more pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof.
  • the blended crystals and adjuvant(s) are then formulated into pharmaceutical delivery units.
  • each unit includes a predetermined amount of the pharmaceutical.
  • the crystals are combined in a delivery unit intended to deliver multiple or sustained dosing of the API over a period of time, such as by subcutaneous implantation of the delivery unit.
  • a further aspect of the method of the present invention involves reconstituting the crystals to liquid form.
  • the harvested crystals are dissolved in a suitable diluent for the crystal lattice component.
  • the dissolution of the crystals releases the API from the crystals.
  • the resulting solution may include other adjuvants, such as excipients, diluents or carriers, and the mixture is formulated under conventional procedures to desired delivery forms.
  • the crystals are used to store the pharmaceutical for a period of time, such as at least one month, or at least one year, and the crystals are subsequently dissolved to use the active pharmaceutical ingredient.
  • the present invention involves the use of any of a wide variety of pharmaceutically-acceptable host crystal systems that can inco ⁇ orate API's in a growing crystal lattice.
  • the crystal lattice component is selected to be compatible with the guest API, and to be suited to the use of the resulting formulation for storage and administration. Selection of the crystal lattice component will involve consideration of such factors as affinity for the API, crystal size distribution and mo ⁇ hology, and desired pharmaceutical concentration and delivery rate, as well as other factors well known in the art of pharmaceutical delivery systems.
  • the crystal systems must consistently inco ⁇ orate the guest active pharmaceutical ingredient in terms of concentration and placement within the crystal lattice.
  • the crystals also must grow under conditions which will not degrade or otherwise adversely affect the viability of the active pharmaceutical ingredient.
  • Preferred host crystal materials are those that have a high affinity for the included API. It appears that the oriented inclusion of the API's is related to the affinity between the crystal lattice component and the API. The affinity between these materials is therefore important in obtaining the desired inclusion of the API's, and also permits control of the inclusion based upon this affinity. For example, the concentration of the pharmaceutical in a crystal can be controlled by selecting the host component to have an affinity for the API which yields the desired inclusion rate. Also, mixtures of host materials, or of host materials and other excipients, can be used to provide an affinity yielding the desired inclusion level. In one aspect of the present invention, the API's are inco ⁇ orated at levels of at least about 0.001% (w/w of guest:host), more preferably at least about 0.1% (w/w).
  • the preferred host crystal materials will also be very stable and readily crystallizable, and will maintain their "order" or crystal mo ⁇ hology when including a guest molecule, particularly large biomolecules.
  • the use of particular host crystal components will also depend on such factors as how small or large the crystals can be produced and how readily they dissolve.
  • the useful crystal sizes will therefore vary accordingly, ranging from submicron to millimeter sizes.
  • the preferred crystals are in the order of 5-100 microns in size.
  • the useful host crystal systems are therefore diverse, and include various small molecule crystal systems which meet the desired criteria.
  • pharmaceutically-acceptable crystal lattice components include sugars, polyhydroxy alcohols, single and polyamino acids, vitamins, salts, metals, preservatives, aromatic compounds especially aromatic acids, purified natural products, and polymers.
  • Preferred crystal lattice components include, for example, sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, and potassium citrate. Also, compatible mixtures of these materials are also useful, and can be selected to obtain the desired rate of inclusion of the pharmaceutical, or to achieve desired characteristics, such as dissolution rate and pharmacokinetic profile, for the product crystals.
  • the crystal lattice components are selected to achieve the desired pharmacokinetics for the final crystals.
  • the term "pharmacokinetics" is used to refer to the profile of the delivery of active pharmaceutical ingredient from the crystals into the circulatory system. This will depend primarily on the concentration of the active pharmaceutical ingredient in the crystals, as well as parameters of the active pharmaceutical ingredient itself. While given crystal lattice components will have associated inclusion and dissolution characteristics, these can be modified by including other crystal lattice components, other API's, or a variety of excipients. Thus, single crystals having two different, co-crystallized lattice components will typically be characterized by pharmacokinetic profiles different from crystals prepared with either of the crystal lattice components alone.
  • the present invention involves the use of mixtures of crystals having different pharmacokinetics in order to achieve desired payout profiles.
  • a pharmaceutical product can be obtained by combining two different types of crystals, one type of crystal using a first crystal lattice component characterized by a first pharmacokinetic profile, and the second type of crystal using a second crystal lattice component characterized by a second pharmacokinetic profile.
  • the mixture of crystals will give a payout of API that is different from either of the individual payouts for the two crystal types.
  • the included API's are similarly diverse, limited simply by the requirements of compatibility with the host crystal and the crystal growth conditions.
  • the active pharmaceutical ingredient cannot be unacceptably degraded or otherwise adversely affected by the conditions under which the crystals are formed. Also, the active pharmaceutical ingredient should remain stable for an extended period of time while included within the host crystal, and pharmaceutically efficacious upon release from the crystal.
  • API's useful in accordance with the present include: antibiotics (such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin), fluoxetine, raloxifene, olanzapine, and nizatidine.
  • antibiotics such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin
  • fluoxetine raloxifene
  • olanzapine olanzapine
  • nizatidine nizatidine
  • Mammalian cell line Choinese Hamster Ovary cells
  • Expression System Natural source - human leukocytes which are exposed to an avian virus in order to produce interferon.
  • Glycoprotein single N-linked complex carbohydrate
  • 166 amino acids with a predicted molecular weight of 22,500 daltons, human sequence, has a specific activity of 200 million units per mg protein.
  • Refolding Conditions • Structure: 165 amino acids with an approximate molecular weight of 18,500 daltons, human sequence but with a serine or cysteine at residue 17. Recombinant form does not contain the carbohydrate moiety found in the natural material. Has a specific activity of 32 million units per mg protein.
  • Cost of therapy is $13,140 (based on 0.25 mg/injection, dose every other day for 1 year; equals 46 mg protein).
  • Formulation Comes in a lyophilized and a solution formulation.
  • the lyophilized formulations when reconstituted with 0.9% benzyl alcohol (supplied) contains either 0.015, 0.025, 0.05, 0.90, or 0.125 mg/mL.
  • Interferon alfa-2b 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, 1 mg/ml human albumin, 1.2 mg/mL methylparaben, and 0.12 mg/mlparaben.
  • These formulations be injected intramuscular, subcutaneous, or intralesional. All formulations and reconstituted products are stored at refrigerated temperatures.
  • Interferon alfa-2a • Product Name: Roferon-A
  • Multi-use and lyophilized formulation indented for intramuscular or subcutaneous administration contains either 0.015, 0.045, 0.090, 0.18 mg/mL.
  • Interferon alfa-2a 9 mg/ml NaCl, 5 mg/ml human albumin, and 3 mg/ml phenol.
  • the lyophilized formulation reconstituted with 3 mL of supplied diluent (6 mg/ml NaCl, 3.3 mg/ml phenol) consists of 0.03 mg/ml Interferon alfa-2a, 9mg/ml NaCl, 1.67 mg/ml human albumin, and 3.3 mg/ml phenol.
  • lyophilized product which is reconstituted with sterile water containing 0.3% m-cresol, 1.7% glycerin (supplied) to 2 mg/mL hGH and has a final pH of approximately 7.5, subcutaneous or intramuscular administration.
  • Each 5 mg lyophilized vial contains 5 mg hGH, 25 mg mannitol, 1.13 mg dibasic sodium phosphate, and 5 mg glycine.
  • Lyophilized product which is reconstituted with bacteriostatic water (0.9% benzyl alcohol, supplied) to 5 mg/mL hGH and has a final pH of approximately 7.4, subcutaneous or intramuscular administration.
  • bacteriostatic water (0.9% benzyl alcohol, supplied
  • Each 5 mg lyophilized vial contains 5 mg hGH, 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg monobasic and 1.3 mg dibasic), and 1.7 mg glycine.
  • Expression System E. coli, expressed with a leading secretion signal precursor which directs the protein to the plasma membrane of the cell where the sequence is removed and the native protein is secreted into the periplasm so that the protein if folded appropriately as it is synthesized.
  • Lyophilized product 212 units glucocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysorbate-80; stored refrigerated
  • Lyophilized product 212 units glucocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysorbate-80; stored refrigerated
  • 5.1 mL of sterile water final pH is approximately 6.1.
  • the reconstituted material is combined with 100 to 200 mL of 0.9% NaCl and administered intravenously.
  • Formulation contains no more that 1% yeast proteins.
  • Epogen or Epoetin alfa also sold under the name Procrit by Ortho Biotech but manufactured by Amgen
  • Formulation Lyophilized solution which is reconstituted with sterile water (stored at refrigerated temperatures for ⁇ 6 hours) or 0.9% benzyl alcohol (can be stored for ⁇ 20 days at refrigerated temperatures) and administered intravenous. After reconstitution, the lyophilized single use product contains either 0.25 mg/mL or 0.50 mg/mL GM-CSF, 40 mg/Ml mannitol, 10 mg/ml sucrose, and 1.2 mg/ml tromethamine (final pH is 7.4 +/- 0.3). The reconstituted solution is then diluted into a 0.9% NaCl bag for IV administration (note if final GM-CSF is below 0.01 mg/mL add human albumin to 0.1% to prevent adso ⁇ tion to the IV bag.
  • G-CSF G-CSF (Granulocyte Colony Stimulating Factor)
  • Formulation Single-use solution formulation containing 0.3 mg/mL G-CSF, 10 mM sodium acetate, 5% mannitol, and 0.004% Tween-80 at a pH of 4.
  • the product is to be stored at refrigerated temperatures and no more than 24 hours at room temperature.
  • Neupogen can be diluted with D5W (do not dilute with saline at any time; product may precipitate), at concentrations below 5 to 15 ⁇ g/mL, and human albumin to 2 mg/mL to prevent adso ⁇ tion to IV bag.
  • Proleukin has a molecular weight of 15,300 daltons and differs from the natural human protein (is not glycosylated, the N-terminal alanine is removed, and has a serine substituted for the free cysteine at position 125).
  • Formulation Lyophilized formulation which is reconstituted with 0.9% benzyl alcohol (supplied) and administered intramuscular or subcutaneous.
  • the lyophilized vial contains 5 mg Somatrem, 40 mg mannitol and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic) and is reconstituted with 1 to 5 mL of 0.9% benzyl alcohol.
  • the lyophilized product is stored at refrigerated temperatures, the reconstituted product is good for 14 days at refrigerated temperatures.
  • Inhalation solution (aerosol mist produced by a compressed air driven nebulizer system). Comes in a single-use 2.5 mL ampule containing 1.0 mg/mL Dnase, 0.15 mg/mL calcium chloride dihydrate, and 8.77 mg ml sodium chloride, at a pH of 6.3. The solution is stored at refrigerated temperatures and should not be exposed to light.
  • M-CSF Macrophage-Colony Stimulating Factor
  • Epoetin Beta (Erythropoietin)
  • EPOGEN 18 Amgen erythropoietin treatment of anemia Epoetin alfa Thousand Oaks, CA associated with chronic renal (rEPO) failure, including patients on dialysis and not on dialysis, and anemia in Retrovir treated HIV-infected patients (June 1989); treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996) PROCRIT ® Ortho Biotech erythropoietin treatment of anemia
  • Epoetin alfa Raritan NJ associated with chronic renal
  • Retrovir treated HIV-infected patients June 1989
  • treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies September 1993
  • PROCRIT was approved for marketing under Amgen' s epoetin alfa PLA.
  • Amgen manufactures the product for Ortho Biotech. Under an agreement between the two companies, Amgen licensed to Ortho Pharmaceutical the U.S. rights to epoetin alfa for indications for human use excluding dialysis and diagnostics.
  • HumalogTM Eli Lilly recombinant diabetes (June 1996) insulin lispro Indianapolis, IN insulin
  • Humulin ® Eli Lilly recombinant diabetes (October 1982) human insulin Indianapolis, IN insulin (recombinant DNA origin)
  • Intron A Schering-Plough interferon hairy cell leukemia (June interferon alfa-2b Madison, NJ 1986); genital warts (June (recombinant) 1988); AIDS-related Kaposi's sarcoma (November 1988); hepatitis C (February 1991); hepatitis B (July 1992); malignant melanoma (December 1995); follicular lymphoma in conjunction with chemotherapy (November 1997)
  • GM-CSF neutropenia resulting from chemotherapy in acute myelogenous leukemia (September 1995); allogeneic bone marrow transplantation (November 1995); peripheral blood progenitor cell mobilization and transplantation (December 1995)
  • rG-CSF rG-CSF CA autologous or allogeneic bone marrow transplantation (June 1994); chronic severe neutropenia (December 1994); support peripheral blood progenitor cell transplantation (December 1995)
  • Novolin ® L Novo Nordisk recombinant insulin-dependent diabetes Lente ® human Pharmaceuticals insulin mellitus (July 1991) insulin zinc Princeton, NJ suspension (recombinant DNA origin)
  • RetevaseTM Boehringer tissue treatment of acute reteplase Mannheim plasminogen myocardial infarction
  • HIV-IT(V) Chiron Viagene gene therapy asymptomatic Phase II Retrovector TM HIV-l San Diego, CA HIV-1 11 IB env/rev retroviral infection vector
  • HIV Vaccine (gp 120) Chiron vaccine AIDS Phase II Emeryville, CA interleukin-10 (IL-10) Schering-Plough interleukin HIV disease Phase I Madison, NJ (see also autoimmune, digestive heart, neurologic, respiratory, skin)
  • ISIS 2922 Isis antisense cytomegalovirus Phase III fomivirsen Pharmaceuticals retinitis Carlsbad, CA
  • GM-CSF memantine Neurobiological AIDS dementia Phase II Technologies complex and Richmond, CA AIDS-related neuropathic pain (see also diabetes)
  • NEUPOGEN Amgen colony treatment and application Filgrastim (rG- Thousand Oaks, stimulating prevention of submitted CSF) CA factor neutropenia in HIV patients (see also cancer, respiratory)
  • TBC-3B Therion Biologies vaccine AIDS prevention Phase I (vaccinia virus Cambridge, MA expressing HIV genes env, gag and pal) AUTOIMMUNE DISORDERS
  • IDEC-131 IDEC MAb systemic lupus Phase I humanized MAb Pharmaceuticals erythematosus San Diego, CA
  • IL-2 fusion protein Seragen fusion rheumatoid Phase I/II DAB 385 IL-2 Hopkinton, MA protein arthritis (see also cancer, skin) interleukin-10 Schering-Plough interleukin rheumatoid Phase II (IL-10) Madison, NJ arthritis (see also AIDS/HIV, digestive, heart, neurologic, respiratory, skin)
  • ISIS 2302 Isis antisense rheumatoid Phase II
  • Betaseron National Cancer interferon non-small-cell lung Phase III recombinant beta Institute cancer see also NCI Trial interferon- lb Bethesda, MD neurologic) Berlex Laboratories Wayne, NJ bispeciftc antibody Chiron MAb cancer Phase I Emeryville, CA
  • CT-2584 Cell therapeutics ovarian, prostate Phase I Seattle, WA cancer, sarcoma cytosine deaminase GenVec gene therapy colon cancer Phase I gene-adenoviral Rockville, MD vector CANCER AND RELATED CONDITIONS
  • DA/Hu(gamma).15- Chiron Viagene gene therapy disseminated Phase I transduced San Diego, CA malignant autologous tumor melanoma cells; ITAT daniplestim Searle growth factor mobilization of Phase III Skokie, IL peripheral blood stem cells dendritic cell therapy Dendreon cellular advanced prostate Phase II/III Mountain View, therapy cancer CA multiple myeloma Phase I
  • EPREX 1 National Cancer erythropoietin neuroblastoma Phase II erythropoietin Institute NCI Trial Bethesda, MD Ortho Biotech Raritan, NJ
  • GM-CSF Powderject vaccine melanoma Phase I cellular cancer Vaccines sarcoma vaccine Madison, WI
  • GM-CSF chemotherapy-induced neutropenia
  • prophylaxis of chemotherapy- induced neutropenia in acute myelogenous leukemia see also AIDS/HIV
  • OncoRad ® PR CYTOGEN MAb targeted radiotherapy for Phase II CYT-356-Y-90 Princeton, NJ prostate malignancies
  • SlgOSlX Ares-Serono and interleukin hematological Phase I/II recombinant Serono Laboratories conditions interleukin-6 (r- Norwell, MA (myelodysplastic IL-6) syndromes, cancer)
  • TBC CEA Therion Biologies vaccine colorectal and lung Phase I/II
  • BetaRx-H VivoRx cellular insulin-dependent Phase I encapsulated Santa Monica, CA therapy diabetes human islets
  • Glucagen TM Novo Nordisk recombinant hypoglycemia Phase III recombinant Pharmacceuticals human protein (see also digestive) human Princeton, NJ glucagon
  • Phamaceuticals ulcerative colitis Carlsbad, CA see also autoimmune, skin, transplantation
  • Zenapax ® Huffmann-La MAb uveitis Phase I/II daclizumab Roche see also cancer, Nutley, NJ neurologic, skin, Protein Design transplantation
  • BioByPassTM GenVec gene therapy cardiovascular disease Phase I therapeutic Rockville, MD including cardiac artery angiogenesis disease and peripheral (VEGF) vascular disease, either as an adjunct or alternative to existing surgical approaches such as cardiac artery bypass grafts and angioplasty
  • Phamaceuticals therapy see also blood) Carlsbad, CA factor Vila Corvas deep vein thrombosis, Phase I inhibitors San Diego, CA pulmonary embolism, unstable angina, myocardial infarction
  • FIBLAST ® Scios growth peripheral vascular Phase II trafermin Mountain View, factor disease, coronary anery CA disease
  • hepatitis C see also cancer
  • hepatitis C PEG- Phase III intron A
  • Rebir ® Serono interferon viral infections Phase II/III recombinant Laboratories see also cancer, interferon beta- la Norwell, MA neurologic
  • RotashieldTM Wyeth-Lederle continuous cell prevention of application rotavirus vaccine, Vaccines & line vaccine rotaviral submitted live, oral, Pediatrics gastroenteritis in tetravalent Philadelphia, PA infants rotavirus vaccine Virus Research vaccine rotavirus in infants Phase II Institute Cambridge, MA
  • AntideTM Ares/Serono and hormone- female infertility Phase I gonadotropin Serono releasing hormone- Laboratories hormone releasing hormone Norwell, MA antagonist antagonist
  • Ta multiple sclerosis see also cancer
  • Vaccine Meriden CT influenza influenza vaccine influenza virus Aviron vaccine prevention of Phase III vaccine (live, Mountain View, CA influenza attenuated) interleukin-4 Immunex recombinant asthma Phase I receptor Seattle, WA soluble receptor interleukin-10 Schering-Plough interleukin acute lung injury Phase I (iL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, neurologic, skin) lisofylline Cell Therapeutics acute lung injury Phase II Seattle, WA (see also other)
  • NEUPOGEN Amgen colony multilobar Phase III Filgrastim (rG- Thousand Oaks, CA stimulation pneumonia, CSF) factor pneumonia sepsis (see also AIDS/HIV, cancer)
  • IL-2 fusion Seragen fusion protein moderate to severe Phase I/II protein Hopkinton, MA psoriasis
  • ISIS 2302 Isis antisense psoriasis Phase II
  • TGF-beta3 OSI growth factor impaired wound Phase II
  • ISIS 2302 Isis antisense renal transplant Phase II Pharmaceuticals rejection (see also autoimmune, digestive, skin)
  • biopharmaceuticals which include, for example, any proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids or other biopolymers.
  • biopharmaceuticals to be included in the crystal formulations of the present invention include the following: insulin, glucagon, Glucagon-Like Peptide- 1 (7-37)OH (GLP-1), human growth hormone, leptin, follicle-stimulating hormone (FSH), ribozyme, and analogs thereof .
  • the API's useful with the present invention include those which themselves may form crystalline products, as well as those which do not.
  • any proteins can be prepared as microcrystalline suspension products, but the results have frequently been unsatisfactory using existing technology.
  • inclusion of these biomolecules into a host crystal system in accordance with the present invention overcomes this limitation on crystallization.
  • the invention further finds utility even with API's that are readily crystallized, such as insulin.
  • the inco ⁇ oration of such API's into a single crystal lattice can be used to enhance stability or provide means of delivery that have different characteristics.
  • Solvents for preparation of the saturated and supersaturated crystal lattice component include, but are not limited to, water, alcohols (e.g., ethanol, isopropanol), other organic solvents, acids, bases, and buffers.
  • the crystals of the present invention are prepared to have a predetermined amount of active pharmaceutical ingredient.
  • the desired amount of active pharmaceutical ingredient will depend on typical considerations, such as the effective amount of API used for administering to a patient.
  • the concentration of API in the crystal is controlled, such as by previously described means, to yield crystals which are readily used in preparing pharmaceutical formulations for administration.
  • the active pharmaceutical ingredient can be inco ⁇ orated into the crystals at any of a wide variety of molar or weight percentages.
  • Preferred percentages can be easily selected by a skilled artisan taking into account the usual considerations for later formulation of the desired pharmaceutical compositions, depending on the application, route of delivery, and desired pharmacological profile. Preferred percentages include, for example, concentrations of 0.01 - 1 weight percent. As used herein, all weight percentages are given as the percent 59 based on the weight of the crystal including the crystal lattice component, the active pharmaceutical ingredient and any other components included within the crystals, unless stated otherwise.
  • the crystals may be prepared at varying size distributions, similarly depending on the subsequent formulating to be done with the crystals, or on crystal growth parameters.
  • the crystals may be harvested and then sorted directly to desired size ranges, or may first be processed, such as by grinding or milling, and then sorted such as by sieving.
  • a desired amount of active pharmaceutical ingredient may be obtained simply by obtaining a determined weight of crystals containing the active pharmaceutical ingredient at a known weight concentration.
  • the useful size or weight range of the crystals of the present invention accordingly varies widely, depending on such factors as the inclusion level of the active pharmaceutical ingredient, the dosage amount for the active pharmaceutical ingredient, and the method of delivery of the crystals.
  • suitable crystals may have an average size distribution of 1 ⁇ m to 1 mm .
  • the crystals of the present invention will typically be used in a formulation comprising a large number of crystals. It is a feature of the present invention that the active pharmaceutical ingredient is included within the crystal lattice component in a predictable, oriented fashion. This leads to a uniform concentration of the active pharmaceutical ingredient as a molar, and therefore weight, percentage of the crystals.
  • a composition of crystals having a substantially uniform weight concentration of active pharmaceutical ingredient as between crystals.
  • substantially uniform weight concentration refers to the fact that the weight concentration of active pharmaceutical ingredient in the various crystals is sufficiently uniform that an acceptably accurate weight of active pharmaceutical ingredient can be obtained based on the weight of the crystals and the average concentration of active pharmaceutical ingredient in such crystals.
  • a composition of crystals in which the size distribution of active pharmaceutical ingredient does not vary between crystals by more than about 20 percent.
  • alternate embodiments may be equally 60 useful, including mixtures of different size crystals.
  • a desired quantity of active pharmaceutical ingredient is then accurately obtained by measuring a weight amount of crystals which, given the concentration of active pharmaceutical ingredient, yields the selected weight of active pharmaceutical ingredient.
  • the crystals and included API's are useful in the crystal form for both the stabilization and storage of the API and for the administration of the API to a patient.
  • patient refers to either humans or non-humans, depending on the nature of the active pharmaceutical ingredient.
  • the crystals may be used as such, and in one aspect of the present invention the crystals consist essentially of simply the crystal lattice component and the API. Alternatively, the crystals include the crystal lattice component and the API in combination with other pharmaceutically-acceptable adjuvants also contained within the crystals.
  • the crystals of the present invention are preferably formulated as pharmaceutical materials for ultimate delivery in solid or liquid form.
  • the crystals are typically formulated with common, compatible, pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof.
  • excipients such as excipients, diluents, carriers or mixtures thereof.
  • pharmaceutically-acceptable refers in this context to the excipients, diluents or carriers, as well as coatings or other components referred to elsewhere, being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • excipients, diluents, and carriers that are suitable for such dosage forms are well known in the art, and include the following: suspension additives such as tonicity modifiers, buffers, precipitants, and preservatives; fillers and extenders such as starch, lactose, dextrose, sucrose, sorbitol, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; reso ⁇ tion accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; adso ⁇ tive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid 61 polyethyl
  • the crystals may be coated to achieve various effects.
  • the crystals are coated with the same crystal lattice component which forms the underlying crystal, but without the included API. This assures that the coating and the underlying crystal have compatibility.
  • the coating is then applied at a thickness which provides the desired effect, such as further protection of the active pharmaceutical ingredient, bulking of the crystal for handling, and/or effecting a sustained or delayed release of the active pharmaceutical ingredient.
  • the same effects can be accomplished by coating the crystals with other compatible coating compositions, such as those which are well known in the pharmaceutical coating art.
  • the crystals can also be coated so as to release the active pharmaceutical ingredient only or preferably in a particular part of the intestinal tract or other route of administration, possibly over a period of time. This is accomplished, in known fashion, using coatings, envelopes, and protective matrices made, for example, from polymeric substances or waxes.
  • the crystals and included API's may be packaged and administered to patients in discrete pharmaceutical dosage forms.
  • the crystals may be used as such in solid form, or may be formulated into liquid solutions or suspensions prior to use.
  • the compositions may accordingly be administered by various routes, for example, by the oral, rectal, vaginal, ocular, buccal, nasal, pulmonary, iontophoretic, topical or parenteral routes. Such compositions form part of the present invention and are prepared in manners well known in the pharmaceutical art.
  • the API's of the present invention are effective over a varied dosage range.
  • Such dosages are readily accommodated by the present invention by permitting various sizes of crystals, concentrations of API, etc. It will be understood that the amount administered will be determined in light of the relevant circumstances, including the condition to be treated, the choice of API to be administered, the size of the patient being treated, and the chosen route of administration. Therefore, specific dosage ranges will differ accordingly, and are not limiting of the scope of the invention in any way. 62
  • compositions are formulated in one embodiment as a unit dosage form.
  • unit dosage form refers to physically discrete units, such as tablets, capsules, and suspensions in vials or cartridge/pen systems suitable as unitary dosages, particularly as unitary daily dosages.
  • Each discrete unit contains a predetermined quantity of active pharmaceutical material calculated to produce the desired effect, e.g., a prophylactic or therapeutic effect.
  • the amount of active pharmaceutical ingredient contained in a given dosage unit can be varied depending on the manner of delivering the crystals. For example, a single dosage unit in tablet form may contain 1/4, 1/3, 1/2 or 1 times the unit dose for the active pharmaceutical ingredient, according to which 1 to 4 tablets would be administered to achieve a unit dose of the active pharmaceutical ingredient.
  • a pharmaceutical product in dosage form comprising a pharmaceutical delivery unit including a dosage amount of active pharmaceutical ingredient.
  • the API is contained within the crystal lattice component, and a sufficient amount of crystals is included within the delivery unit to constitute the dosage amount of the API.
  • the dosage amount of pharmaceutical may be obtained by provision of one or more crystals of the present invention.
  • One form of the product consists essentially of a dosage amount of the crystals.
  • the pharmaceutical product consists of the dosage amount of the crystals.
  • the ultimate delivery forms may include, for example, tablets, soft and hard gelatin capsules, pellets, granules, marumes, lozenges, sachets, cachets, elixirs, suspensions, ointments, suppositories, injection solutions and suspensions, nonpareils, spheres and sterile packaged powders.
  • the crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants, including excipients, diluents and carriers, as already described.
  • One preferred form of the pharmaceutical product consists essentially of the crystals, and an alternate form consists of the crystals and the pharmaceutically-acceptable adjuvants.
  • the delivery forms are prepared by conventional techniques such as disclosed in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, PA (1995), which is inco ⁇ orated herein by reference, or other treatises available to the skilled artisan.
  • Compressed tablets are prepared by well-known means which are conventional in the art.
  • the tablets may be prepared by wet or dry granulation methods or by direct compression, and may be produced by any of a wide variety of tabletting machines.
  • Tablet formulations usually inco ⁇ orate diluents, binders, lubricants and disintegrators, as well as the crystals with included API's.
  • Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful.
  • Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
  • Certain solid pharmaceutical dosage forms of the present invention may be coated in conventional fashion with a wide variety of materials utilizing various processes.
  • the products of the present invention may be sugar coated or film coated in accordance with well-known techniques.
  • the coatings serve an aesthetic pu ⁇ ose as well as a practical one. Coatings can mask an unpleasant taste or odor, can increase ease of ingestion by the patient, and can serve to improve the ultimate appearance of the dosage form. Similarly, coatings can protect the product from the effects of air, moisture and light, can improve product identification, and can facilitate handling in packaging and fill lines during manufacture.
  • Various adjuvants may be included in the coating formulations as is well known in the art. These include, for example, permeability enhancers, plasticizers, antitacking agents and the like.
  • permeability enhancers include, for example, plasticizers, antitacking agents and the like.
  • a discussion of coating techniques and adjuvants is presented in United States Patent No. 5,015,480, issued to Childers et al. on May 14, 1991, the pertinent portions of which are hereby inco ⁇ orated herein by reference. Further information pertinent to coating processes and equipment may be obtained from Remington's Pharmaceutical Sciences, supra. Tablets are often coated with sugar as a flavorant and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet.
  • the compounds may also be formulated as chewable tablets by using large amounts of 64 pleasant-tasting substances such as mannitol in the formulation, as is now well- established practice.
  • Instantly dissolving tablet-like formulations are also now frequently used to assure that the subject consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some subjects.
  • a lubricant is used in a tablet formulation to prevent the tablet and punches from sticking in the die of the tabletting machine.
  • the lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
  • Tablet disintegrators are substances which swell when wetted to break up the tablet and release the crystals. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate.
  • Enteric formulations are used to protect crystals and the included API's from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
  • the crystals with included API's may similarly be formulated into capsules for administration.
  • Such capsules are prepared utilizing conventional encapsulating methods.
  • a general method of manufacture involves preparing the crystals for use in capsules, such as by milling the crystals to a suitable size.
  • the crystals are blended with desired excipients, diluents or carriers, and the resulting mixture is filled into suitably-sized capsules, typically hard gelatin capsules, using conventional capsule-filling machines.
  • the usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
  • Cocoa butter is a traditional suppository base, which 65 may be modified by addition of waxes to raise its melting point slightly.
  • Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are also in wide use.
  • the crystals can also be similarly formulated as elixirs or suspensions for convenient oral administration or for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.
  • the inventive crystals enable the design of sustained-release formulations based upon various factors to yield both the desired amount of active pharmaceutical ingredient and the desired pharmacokinetic profile for delivery of the active pharmaceutical ingredient.
  • Selectively inco ⁇ orating the active pharmaceutical ingredient into the crystal lattice, e.g., into a specific crystal growth sector modulates the release profiles and can therefore be used to effect desired pharmacological properties.
  • the choice of the crystal component and the process used to grow the crystals of excipient host and guest active pharmaceutical ingredient can be selected and/or modified to adjust parameters such as the delivery rate of the active pharmaceutical ingredient upon use of the formulation.
  • the active pharmaceutical ingredient is inco ⁇ orated into the crystal matrix at a selected rate, typically as only a small weight percentage of the overall crystal. This permits moderate and uniform rates of release.
  • Various approaches may be used to accomplish a delayed or sustained release of active pharmaceutical ingredient from the crystals.
  • the crystals of the desired size are combined with a compatible preservative and the mixture is injected subcutaneously or surgically implanted to provide a prolonged payout as the crystals dissolve as a result of contact with the surrounding body tissue and fluid.
  • the concentration of the active pharmaceutical ingredient in the crystals is reduced in order to effect a sustained release over time.
  • larger crystals may be used to provide for more prolonged payout of the active pharmaceutical ingredient.
  • coatings on the crystals are used to affect the rate of release of the active pharmaceutical ingredient. Such coatings may comprise the same crystal lattice component but without the included active pharmaceutical ingredient, as well as other coating compositions useful for this pu ⁇ ose. 66
  • the crystals of the present invention can be used to isolate and/or store the active pharmaceutical ingredient for later reconstitution into solution.
  • the crystals may be stored for extended periods of time prior to reconstitution in view of the added stability accorded the API's by the encompassing crystal lattice component.
  • the crystals are then combined with pharmaceutically-acceptable excipients, diluents or carriers to prepare the solutions for subsequent administration.
  • the crystals are readily dissolved or suspended in appropriate diluents, which may be selected, for example, from the list previously provided with regard to diluents used to initially prepare the crystals.
  • Such solutions of dissolved crystals provide the active pharmaceutical ingredient free of the previously encompassing crystal lattice component.

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Abstract

Pharmaceutical compositions comprising crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the active pharmaceutical ingredients to a patient. The crystals are typically combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing predetermined amounts of the pharmaceuticals. Also provided are methods for preparing the crystals, and methods for storing and administering the active pharmaceutical ingredient either included within the crystals or upon reconstitution of the crystals to a solution.

Description

PHARMACEUTICAL MATERIALS AND METHODS FOR THEIR PREPARATION AND USE
BACKGROUND OF THE INVENTION
Field of the Invention:
The present invention relates to pharmaceutical formulations involving the inclusion of an active pharmaceutical ingredient ("API") in a pharmaceutically- acceptable single crystal matrix. More particularly, the crystals contain growth- sector specific, oriented inclusions of active pharmaceutical ingredients which are isolated. The active pharmaceutical ingredients have higher stability and shelf-life, and can be delivered in conventional dosage forms. This invention has general application to active pharmaceutical ingredients, and in one aspect has particular application to biopharmaceuticals. As used herein, the term "biopharmaceuticals" is used to refer to a subset of API's which are polymeric in nature, including for example, proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids. Description of the Prior Art:
There is a continuing need for pharmaceutical compositions which are capable of maintaining the quality and efficacy of the API during storage and delivery. The loss of potency of an API is a critical concern in assuring that viable, effective drugs are delivered to patients. It is similarly desirable to have formulations which do not require special packaging or handling. Further, it remains a constant goal to provide active pharmaceutical ingredients in a form which facilitates their use by the consumer, such as through convenient dosage forms. The present invention addresses these and other issues concerning pharmaceutical compositions and formulations.
Although not limited to biopharmaceuticals, the usefulness of the present invention is well exemplified with respect to biopharmaceuticals, many of which demonstrate the problems encountered in prior-art approaches. Ensuring long-term stability and maintaining activity of biopharmaceuticals is a prevalent concern. The chemical complexity and conformational fragility of protein drugs, for example, make them highly susceptible to both physical and chemical instabilities and threaten their emergence into the marketplace. Denaturation, adsorption with container walls, aggregation, and precipitation can result from non-covalent interactions between a drug and its environment. Insulin, for instance, has been shown to adsorb onto the surfaces of glass and plastic containers, and to have interactions at air-water interfaces, leading to denaturation, aggregation and precipitation. For example, upon denaturation human growth hormone (HGH) forms dimers and higher molecular weight aggregates, and glucagon in solution has been shown to readily gel or aggregate when subjected to mechanical stress. As a further example, researchers have distinguished nine major reaction mechanisms by which proteins degrade, including hydrolysis, imide formation, deamidation, isomerization, racemization, diketopiperazine formation, oxidation, disulfide exchange, and photodecomposition. The rates of these deleterious processes depend in large measure on the protein and its environment. The primary chemical degradation products of glucagon, for example, include oxidation of Met (27), deamidation of Gin (24), and acid-catalyzed hydrolysis at Asp (9), Asp (15) and Asp (21). HGH undergoes chemical decomposition via oxidation at Met (14) and deamidation at Asn (149).
A critical challenge of product development science in the pharmaceutical industry therefore has been devising formulations that maintain the stability of the active pharmaceutical ingredient over an acceptable shelf-life. This has been especially difficult to achieve for certain API's which are unstable in solution or with respect to many common formulation processes. Developing techniques for stabilization and storage looms as a great impediment to the pharmaceutical industry. Formulation scientists have consequently used a variety of techniques to enhance the stability of API's while maintaining other important product characteristics such as biocompatibility, absorption, pharmacokinetics, efficacy and excretion.
One technique used in formulating biopharmaceuticals has been lyophilization of the biopharmaceutical solution in the presence of excipients, buffers and/or bulking agents. However, even lyophilized preparations must typically be stored under refrigeration, a requirement which is neither technically nor economically feasible in many markets and inhibits flexibility of patient use. There has therefore been a continuing demand for formulations of many biopharmaceuticals which would permit their storage at ambient temperatures. This would permit more rapid development of products, increasing flexibility in shipping, storing and carrying the drug products, and allowing introduction and use of such products in markets where refrigeration is too costly. Moreover, the increased stabilization of biopharmaceuticals would naturally improve the general use of the biopharmaceuticals where shelf life is an important consideration, whether or not refrigeration or other concerns are at issue. The prior art use of excipients in the lyophilization of biopharmaceuticals has been directed away from inclusion of the biopharmaceuticals in single crystals in the manner of the present invention. It has been widely assumed that amorphous glasses are critical in the stabilization of biopharmaceuticals by such excipients in lyophilized form, and it has been suggested that the drug molecules must exist in amoφhous regions between the crystalline domains. See, e.g., M. J. Pikal, "Freeze Drying of Proteins", to be published in Peptide and Protein Delivery, 2nd Ed., V. H. L. Lee, Marcel Dekker, Preprint, 1995. Implicit in this reasoning is the conclusion that the biopharmaceuticals could not exist as guests within single crystals.
In the process of lyophilization, typically an aqueous solution containing a biopharmaceutical with a limited amount of excipient(s) is frozen and then dried under vacuum to produce solids of sufficient stability for storage and distribution. Excipients are added to prevent blow out of the product, to provide stability during lyophilization and/or dissolution, and to enhance compatibility for parenteral use. Various excipients used with lyophilization have included salts, metal ions, polyalcohols, surfactants, reducing agents, chelating agents, other proteins, amino acids, fatty acids, and phospholipids. The more frequently used excipients include mannitol, alanine, glycine, sorbitol, lactose, arginine, and maltose. The results obtained with such excipients, however, have usually been inconsistent. Most lyophilized biopharmaceuticals are amoφhous powders that have no specific structure, and as a result, the amount and location of the incoφorated biopharmaceutical varies widely for the product particles. Also, they are typically readily dissolved, rendering them unsuitable for use as a sustained-release material. Further, there is no isolation of the pharmaceutical molecules from the environment or one another, leaving them susceptible to degradation by various mechanisms. Studies have shown that lyophilization of excipients can typically damage proteins rather than protect them. See, e.g., J. F. Caφenter, J. H. Crowe, "Infrared spectroscopic studies of the interaction of carbohydrates with dried proteins", Biochemistry 1989, 28, 3916-3922; J. F. Caφenter, S. Prestrelski, T. Arakawa, "Separation of freezing- and drying-induced denaturation of lyophilized proteins by stress-specific stabilization: I. Enzyme activity and calorimetric studies," Arch. Biochem. Biophys. 1993, 303, 456-464. K. Izutsu, S. Yoshioka, Y. Takeda, "The effects of additives on the stability of freeze-dried β-galactosidase stored at elevated temperatures", Int. J. Pharm. 1991, 71, 137-146. K. Izutsu, S. Yoshioka, T. Teroa, "Decreased protein-stabilizing effects of cryoprotectants due to crystallization", Pharm. Res. 1993, 10, 1232-1237. Crystallized pharmaceuticals have been used in some instances, but there have been inherent limitations. Some API's , e.g. insulin, can be crystallized themselves, and are useful in that form for administration to patients. However, the majority of biopharmaceuticals either do not crystallize or the crystallization is very difficult, particularly on a commercial scale. Further, crystallization procedures are limited to the use of pharmaceutically-acceptable ingredients and process conditions that do not adversely affect the active pharmaceutical ingredient, thus further constraining the ability to obtain desired microcrystalline suspensions.
The fact that macromolecules are routinely isolated in sub-millimolar concentrations in a variety of crystals is known. See, e.g., K. Strupat, M. Karas, F. Hillenkamp, Int. J. Mass Spec. Ion Proc, 1 11, 89-102, 1991. Also, certain aromatic acids have been employed as hosts for biopolymer guests in crystals for use in matrix-assisted laser desoφtion ionization (MALDI) mass spectrometry, but not for the puφoses of the present invention. See, Review by F. Hillenkamp, M. Karas, R.C. Beavis, B.T. Chait, Anal. Chem, 63, 1193A-1203A; S. Borman,
Chem. Eng. News, 23-25, June 19, 1995. However, crystallization conditions in these studies were optimized for characterization of the incoφorated biopolymers. There were no investigations into optimizations that would be relevant to pharmaceutical preparations or operations such as homogeneity of the concentration of the inclusions, process scale-up, process robustness, chemical and physical stability of the preparations, suspendability in biocompatible solutions, preservative requirements and compatibility, container/closure system compatibility, and pharmacokinetic profiles.
The difficulty in obtaining suitable single crystals of some biopolymers has encouraged structural chemists to partially orient such molecules with electric, magnetic, or flow fields, by dissolution in liquid crystals or stretched gels, and as monolayers. In a similar effort, the isolation of biopolymers in a single crystal matrix has recently been studied in an effort to use such crystals for structural analysis of the biopolymers. Such isolation technique is described in "Single Crystal Matrix Isolation of Biopolymers," J. Chmielewski, J.J. Lewis, S. Lovell, R. Zutshi, P. Savickas, CA. Mitchell, J.A. Subramony, and B. Kahr, J. Am. Chem. Sόc. 1997, 119, 10565-10566. However, this article simply demonstrates that certain biopolymers are oriented by the host lattice, and the article suggests the use of such crystals for analyzing spectral anisotropies in biological molecules which could not otherwise be crystallized. This article does not discuss or suggest the use of this technique for enhancement of stability or sustained release of pharmaceuticals, or their administration to patients. Further, the proteins studied were not of pharmaceutical interest, the crystal materials described in this article, namely phthalic acid, gentisic acid and sinapic acid, were not selected or evaluated for biocompatibility, and the crystal sizes were not optimized for particular routes of administration. Therefore, the produced crystals with included biopolymers would not be suitable for administration to patients.
Other prior art procedures have required the use of polymers that are difficult to prepare, require harsh preparation conditions that can be harmful to the API's, and yield inconsistent results. For example, United States Patent No. 5,075,291 describes a process for preparing a uniformly-dispersed, pharmaceutically-active material in a crystalline sugar alcohol matrix. However, this process requires the addition of the API into a molten sugar alcohol with considerable mechanical agitation. Many API's and virtually all biopharmaceuticals would not be stable in the extreme temperature of 110°C and the physical stresses of a high-shear vortex mixer used for agitation. The present invention does not require these extremes of temperature and physical agitation. Also, the process of the present invention slowly includes the API into the growing crystal lattice in specific growth sectors, instead of homogeneous mixing and entrapping of the active pharmaceutical ingredient in a viscous melt.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to pharmaceutical compositions comprising single crystals of a pharmaceutically-acceptable crystal lattice component, and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation. The crystals are prepared using components and methods which yield crystals having suitable purity and efficacy for use in administering the API's to a patient. The crystals may be coated or combined with adjuvants such as excipients, diluents or carriers, and are preferably formulated into tablets, capsules, suspensions, and other conventional forms containing dosage amounts of the API's. Alternatively, the crystals are prepared as depot formulations which may be administered, as by subcutaneous injection or implantation, to provide a long-term payout or sustained release of the active pharmaceutical ingredient. The present invention further provides methods for preparing the crystals and for storing and administering the active pharmaceutical ingredient either in crystal form or upon reconstitution to a solution.
Accordingly, it is an object of the present invention to provide single crystals which include API's in a growth-sector specific orientation. It is a feature of the invention that the API's are included at predictable, uniform concentrations that permit use of the crystals in formulating dosage amounts of the API's. Another object of the present invention is to provide compositions comprising API's included in single crystals to provide improved stability and shelf-life. The active pharmaceutical ingredients may therefore be stored for extended periods of time prior to use either as crystals or as reconstituted solutions. It is a further object of the present invention to provide single crystals with included API's to provide quick, delayed-release or sustained-release formulations for flexibility in pharmacokinetic profiles in delivery of the API's to patients.
Another object of the present invention is to provide pharmaceutical delivery units including an amount of single crystals sufficient to provide a dosage amount of the included active pharmaceutical ingredient. Alternatively, the pharmaceutical delivery units include a quantity of crystals sufficient to provide a prolonged payout of the active pharmaceutical ingredient. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants including excipients, diluents and carriers.
A further object of the present invention is to provide methods for preparing compositions comprising single crystals with growth-sector specific inclusions of API's.
It is another object of the present invention to provide methods for the storage and administration of API's utilizing inclusion of the API's within single crystals. Other objects, features, and advantages of the present invention will be apparent to those skilled in the art from the following description and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a photomicrograph illustrating fluorescence of a single crystal of green fluorescent protein in α-lactose monohydrate (1.8 (h) x 0.8 (w) x 0.5 (d) mm3) with an idealized representation of habit. The sides of the crystal in the photomicrograph are bright due to internal reflection.
Figure 2 is a graph of the fluorescence decay of the green fluorescent protein at 333°K in several environments: mixed crystal in α-lactose monohydrate (triangle), saturated lactose solution (square), and lyophilized α-lactose monohydrate (diamond).
DESCRIPTION OF THE PREFERRED EMBODIMENT
For the puφoses of promoting an understanding of the present invention, reference will now be made to the embodiments described hereafter. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended, such modifications and applications of the principles of the invention as described herein being contemplated as would normally occur to one skilled in the art to which the invention relates.
The present invention utilizes single-crystal matrix inclusion of active pharmaceutical ingredients ("API's") to achieve advantageous storage and delivery of the API's. This invention has application to a wide range of API's to provide enhanced stability and/or delivery of the active pharmaceutical ingredients. For some applications, such as for many biopharmaceuticals, the invention is particularly advantageous in providing greater stability over time and in providing alternative delivery and sustained release formulations to patients . The small molecule host crystals comprise a crystal lattice component which includes the API's in an oriented, growth-sector specific manner. The crystals and included API's are prepared to be pharmaceutically acceptable and pure, thereby being useful for administration to patients to be treated with the API's. As used herein, the term "pharmaceutically-acceptable" refers to sufficient quality to meet regulatory and compendial requirements for administration to humans and/or animals. The crystals provide a regular, predictable inclusion of the guest active pharmaceutical ingredient, and the crystals can consequently be used for obtaining a predetermined amount of the active pharmaceutical ingredient for delivery to a patient. In one aspect, the host crystal gradually dissolves upon contact with body tissue or fluids, and is therefore useful as a system for delivery of the active pharmaceutical ingredient into the body. Alternatively, the crystals and included active pharmaceutical ingredient may be reconstituted into a solution for administration to a patient.
The active pharmaceutical ingredient molecules are generally isolated from one another and are insulated from the environment by the host crystal. This leads to reduced susceptibility of the API to degradation, and therefore enhanced stability and shelf-life. Also, the use of appropriate host crystal compounds, or selected dosage forms, permits the design of quick, delayed, or sustained-release formulations for delivery of the active pharmaceutical ingredient. Sustained- release formulations are particularly advantageous for treatment of chronic conditions as they provide a consistent amount of drug delivery over a long period of time to improve ease of use and patient compliance in administering the API.
The crystals preferentially incoφorate the active pharmaceutical ingredient on certain faces, thereby providing a growth-sector specific inclusion and orientation to the API's. As used herein, the term "growth-sector specific inclusion and orientation," and equivalent terminology, refers to the fact that the API molecules are included primarily at certain faces of the crystal matrix. The growth-sector specific inclusion and orientation can be determined by one skilled in the art, as demonstrated in the examples herein, by fluorescence microscopy and anisotropy measurements, single crystal desoφtion mass spectrometry, and autoradiography of 14C-labeled material. In one embodiment, at least about
0.001% (on weight/weight (w/w) basis) of the pharmaceutical is included within specific faces of the crystal matrix, and in another embodiment at least about 0.1% (w/w) and up to about 10%. The crystal parameters, including the particular crystal lattice component for a given API, the concentration of API, the use of crystal adjuvants, and the crystallization conditions, are selected to achieve the growth-sector specific inclusion and orientation of the API within the crystals.
The method of the present invention broadly involves the including of the active pharmaceutical ingredient into the single crystal matrix formed from a pharmaceutically-acceptable crystal lattice component. As used herein, the term "included" in the crystals refers to the active pharmaceutical ingredient being chemically adsorbed within the crystal lattice as the crystal is formed. This inclusion of the active pharmaceutical ingredient molecules is distinguished from crystallization of the API molecules with one another, and from simple and random entrapment of the API molecules by the formed crystal. The crystal product of the present invention is ordered, in contrast to the amoφhous material produced by other approaches. The API is incoφorated in the crystal in relation to its degree of affinity for the crystal lattice molecules. The crystal lattice component is therefore selected to be both chemically and physically compatible with the API such that the API is received by the crystal during formation, and remains stable and efficacious while within the crystal and upon release therefrom. In a typical approach, the including of the active pharmaceutical ingredient involves combining the crystal lattice component, the active pharmaceutical ingredient and a pharmaceutically-acceptable adjuvant in a liquid state. The crystal lattice component is then crystallized under pharmaceutically-acceptable conditions to form the inventive crystals. For example, one method uses spiking of the API into a saturated or supersaturated solution of the crystal lattice component in a suitable organic and/or aqueous solvent system. Alternately, the saturated or supersaturated solution of the crystal lattice component may be spiked into the API solution. Other components may also be added to the solution, including compounds which facilitate or modify crystal growth or which are desired for incoφoration in the final formulation. The solution may be seeded using any of a variety of conventional techniques.
In one approach, the solution is allowed to evaporate and/or equilibrate to cooler conditions for growth of the crystals. The crystals are then grown as the solvent is slowly evaporated away and or the solution is cooled, with the evaporation and temperature gradient conditions being selected dependent on such factors as the solvent system and the desired crystal size. The crystals containing the active pharmaceutical ingredient are harvested from the remaining solution and are preferably washed to remove surface contamination. This procedure yields crystals which include the active pharmaceutical ingredient at a predictable concentration and facial orientation.
In accordance with the present invention, crystals are grown under pharmaceutically-acceptable conditions. As used herein, the term "pharmaceutically-acceptable conditions" refers to the use of crystal and API compounds which are pharmaceutically-pure, and for which such pharmaceutical purity is maintained in the final crystals. The crystal and API compounds are pharmaceutically pure, or have pharmaceutical purity, if they are of sufficient purity to be suitable for administration under applicable FDA or other administrative regulations regarding purity. The term pharmaceutically-acceptable conditions further refers to the use of crystallization conditions through which the API compounds retain pharmaceutical efficacy in the final crystals and upon subsequent administration to patients.
The present invention readily allows the inclusion of API's by affinity with the small host molecules in the growing crystal lattice. This overcomes many of the limitations associated with previous approaches. The processing involved with preparing the present crystals does not expose the API's to harsh conditions, thereby substantially reducing or avoiding the possible degradation or disruption of the structural aspects of the API which could occur with prior art techniques. The inventive crystals have an added advantage in that they do not interfere with normal analytical methodologies used for characterizing the pharmaceutical product. The small host molecules can be easily separated on the basis of molecular size, which is not the case for prior art techniques which use polymers that interfere with analytical methodologies.
The API molecules are incoφorated into the host crystals typically at rates of at least about 0.001% (w/w), preferably at least about 0.1%, and more preferably about 1% to about 10% (w/w). Alternatively, the API molecules are included at rates of at least about 0.01%, and as much as at least about 1% (w/w). The limited molar concentration of the active pharmaceutical ingredient in the host crystals means that the active pharmaceutical ingredient molecules are generally isolated from one another in the crystals. Isolation of the API molecules is particularly advantageous for those molecules, such as certain biopharmaceuticals, which could otherwise react with one another (e.g., by polymerization) or the surrounding environment. The degree of isolation can be verified by those skilled in the art using atomic force microscopy or reaction fluorescence energy techniques. The present invention has a particular application to guest-host systems in which the guest API molecules are reactive with one another, but in which these molecules are sufficiently isolated from one another in the crystals as to substantially prevent such interaction. Consequently, the invention provides containment of the API molecules in the solid state crystals and provides for the API to be comformationally stable.
The method preferably involves preparing a mixture of crystals of substantially uniform size. This may include processing of the harvested crystals, such as by grinding or milling, to reduce the crystals to a substantially uniform size. Greater uniformity can be achieved by sorting the processed crystals, such as by sieving. A preferred method further includes obtaining crystals which have a substantially uniform concentration of pharmaceuticals, for example, about 1% (w/w) of pharmaceuticals, that do not vary between crystals by more than 10 percent.
The method of the present invention may further include formulating the crystals into pharmaceutical preparations. For example, the collected crystals may optionally be coated with a suitable composition. Coated or uncoated crystals may be blended with one or more pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. The blended crystals and adjuvant(s) are then formulated into pharmaceutical delivery units. In one embodiment, each unit includes a predetermined amount of the pharmaceutical. Alternatively, the crystals are combined in a delivery unit intended to deliver multiple or sustained dosing of the API over a period of time, such as by subcutaneous implantation of the delivery unit. A further aspect of the method of the present invention involves reconstituting the crystals to liquid form. In accordance with this method, the harvested crystals are dissolved in a suitable diluent for the crystal lattice component. The dissolution of the crystals releases the API from the crystals. The resulting solution may include other adjuvants, such as excipients, diluents or carriers, and the mixture is formulated under conventional procedures to desired delivery forms. In a particular aspect of the present invention, the crystals are used to store the pharmaceutical for a period of time, such as at least one month, or at least one year, and the crystals are subsequently dissolved to use the active pharmaceutical ingredient. The present invention involves the use of any of a wide variety of pharmaceutically-acceptable host crystal systems that can incoφorate API's in a growing crystal lattice. The crystal lattice component is selected to be compatible with the guest API, and to be suited to the use of the resulting formulation for storage and administration. Selection of the crystal lattice component will involve consideration of such factors as affinity for the API, crystal size distribution and moφhology, and desired pharmaceutical concentration and delivery rate, as well as other factors well known in the art of pharmaceutical delivery systems. The crystal systems must consistently incoφorate the guest active pharmaceutical ingredient in terms of concentration and placement within the crystal lattice. The crystals also must grow under conditions which will not degrade or otherwise adversely affect the viability of the active pharmaceutical ingredient.
Preferred host crystal materials are those that have a high affinity for the included API. It appears that the oriented inclusion of the API's is related to the affinity between the crystal lattice component and the API. The affinity between these materials is therefore important in obtaining the desired inclusion of the API's, and also permits control of the inclusion based upon this affinity. For example, the concentration of the pharmaceutical in a crystal can be controlled by selecting the host component to have an affinity for the API which yields the desired inclusion rate. Also, mixtures of host materials, or of host materials and other excipients, can be used to provide an affinity yielding the desired inclusion level. In one aspect of the present invention, the API's are incoφorated at levels of at least about 0.001% (w/w of guest:host), more preferably at least about 0.1% (w/w).
The preferred host crystal materials will also be very stable and readily crystallizable, and will maintain their "order" or crystal moφhology when including a guest molecule, particularly large biomolecules. The use of particular host crystal components will also depend on such factors as how small or large the crystals can be produced and how readily they dissolve. For various routes of administration, it is desirable to have very small crystals (e.g., pulmonary), moderately sized crystals (e.g., injectable), or very large crystals (e.g., implantation and long term payout). The useful crystal sizes will therefore vary accordingly, ranging from submicron to millimeter sizes. In one aspect of the present invention, the preferred crystals are in the order of 5-100 microns in size.
The useful host crystal systems are therefore diverse, and include various small molecule crystal systems which meet the desired criteria. Examples of pharmaceutically-acceptable crystal lattice components include sugars, polyhydroxy alcohols, single and polyamino acids, vitamins, salts, metals, preservatives, aromatic compounds especially aromatic acids, purified natural products, and polymers. Preferred crystal lattice components include, for example, sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, and potassium citrate. Also, compatible mixtures of these materials are also useful, and can be selected to obtain the desired rate of inclusion of the pharmaceutical, or to achieve desired characteristics, such as dissolution rate and pharmacokinetic profile, for the product crystals.
The crystal lattice components are selected to achieve the desired pharmacokinetics for the final crystals. As pertains to the present invention, the term "pharmacokinetics" is used to refer to the profile of the delivery of active pharmaceutical ingredient from the crystals into the circulatory system. This will depend primarily on the concentration of the active pharmaceutical ingredient in the crystals, as well as parameters of the active pharmaceutical ingredient itself. While given crystal lattice components will have associated inclusion and dissolution characteristics, these can be modified by including other crystal lattice components, other API's, or a variety of excipients. Thus, single crystals having two different, co-crystallized lattice components will typically be characterized by pharmacokinetic profiles different from crystals prepared with either of the crystal lattice components alone. Similarly, including excipients or other API's will provide altered rates of inclusion or dissolution for the resulting crystals, providing an associated modification in the pharmacokinetic profile for the resulting crystals. In a related aspect, the present invention involves the use of mixtures of crystals having different pharmacokinetics in order to achieve desired payout profiles. For example, a pharmaceutical product can be obtained by combining two different types of crystals, one type of crystal using a first crystal lattice component characterized by a first pharmacokinetic profile, and the second type of crystal using a second crystal lattice component characterized by a second pharmacokinetic profile. The mixture of crystals will give a payout of API that is different from either of the individual payouts for the two crystal types. The included API's are similarly diverse, limited simply by the requirements of compatibility with the host crystal and the crystal growth conditions. The active pharmaceutical ingredient cannot be unacceptably degraded or otherwise adversely affected by the conditions under which the crystals are formed. Also, the active pharmaceutical ingredient should remain stable for an extended period of time while included within the host crystal, and pharmaceutically efficacious upon release from the crystal.
Given the foregoing criteria, examples of API's useful in accordance with the present include: antibiotics (such as dirithryomycin, loracarbef, tilmicosin, vancomycin, tylosin, monensin), fluoxetine, raloxifene, olanzapine, and nizatidine. A more complete list of API's useful in accordancw with the present invention would include those identified in the following Table A.
TABLE A Marketed Recombinant Protein Products Tissue Plasminogen Activator, T-PA
• Product name: Activase (Generic name: Altepase)
• Produced by: Genentech
• Indication: Human use, Acute myocardial infarction
• Date of approval: Nov. 87, Patent expires on Dec. 2000. • Formulation: Intravenous injection. Lyophilized powder which is reconstituted with sterile water (supplied) to lmg/mL and results in a final pH of 7.3. Can not be reconstituted with preserved water due to precipitation. The lmg/mL solution can be diluted 1 : 1 with 0.9% NaCl or D5W and help for 8 hours at room temperature. TPA is incapable with preservatives.
Ingredients 100 mg vial 50 mg vial 20 mg vial
T-PA 100 mg 50 mg 20 mg
L- Arginine 3.5 g 1.7 g 0.7 g
Phosphoric acid 1 g 0.5 g 0.2 g
Polysorbate 80 < 11 mg < 4 mg < 1.6 mg
Vacuum No Yes Yes • Expression System: Mammalian cell line (Chinese Hamster Ovary cells)
• Refolding Conditions:
• Structure: Glycoprotein of 527 amino acids, sequence from human melanoma cell line, activity of 580,000 IU/mg.
• Additional Information: Sales > $100 million. Cost of therapy $2,750 (100 mg).
Interferon Gamma- lb
• Product name: Actimmune
• Produced by: Genentech • Indication: Human use, chronic granulomatous disease
• Date of approval: Dec. 1990
• Formulation: Single dose solution formulation (0.5 mL), subcutaneous injection. Each 0.5 mL contains 100 μg interferon gamma-lb, 20 mg mannitol, 0.36 mg sodium succinate, 0.05 mg polysorbate-20 in sterile water. • Expression System: E. coli
• Refolding Conditions:
• Post-Transitional Modification:
• Structure: Single chain; Human sequence, 140 amino acids, 16,465 molecular weight, non-covalent dimeric form in solution, activity of 30 Million units/mg. • Additional Information: 14% injection site irritation vs. 2% in placebo. Cost $140 for 50μg.
Interferon alfa-n3 (natural source, not recombinant)
• Product name: Alferon N • Produced by: Interferon Science (New Brunswick, NJ) • Indication: Human use, Genital Warts
• Date of approval: Jun 90
• Formulation: Preserved solution formulation (each mL contains 5 million IU of interferon alfa-n3 in phosphate buffered saline containing 3.3 mg phenol and 1 mg human albumin). Injected intralesional twice weekly for up to 8 weeks
(50μL injected into each wart, 500μL total dose per treatment).
• Expression System: Natural source - human leukocytes which are exposed to an avian virus in order to produce interferon.
• Refolding Conditions: None • Structure: Approximately 166 amino acids with a molecular weight ranging from 16 to 27 kDa, specific activity of 20,000 IU/mg or greater.
• Additional Information: Cost $ 142 per mL.
Beta Interferon la • Product Name: Avonex
• Produced by: Biogen (Cambridge, MA)
• Indication: Human use, Multiple Sclerosis
• Date of approval: May 95
• Formulation: Lyophilized powder (stored refrigerated or at 25 °C for <30 days) which is reconstituted with sterile water (supplied, 1.1 mL) to 30 μg/mL beta interferon la, 15 mg/niL human albumin, 5.8 mg/ml NaCl, 5.7 mg/ml dibasic Na phosphate, 1.2 mg/ml monobasic sodium phosphate, and has a pH of approximately 7.3 (recon solution is stable for 6 hours at refrigerated temperatures). Weekly intramuscular injection by patient or doctor (dosed for 1-2 years in clinical trials).
• Expression System: Mammalian cells (Chinese Hamster Ovary cells)
• Refolding Conditions:
• Structure: Glycoprotein (single N-linked complex carbohydrate), 166 amino acids with a predicted molecular weight of 22,500 daltons, human sequence, has a specific activity of 200 million units per mg protein.
• Additional Information: Cost $ 180 per vial (33μg).
Interferon beta- lb
• Product Name: Betaseron • Produced by: Berlex Laboratories (Wayne, NJ and Chiron, Emeryville, CA)
• Indication: Human use, Multiple Sclerosis
• Date of approval: July 93
• Formulation: Lyophilized product (stored refrigerated) which is reconstituted with 0.54% NaCl (supplied, to 0.25 mg/mL interferon beta-lb, 12.5 mg/mL human albumin, 12.5 mg/ml dextrose, and has a pH of approximately 7.3
(recon solution is stable for 3 hours). Injected subcutaneously every other day (chronic use).
• Expression System: E. coli
• Refolding Conditions: • Structure: 165 amino acids with an approximate molecular weight of 18,500 daltons, human sequence but with a serine or cysteine at residue 17. Recombinant form does not contain the carbohydrate moiety found in the natural material. Has a specific activity of 32 million units per mg protein.
• Additional Information: Sales > $500 million. Cost of therapy is $13,140 (based on 0.25 mg/injection, dose every other day for 1 year; equals 46 mg protein).
Interferon alfa-2b
• Product Name: Intron A
• Produced by: Schering-Plough (Madison, NJ) • Indication: Human use, Hairy cell leukemia, genital warts, Hepatitis, Melanoma, Kaposi's sarcoma
• Date of approval: June 86
• Formulation: Comes in a lyophilized and a solution formulation. The lyophilized formulations when reconstituted with 0.9% benzyl alcohol (supplied) contains either 0.015, 0.025, 0.05, 0.90, or 0.125 mg/mL. Interferon alfa-2b, 20 mg/ml glycine, 2.3 mg/ml sodium phosphate dibasic, 0.55 mg/ml sodium phosphate monobasic, 1 mg/ml human albumin, 1.2 mg/mL methylparaben, and 0.12 mg/ml propylparaben. These formulations be injected intramuscular, subcutaneous, or intralesional. All formulations and reconstituted products are stored at refrigerated temperatures.
• Expression System: E. coli
• Refolding Conditions:
• Structure: Water soluble protein a molecular weight of 19,271 daltons. The interferon alfa-2b gene is derived from human leukocytes. • Additional Information: Sales > $500 Million. Cost of therapy is $16,445 (5 million units every day for 1 year, this is equal to 9 mg protein). Specific activity is 200 million units per mg protein.
Interferon alfa-2a • Product Name: Roferon-A
• Produced by: Hoffmann-La Roche (Nutley, NJ)
• Indication: Human use, Hairy cell leukemia, genital warts, Hepatitis, Melanoma, Kaposi"sarcom, myelogenous leukemia
• Date of approval: June 1986 • Formulation: Multi-use and lyophilized formulation indented for intramuscular or subcutaneous administration. Multi-use formulation contains either 0.015, 0.045, 0.090, 0.18 mg/mL. Interferon alfa-2a, 9 mg/ml NaCl, 5 mg/ml human albumin, and 3 mg/ml phenol. The lyophilized formulation reconstituted with 3 mL of supplied diluent (6 mg/ml NaCl, 3.3 mg/ml phenol) consists of 0.03 mg/ml Interferon alfa-2a, 9mg/ml NaCl, 1.67 mg/ml human albumin, and 3.3 mg/ml phenol.
• Expression System: E. coli (tetracycline promoter).
• Refolding Conditions:
• Structure: Protein of 165 amino acids having a molecular weight of 19,000 daltons Additional Information: Cost of therapy is $59,200 (28mg protein over 1 year). Specific activity is 200 million international units per mg protein.
Human Growth Hormone (Somatropin) Product Name: Bio Tropin Produced by: Bio-Technology General (Iselin, NJ) Indication: Human use, Growth Deficiency Date of approval: May 95 • Formulation:
Expression System: Refolding Conditions: Structure: Additional Information:
Human Growth Hormone (Somatropin)
Product Name: Genotropin
Produced by: Pharmacia and Upjohn (Kalamazoo, MI)
Indication: Human Use, Growth Deficiency • Date of approval: Aug 95
Formulation:
Expression System:
Refolding Conditions:
Structure: • Additional Information:
Human Growth Hormone (Somatropin)
• Product Name: Humatrope
• Produced by: Eli Lilly (Indianapolis, IN) • Indication: Human use, Growth Deficiency
• Date of approval: March 87
• Formulation: Lyophilized product which is reconstituted with sterile water containing 0.3% m-cresol, 1.7% glycerin (supplied) to 2 mg/mL hGH and has a final pH of approximately 7.5, subcutaneous or intramuscular administration. Each 5 mg lyophilized vial contains 5 mg hGH, 25 mg mannitol, 1.13 mg dibasic sodium phosphate, and 5 mg glycine.
• Expression System: E. coli.
• Refolding Conditions:
• Structure: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary-derived material.
• Additional Information: Cost $210 per 5 mg hGH
Human Growth Hormone (Somatropin)
• Product Name: Norditropin • Produced by: Novo Nordisk (Princeton, NJ) • Indication: Human use, Growth Deficiency
• Date of approval: July 91
• Formulation:
• Expression System: • Refolding Conditions:
• Structure:
• Additional Information:
Human Growth Hormone (Somatropin) • Product Name: Nutropin and Nutropin AQ
• Produced by: Genentech
• Indication: Human use, Growth Deficiency
• Date of approval: March 1994
• Formulation: Lyophilized product which is reconstituted with bacteriostatic water (0.9% benzyl alcohol, supplied) to 5 mg/mL hGH and has a final pH of approximately 7.4, subcutaneous or intramuscular administration. Each 5 mg lyophilized vial contains 5 mg hGH, 45 mg mannitol, 1.7 mg sodium phosphates (0.4 mg monobasic and 1.3 mg dibasic), and 1.7 mg glycine.
• Expression System: E. coli, expressed with a leading secretion signal precursor which directs the protein to the plasma membrane of the cell where the sequence is removed and the native protein is secreted into the periplasm so that the protein if folded appropriately as it is synthesized.
• Refolding Conditions: None, expressed folded in E. coli.
• Structure: 191 amino acids, molecular weight of 22,125 daltons, sequence is identical to human pituitary-derived material.
• Additional Information: Cost $420 per 10 mg hGH.
β-Glucocerebrosidase (imiglucerase)
(β-D-Glucosyl-N-acylsphingosine glucohydrolase, E.C.3.2.1.45) • Product Name: Cerezyme
• Produced by: Genzyme (Cambridge, MA)
• Indication: Human use, Graucher's disease
• Date of approval: May 94
• Formulation: Lyophilized product (212 units glucocerebrosidase, 155 mg mannitol, 70 mg sodium citrate, and 0.53 mg polysorbate-80; stored refrigerated) is reconstituted with 5.1 mL of sterile water, final pH is approximately 6.1. The reconstituted material is combined with 100 to 200 mL of 0.9% NaCl and administered intravenously.
• Expression System: Mammalian cell culture (Chinese Hamster Ovary cells) • Refolding Conditions:
• Structure: Monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites, molecular weight is 60,430 daltons. Recombinant protein differs from human placental glucocerebrosidase by a arginine substitued for histidine at position 495 and the glycosylation sites have been modified to terminate in mannose sugars (which are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease).
• Additional Information: Oφhan Drug, sales > $100 million, Cost of therapy is $351,130 (1 year).
Hepatitis B Surface Antigen
• Product Name: Engerix-B
• Produced by: SmithKline Beechman (Philadelphia, PA
• Indication: Human use, Hepatitis B • Date of approval: Sept 89
• Formulation: Suspension (20μg/mL hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal, 9 mg/ml NaCl, 1.7 mg/ml sodium phosphates). Intramuscular administration.
• Expression System: A portion of the hepatitis B virus gene, coding for hepatitis B surface antigen, in cloned into yeast (Sacccharomyces cerevisiae)
• Refolding Conditions:
• Structure:
• Additional Information: Formulation contains no more that 5% yeast proteins.
Hepatitis B Surface Antigen
• Product Name: Recombivax HB
• Produced by: Merck (Whithouse Station, NJ)
• Indication: Human use, Hepatitis B prevention • Date of approval: July 1986
• Formulation: Suspension (lOμg/mL hepatitis B surface antigen adsorbed onto 0.5 mg aluminum, 1:20,000 thimerosal) Intramuscular administration.
• Expression System: A portion of the hepatitis B virus gene, coding for hepatitis B surface antigen, in cloned into yeast (Sacccharomyces cerevisiae) • Refolding Conditions:
• Structure:
• Additional Information: Formulation contains no more that 1% yeast proteins.
Erythropoietin (rEPO)
• Product Name: Epogen or Epoetin alfa (also sold under the name Procrit by Ortho Biotech but manufactured by Amgen)
• Produced by: Amgen (Thousand Oaks, CA)
• Indication: Human use, Anemia • Date of approval: June 89, Patent expires in 2004 (December)
• Formulation: Two solution formulations, single dose and multi-dose. Single- dose is preservative free and each mL contains 2000, 3000, 4000, or 10000 units Epogen, 2.5 mg human albumin, 5.8 mg sodium citrate, 5.8 NaCl, and 0.06 mg citric acid in water for injection, pH 6.9 +/- 0.3. The preserved multi- dose product contains 10,000 units Epogen, 2.5 mg human albumin, 1.3 mg sodium citrate, 8.2 mg sodium chloride, 0.11 mg citric acid and 1% benzyl alcohol per mL of solution, pH is 6.1 +/- 0.3. Both solutions are stored refrigerated.
• Expression System: Mammalian cell • Refolding Conditions:
• Structure: Glycoprotein of 165 amino acids having a molecular weight of 30,400 daltons, sequence identical to that of the human protein.
• Additional Information: Sales > $500 million, Cost $120 for 10,000 units. Human Insulin
Product Name: Humulin
Produced by: Eli Lilly (Indianapolis, IN)
Indication: Human use, Diabetes
Date of approval: Oct 82 • Formulation:
Expression System: E. Coli
Refolding Conditions:
Structure:
Additional Information: Sales > $500 Million
Human Insulin
Product Name: Novolin
Produced by: Novo Nordisk (Princeton, NJ)
Indication: Human use, Diabetes
Date of approval: July 91
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications
Structure:
Additional Information:
LysPro Human Insulin Product Name: Humulog Produced by: Eli Lilly (Indianapolis, IN) Indication: Human use, Diabetes Date of approval: June 1996 Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications Structure: Additional Information: GM-CSF (Granulocyte Macrophage-Colony Stimulating Factor)
• Product Name: Leukine
• Produced by: Immunex (Seattle, WA)
• Indication: Human use, Bone marrow transplantation, Hodgkin's Disease, Leukemia
• Date of approval: Mar 91
• Formulation: Lyophilized solution which is reconstituted with sterile water (stored at refrigerated temperatures for <6 hours) or 0.9% benzyl alcohol (can be stored for <20 days at refrigerated temperatures) and administered intravenous. After reconstitution, the lyophilized single use product contains either 0.25 mg/mL or 0.50 mg/mL GM-CSF, 40 mg/Ml mannitol, 10 mg/ml sucrose, and 1.2 mg/ml tromethamine (final pH is 7.4 +/- 0.3). The reconstituted solution is then diluted into a 0.9% NaCl bag for IV administration (note if final GM-CSF is below 0.01 mg/mL add human albumin to 0.1% to prevent adsoφtion to the IV bag.
• Expression System: Yeast (S. Cerevisiae)
• Refolding Conditions: None, expressed folded
• Structure: Glycoprotein of 127 amino acids characterized by 3 primary molecular species having molecular masses of 19,500, 16800, and 15500 daltons. The primary sequence differs from natural human GM-CSF by a substitution of leucine at position 23, and the carbohydrate moiety may be different from native.
• Additional Information: Specific activity is 5X107 colony forming units per mg protein. Sargramostim is the proper name for yeast-derived recombinant GM-CSF. Cost for a 0.5 mg GM-CSF vial is $178.
G-CSF (Granulocyte Colony Stimulating Factor)
• Product Name: Neupogen
• Produced by: Amgen (Thousand Oaks, CA) • Indication: Human use, Neutropenia, bone marrow transplantation, anemia
• Date of approval: Feb 91
• Formulation: Single-use solution formulation containing 0.3 mg/mL G-CSF, 10 mM sodium acetate, 5% mannitol, and 0.004% Tween-80 at a pH of 4. The product is to be stored at refrigerated temperatures and no more than 24 hours at room temperature. If required, Neupogen can be diluted with D5W (do not dilute with saline at any time; product may precipitate), at concentrations below 5 to 15μg/mL, and human albumin to 2 mg/mL to prevent adsoφtion to IV bag.
• Expression System: E. coli. • Refolding Conditions:
• Structure: A 175 amino acid protein with a molecular weight of 18,800 daltons. The protein has an amino acid sequence identical to the human protein except for an additional N-terminal methionine (necessary for expression in E. coli). The human protein is glycosylated but the recombinant Neupogen is not. • Additional Information: Sales > $500 million. Filgrastim is the name given to recombinant methionyl human G-CSF. Cost of therapy (lung cancer) is $2,130 (4.2 mg protein over 14 days). Specific activity is 30 million units per mg protein.
Satumomab Pendetide
Product Name: OncoScint CR OV
Produced by: Cytogen (Princeton, NJ)
Indication: Human use, Colorectal and ovarian cancers
Date of approval: Dec 92
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure: Additional Information:
Interleukin-2
• Product Name: Proleukin (generic name: Aldesieukin)
• Produced by: Chiron (Emeryville, CA)
• Indication: Human use, Renal cell carcinoma • Date of approval: May 1992
• Formulation: Single-use lyophilized formulation which is reconstituted with 1.2 mL sterile water and administered intravenously. Each reconstituted product contains 1.1 mg/mL Proleukin, 50 mg/ml mannitol, and 0.18 mg/ml dibasic sodium phosphate (pH is 7.5 +/- 0.3). Lyophilized product is stored at refrigerated temperatures, reconstituted product is stable up to 48 hours at refrigerated to room temperatures, but should be stored in refrigerator due to lack of preservatives. Addition of preservatives results in increased aggregation, addition of human albumin alters pharmacology.
• Expression System: E. Coli (tetracycline promoter). • Refolding Conditions:
• Structure: Proleukin has a molecular weight of 15,300 daltons and differs from the natural human protein (is not glycosylated, the N-terminal alanine is removed, and has a serine substituted for the free cysteine at position 125).
• Additional Information: Specific activity is 18 million international units per 1.1 mg protein. Cost is $395 per 1.3 mg protein.
Somatrem
• Product Name: Protropin
• Produced by: Genentech (S. San Francisco, CA) • Indication: Human use, Growth deficiency
• Date of approval: Oct 1985, patent expired on Oct 1992
• Formulation: Lyophilized formulation which is reconstituted with 0.9% benzyl alcohol (supplied) and administered intramuscular or subcutaneous. The lyophilized vial contains 5 mg Somatrem, 40 mg mannitol and 1.7 mg sodium phosphates (0.1 mg sodium phosphate monobasic and 1.6 mg sodium phosphate dibasic) and is reconstituted with 1 to 5 mL of 0.9% benzyl alcohol. The lyophilized product is stored at refrigerated temperatures, the reconstituted product is good for 14 days at refrigerated temperatures.
Expression System: E. Coli
Refolding Conditions:
Structure: Contains 192 amino acids with a molecular weight of 22,000 daltons. Identical to human sequence but contains an extra methionine at the
N-terminus.
Additional Information: Sales > $100 million. Cost of therapy is $13,110 (1 year, 313 mg protein)
Dnase (deoxyribonuclease I)
• Product Name: Pulmozyme
• Produced by: Genentech (S. San Francisco, CA)
• Indication: Human use, Cystic fibrosis • Date of approval: Dec 1993
• Formulation: Inhalation solution (aerosol mist produced by a compressed air driven nebulizer system). Comes in a single-use 2.5 mL ampule containing 1.0 mg/mL Dnase, 0.15 mg/mL calcium chloride dihydrate, and 8.77 mg ml sodium chloride, at a pH of 6.3. The solution is stored at refrigerated temperatures and should not be exposed to light.
• Expression System: Mammalian cells (Chinese hamster Ovary cells)
• Refolding Conditions:
• Structure: Glycoprotein of 260 amino acids having a molecular weight of 37,000 daltons. The primary sequence is identical to that of the native human enzyme.
• Additional Information: Sales > $100 Million. Cost is $32 for 2.5 mg of protein (1 ampule)
M-CSF (Macrophage-Colony Stimulating Factor)
Product Name: Leucomax (generic name: Molgramostim)
Produced by:
Indication: Human use,
Date of approval: FDA unapproved
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information:
Epoetin Beta (Erythropoietin)
• Product Name: Marogen
• Produced by:
• Indication: Human use, • Date of approval: • Formulation:
• Expression System:
• Refolding Conditions:
• Post-Transitional Modifications:
• Structure:
• Additional Information:
Polyribonucleotide
Product Name: Ampligen • Produced by:
Indication: Human use,
Date of approval: FDA Unapproved
Formulation:
Expression System: • Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information: Human Serum Albumin Product Name: Produced by: Indication: Date of approval: Formulation: Expression System: Refolding Conditions: Post-Transitional Modifications: Structure: Additional Information:
Septomonab?
Product Name: Gentoxin
Produced by:
Indication: Human use,
Date of approval: Not FDA approved
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information:
Protein • Product Name: Produced by:
Indication:
Date of approval:
Formulation:
Expression System:
Refolding Conditions:
Post-Transitional Modifications:
Structure:
Additional Information:
TABLE A
APPROVED BIOTECHNOLOGY DRUGS AND VACCINES
Product
Product Name Company Category Indication
Coravax ™ Merck recombinant vaccination of infants
Haemophilus b Whitehouse Station, vaccine beginning at two months of conjugate NJ age against both invasive
(meningococcal Haemophilus influenzae type protein conjugate) b diseases (Hib) and hepatitis and hepatitis b B (October 1996)
(recombinant) vaccine
Engenix-B® S ithKline recombinant hepatitis B (September 1989)
Hepatitis B vaccine Beecham vaccine
(recombinant) Philadelphia, PA
EPOGEN18' Amgen erythropoietin treatment of anemia Epoetin alfa Thousand Oaks, CA associated with chronic renal (rEPO) failure, including patients on dialysis and not on dialysis, and anemia in Retrovir treated HIV-infected patients (June 1989); treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996) PROCRIT® Ortho Biotech erythropoietin treatment of anemia
Epoetin alfa Raritan, NJ associated with chronic renal
(rEPO) failure, including patients on dialysis and not on dialysis, and anemia in Retrovir treated HIV-infected patients (June 1989); treatment of anemia caused by chemotherapy in patients with non-myeloid malignancies (April 1993); prevention of anemia associated with surgical blood loss, autologous blood donation adjuvant (December 1996) (PROCRIT was approved for marketing under Amgen' s epoetin alfa PLA. Amgen manufactures the product for Ortho Biotech.) Under an agreement between the two companies, Amgen licensed to Ortho Pharmaceutical the U.S. rights to epoetin alfa for indications for human use excluding dialysis and diagnostics.
Genotropin™ Pharmacia & Upjohn human growth short stature in children somatropin (rDNA Kalamazoo, MI hormone due to growth hormone origin) for injection deficiency (August 1995)
Gere 51 Serono Laboratories growth factor evaluation of the ability human growth Norwell, MA of the somatotroph of hormone the pituitary gland to releasing factor secrete growth hormone (December 1990); pediatric growth hormone deficiency (October 1997)
Gonal-F® Serono Laboratories recombinant female infertility recombinant human Norwell, MA fertility (September 1997) follicle-stimulating hormone hormone (r-FSH)
Humalog™ Eli Lilly recombinant diabetes (June 1996) insulin lispro Indianapolis, IN insulin
Humatrope® Eli Lilly humane human growth hormone somatropin (rDNA Indianapolis, IN growth deficiency in children origin) for injection hormone (March 1987)
TABLE A
APPROVED BIOTECHNOLOGY DRUGS AND VACCINES
Product Name Company Product Category Indication
Humulin® Eli Lilly recombinant diabetes (October 1982) human insulin Indianapolis, IN insulin (recombinant DNA origin)
Infergen® Amgen interferon treatment of chronic hepatitis interferon alfacon-1 Thousan Oaks, CA C viral infection (October 1997)
Intron A Schering-Plough interferon hairy cell leukemia (June interferon alfa-2b Madison, NJ 1986); genital warts (June (recombinant) 1988); AIDS-related Kaposi's sarcoma (November 1988); hepatitis C (February 1991); hepatitis B (July 1992); malignant melanoma (December 1995); follicular lymphoma in conjunction with chemotherapy (November 1997)
KoGENate® Bayer Corporation, clotting factor treatment of hemophilia A antihemophiliac Pharmaceutical (February 1993) factor (recombinant) Division
West Haven, CT
Leukine™ Immunex colony stimulating autologous bone marrow sargramostim Seattle, WA factor transplantation (March
(GM-CSF) 1991); neutropenia resulting from chemotherapy in acute myelogenous leukemia (September 1995); allogeneic bone marrow transplantation (November 1995); peripheral blood progenitor cell mobilization and transplantation (December 1995)
MyoScint® Centocor MAb myocardial infarction imiclromab Malvern, PA imaging agent (July 1996) penietate
Neumega® Genetics Institute MAb prevention of severe oprelvekin Cambridge, MA chemotherapy-induced thrombocytopenia (November 1997)
NEUPOGEN® Amgen colony stimulating chemotherapy-induced
Filgrastim Thousand Oaks, factor neutropenia (February 1991);
(rG-CSF) CA autologous or allogeneic bone marrow transplantation (June 1994); chronic severe neutropenia (December 1994); support peripheral blood progenitor cell transplantation (December 1995)
Norditropin® Novo Nordisk human growth treatment of growth failure in somatropin Pharmaceuticals hormone children due to inadequate
(rDNA orgin) for Princeton, NJ growth hormone secretion injection (May 1995)
Novolinw 70/30 Novo Nordisk recombinant insulin-dependent diabetes 70% NPH human Pharmaceuticals insulin mellitus (July 1991) insulin isophane Princeton, NJ suspension & 30% regular, human insulin injection (recombinant DNA origin) Novolin® L Novo Nordisk recombinant insulin-dependent diabetes Lente®, human Pharmaceuticals insulin mellitus (July 1991) insulin zinc Princeton, NJ suspension (recombinant DNA origin)
APPROVED BIOTECHNOLOGY DRUGS AND VACCINES
Product
Product Name Company Category Indication
Novolin® N Novo Nordisk recombinant insulin-dependent diabetes
NPH human insulin Pharmaceuticals insulin mellitus (July 1991) isophane suspension Princeton, NJ
(recombinant DNA origin)
Novolin® R Novo Nordisk recombinant insulin-dependent diabetes regular, human insulin Pharmaceuticals insulin mellitus (July 1991)
(recombinant DNA Princeton, NJ origin)
Nutropin® Genentech human growth growth failure in children somatropin for S. San Francisco, hormone due to chronic renal injection CA insufficiency, growth hormone inadequacy in children (March 1994); Turner's syndrome (December 1996); growth hormone inadequacy in adults (December 1997)
Nutropin AQ™ Genentech human growth growth failure in children somatropin (liquid) S. San Francisco, hormone due to chronic renal
CA insufficiency, growth hormone inadequacy in children (December 1995); Turner's syndrome (December 1996); growth hormone inadequacy in adults (December 1997)
OncoScinf® CYTOGEN MAb detection, staging and
CR/OV Princeton, NJ follow-up of colorectal and satumomab pendetide ovarian cancers (December 1992)
ORTHOCLONE Ortho Biotech MAb reversal of acute kidney
OKT® 3 Raritan, NJ transplant rejection (June muromonab-CD3 1986); reversal of heart and liver transplant rejection (June 1993)
Proleukin® Chiron interleukin renal cell carcinoma (May aldesleukin Emeryville, CA 1992); metastatic
(interleukin-2) melanoma (January 1998)
ProstaScint® CYTOGEN MAb detection, staging and capromab pentetate Princeton, NJ follow-up of prostate adenocarcinoma (October 1996) Protropin Genentech human growth human growth hormone somatrem for injection S. San Francisco, hormone deficiency in children
CA (October 1985)
Pulenozyme Genentech recombinant cystic fibrosis (December domase alpha, S. San Francisco, DNase 1993); management of recombinant CA advanced cystic fibrosis (December 1996)
Recombinate™ Baxter clotting factor hemophilia A (December antihemophilic factor Healthcare/Hyland 1992) recombinant Division Glendale,
(rAHF) CA Genetics Institute Cambridge,
MA
RECOMBΓVAX HB® Merck recombinant hepatitis B prevention hepatitis B vaccine Whitehouse Station, vaccine (July 1986)
(recombinant), MSD NJ
Refludan™ Hoechst Marion recombinant heparin-induced lepirudin (rDNA) for Roussel anticoagulant thrombocysopenia type II injection Kansas City, MO (March 1998)
APPROVED BIOTECHNOLOGY DRUGS AND VACCINES
Product
Product Name Company Category Indication
Regranex® Ortho-McNeil growth factor lower extremity diabetic becaplermin Pharmaceuticals neuropathic ulcers
Raritan, NJ (December 1997)
ReoPro® Censocor MAb anti-platelet prevention of abciximab Malvern, PA blood clots in the setting of
Eli Lilly high-risk percutaneous
Indianapolis, IN transluminal coronary angioplasty (December 1994); refractory unstable angina when percutaneous coronary intervention is planned (November 1997)
Retevase™ Boehringer tissue treatment of acute reteplase Mannheim plasminogen myocardial infarction
Gaithersburg, MD factor (October 1996)
Centocor
Malvern, PA
Rituxan® Genentech MAb treatment of relapsed or rituximab S. San Francisco, refractory low-grade or
CA follicular CD20-positive B-
IDEC cell non-Hodgkin's
Pharmaceuticals lymphoma (November
San Diego, CA 1997);
Roferon®-A Hoffmann-La Roche interferon hairy cell leukemia (June interferon alfa-2a, Nutley, NJ 1986); AIDS-related recombinant Kaposi's sarcoma (November 1988); chronic myelogenous leukemia (November 1995); hepatitis C (November 1996) Saizen Serono Laboratories human growth pediatric growth hormone somatropin (rDNA Norwell, MA hormone deficiency (October 1996) origin) for injection
Serostim ™ Serono Laboratories human growth treatment of AIDS- somatropin (Rdna Norwell, MA hormone associated origin) for injection catabolism/wasting (August 1996); pediatric HIV failure to thrive (February 1998)
Verluma® Boehringer MAb detection of small-cell lung nofetumornab Ingelheim cancer (August 1996) Ridgefield, CT NeoRx Seattle, WA
Vistide® Gilead Sciences nucleotide cytomegalovirus retinitis in cidosovir injection Foster City, CA analogue AIDS patients (June 1996)
Zenapaz Hoffmann-La Roche MAb prevention of acute kidney daclizumab Nutley, NJ transplant rejection (December 1997)
The content of this survey has been obtained through government and industry sources based on the latest information. The information may not be comprehensive. For more specific information about a particular product, contact the individual company directly.
PhRMA Internet address: http://www.Dhrma.or£
Provided as a Public Service by PhRma. Founded in 1958 as the Pharmaceutical Manufacturers Association. Copyright © 1998 by the Pharmaceutical Research and Manufacturing of America. Permission to reprint is awarded if proper credit is given.
BIOTE CHNOLOGY MEDI CINES IN DEVELOPMENT
AIDS/HIV INFECTION AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
AD-439 and Tanox Biosystems MAb HIV Phase II
AD-519 Houston, TX infection, combination AIDS
AD-439 MAb, Tanox Biosystems MAb HIV Phase II anti-HIV to V3 loop of Houston, TX infection, gp 120 protein; AIDS neutralizing antibody
AD-519 MAb, Tanox Biosystems MAb HIV Phase II anti-HIV to C4 region Houston, TX infection, of gp 120 protein; AIDS neutralizing antibody
Alferon LDO® Interferon Sciences interferon AIDS-related Phase I/II interferon alfa-n3 New Brunswick, NJ complex, AIDS
Alferon N Interferon Sciences . . . ® interferon HIV infection Phase III injection New Brunswick, NJ (see also interferon alfa-n3 infectious diseases) co-infection Phase II (HIV/HCV) ALVAC-MN Pasteur Merieux vaccine HIV infection Phase II 12-TMG (vCP205) Connaught Lyons, France Virogenetics Albany, NY
Ampligen TB — Hemispherx interferon HIV infection Phase II
Biophama (see also
New York, NY cancer, infectious diseases, other) autologous gene- SyStemix gene therapy HIV infection Phase I modified hematopoietic Palo Alto, CA stem cells gene therapy Cell Genesys gene therapy HIV infection Phase II Foster City, CA Hoechst Marion Roussel Kansas City, MO gp 120 vaccine VaxGen vaccine AIDS Phase II
S. San Francisco,
CA
HIV-IT(V) Chiron Viagene gene therapy asymptomatic Phase II Retrovector ™ HIV-l San Diego, CA HIV-1 11 IB env/rev retroviral infection vector
HIV Vaccine (gp 120) Chiron vaccine AIDS Phase II Emeryville, CA interleukin-10 (IL-10) Schering-Plough interleukin HIV disease Phase I Madison, NJ (see also autoimmune, digestive heart, neurologic, respiratory, skin)
AIDS/HIV INFECTION AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
ISIS 2922 Isis antisense cytomegalovirus Phase III fomivirsen Pharmaceuticals retinitis Carlsbad, CA
ISIS 13312 Isis antisense cytomegalovirus Phase I
Pharmaceuticals retinitis Carlsbad, CA
Leukine™ Immunex colony adjuvant to Phase II sargramostim Seattle, WA stimulating AIDS therapy,
(GM-CSF) factor HIV infection, prevention of infection in HIV patients (see also cancer.) memantine Neurobiological AIDS dementia Phase II Technologies complex and Richmond, CA AIDS-related neuropathic pain (see also diabetes)
MPL® Ribi ImmunoChem vaccine AIDS Phase I immunomodulator Hamilton, MT (see also vaccine infectious diseases)
NEUPOGEN® Amgen colony treatment and application Filgrastim (rG- Thousand Oaks, stimulating prevention of submitted CSF) CA factor neutropenia in HIV patients (see also cancer, respiratory)
Ovidrel® Ares-Serono and recombinant Kaposi's Phase I/II recombinant Serono gonadotropin sarcoma, AIDS- human chorionic Laboratories related gonadotropin (r- Norwell, MA hypogonadism hCG) (see also infertility)
PEG interleukin-2 Chiron interleukin HIV infection in Phase II Emeryville, CA combination with Retrovir®
PMPA Gilead Sciences nucleotide HIV infection, Phase II Foster City, CA analogue AIDS
Prevention ™ Gilead Sciences nucleotide HIV infection, Phase III adefovir Foster City, CA analogue AIDS dipivoxil
PRO 367 Progenies HIV infection Phase I Pharmaceuticals Tarrytown, NY
PRO 542 Progenies HIV infection Phase I Pharmaceuticals Tarrytown, NY
Proleukin Chiron interleukin HIV infection in Phase II/III aldesleukin Eneryville, CA combination
(interleukin-2) with Retrovir® (see also cancer)
Rensune HIV-1 Immune Response immune- HIV seropositive Phase III immunogen Corp. based therapy Carlsbad, CA retroviral vector Chiron gene therapy HIV infection Phase I/II with 2 ribozymes Emeryville, CA
TBC-3B Therion Biologies vaccine AIDS prevention Phase I (vaccinia virus Cambridge, MA expressing HIV genes env, gag and pal) AUTOIMMUNE DISORDERS
Product Development
Product Name Company Category Indication Status adenosine deaminase- National Cancer gene therapy severe Phase I transduced autologous Institute combined NCI Trial CD34+PBC or Bethesda, MD immunodeficien umbilical cord/placental cy blood cells adenosine deaminase- National Cancer gene therapy severe Phase I transduced T cells Institute combined NCI Trial Bethesda, MD immunodeficien cy
AnergiX ™-RA Anergen functional rheumatoid Phase I
Redwood City, antigenics arthritis
CA immunotherapy
AnervaX™ Anergen peptide rheumatoid Phase II
Redwood City, vaccine arthritis
CA
Avakine ™ Centocor MAb rheumatoid Phase III chimeric anti-TNF Malvern, PA arthritis antibody (see also digestive)
CD40 ligand antibody Biogen MAb lupus, immune Phase II Cambridge, MA thrombocytopen ic purpura clenoliximab IDEC MAb rheumatoid Phase II
Pharmaceuticals arthritis San Diego, CA SmithKline Beecham Philadelphia, PA
ConXn™ Connetics recombinant sclerodema Phase II relaxin Palo Alto, CA soluble receptor
Enbrel Immunex recombinant rheumatoid Phase III tumor necrosis factor Seattle, WA soluble arthritis
(TNF) receptor Wueth-Ayerst receptor Laboratories Philadelphia, PA h5Gl.l Alexion MAb lupus, Phase I/II
Pharmaceuticals rheumatoid New Haven, CT arthritis
IDEC-131 IDEC MAb systemic lupus Phase I humanized MAb Pharmaceuticals erythematosus San Diego, CA
IL-2 fusion protein Seragen fusion rheumatoid Phase I/II DAB 385 IL-2 Hopkinton, MA protein arthritis (see also cancer, skin) interleukin-10 Schering-Plough interleukin rheumatoid Phase II (IL-10) Madison, NJ arthritis (see also AIDS/HIV, digestive, heart, neurologic, respiratory, skin)
IR 501 Immune Response vaccine rheumatoid Phase II therapeutic vaccine Corp. arthritis Carlsbad, CA
ISIS 2302 Isis antisense rheumatoid Phase II
Pharmaceuticals arthritis Carlsbad, CA (see also digestive, skin, transplantation)
AUTOIMMUNE DISORDERS
Product Development
Product Name Company Category Indication Status
MDX-33 Medarex MAb Autoimmune diseases, Phase I Annandale, NJ idiopathic thrombocytopenic purpura
ORTHOCLONE Ortho Biothech MAb treatment of CD4-mediated Phase II OKT-4A Rarian, NJ autoimmune diseases (see also transplantation)
Quadrakine Schering- interleuki rheumatoid arthritis Phase I interleukin-4 Plough n
(IL-4) Madison, NJ
SMART™ Anti- Protein Design MAb autoimmune diseases Phase I CD3 HuM291 Labs (see also transplantation)
Mountain View, CA
BLOOD DISORDERS
Product Development
Product Name Company Category Indication Status
CPC-1 11 Cypros cellular sickle cell Phase II
Pharmaceuticals therapy disease Carlsbad, CA (see also heart)
Factor VIII Transkaryotic gene therapy hemophilia A Phase I Therapies Cambridge, MA
GA-EPO Hoechst Marion erythropoietin anemia Phase II
Roussel associated with
Kansas City, MO chronic renal
Transkaryotic failure
Therapies
Cambridge, MA
Kogenate-N Bayer clotting factor hemophilia A Phase III tFVIII Berkeley, CA NovoSeven® Novo Nordisk clotting factor treatment of Phase III recombinant factor Vila Pharmaceuticals hemophilia Princeton, NJ A&B with and without antibodies against factors VIII/IX
Optro™ Somatogen recombinant oxygen- Phase II recombinant human Boulder, CO human carrying agent henoglobin hemoglobin and alternative
(rHbl . l) to red blood cell transfusion stimulation of Phase I red blood cell formulation
ReFacto® Genetics institute clotting factor hemophilia A Phase III recombinant factor VIII Cambridge, MA
YM-337 MAb Yamanouchi USA MAb platelet Phase I White Plains, NY aggregation
Protein Design Labs
Mountain View, CA
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
1311-chTNT-l/B Techniclone MAb malignant glioma Phase I Tustin, CA
Aastrom™ Cell Aastrom cellular cancer Phase II Production System Biosciences therapy immunosuppression/ stern and Ann Arbor, MI blood and immune progenitor cell system recovery for expansion from patients receiving bone marrow and ablative umbilical cord chemotherapy blood
Actimmune National Cancer interferon colon, lung, ovarian, Phase II interferon gamma- Institute prostate cancers, NCI Trial lb Bethesda, MD melanoma Genentech S. San Francisco, CA
AFP-Scan ™ Immunomedics MAb extent of disease Phase II technetium-99m- Morris Plains, staging of liver and
Fab' fragment NJ germ cell cancers
(germ cell) allogeneic SyStemix cellular advanced leukemia, Phase I hematopoietic stem Palo Alto, CA therapy lymphoma, cell transplantation myelodysplastic syndromes Allovectin-7 Vical gene therapy advanced metastatic Phase II DNA lipid San Diego, CA melanoma, non- complex encoding resectable squamous HLA-B7 antigen cell carcinoma of the head and neck
ALT Cellcor cellular metastatic renal cell Phase III
(autolymphocyte Newton, MA therapy carcinoma (kidney completed therapy) CYTOGEN cancer) Princeton, NJ
ALVAC-B7.1 National Cancer gene therapy melanoma Phase I Institute NCI Trial Bethesda, MD
ALVAC-CEA- National Cancer gene therapy advanced Phase I
B7.1 Institute adenocarcinomas NCI Trial Bethesda, MD
ALVAC-CEA National Cancer vaccine advanced cancers Phase I vaccine Institute NCI Trial Bethesda, MD
ALVAC-IL-12 National Cancer vaccine melanoma Phase I vaccine Institute NCI Trial
Bethesda, MD
Pasteur
Merieux
Connaught
Lyons, France
Ampligen® Hemispherx interferon renal cancer Phase I/II Bioplama (see also AIDS/HIV,
New York, NY infectious diseases, other) anti-cancer T-Cell Cell Genesys gene therapy colon cancer Phase I/II gene therapy Foster City, CA anti-idiotype Novartis MAb cancer Phase I monoclonal Pharmaceuticals antibody East Hanover, NJ
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status anti-Tac(Fv)-PE38 National Cancer MAb + toxin leukemia, lyphoma Phase I immunotoxin Institute NCI Trial Bethesda, MD anti-transferrin National Cancer MAb advanced, refractory Phase I receptor MAb Institute solid tumors NCI Trial Bethesda, MD anti-VEGF Genentech MAb cancer Phase I humanized MAb S. San Francisco,
CA autologous SySternix cellular hematopoietic Phase I II hematopoietic stem Pala Alto, CA therapy reconstitution in cells for autologous patients with hematopoietic multiple myeloma, transplantation non-Hodgkin's lymphoma, breast cancer autologous peptide- National Cancer cellular advanced solid Phase I speciftc activated Institute therapy tumors NCI Trial lymphocytes Bethesda, MD autologous National Cancer gene therapy breast cancer, Phase I transduced CD34+ Institute myeloma NCI Trial bone marrow and Bethesda, MD peripheral blood stem cells
Avicidin MAb colorectal, colorectal, Phase II
MAb conjugate lung, prostate pancreatic cancers cancers
Avicine ™ AVI BioPharma vaccine colorectal, Phase II
CTP-37 Portland, OR pancreatic cancers
Avonex® Biogen interferon glioma Phase II interferon beta- 1 A Cambridge, MA (see also neurologic)
B7 transfected National Cancer vaccine melanoma Phase I allogeneic Institute NCI Trial melanoma cell Bethesda, MD vaccine
BEC2, anti- ImClone vaccine melanoma, small- Phase I idiotype MAb Systems cell lung cancer Somerville, NJ
Betaseron National Cancer interferon non-small-cell lung Phase III recombinant beta Institute cancer (see also NCI Trial interferon- lb Bethesda, MD neurologic) Berlex Laboratories Wayne, NJ bispeciftc antibody Chiron MAb cancer Phase I Emeryville, CA
C225, anti-EGFR ImClone MAb epidermal growth Phase II chimeric MAb Systems factor receptor Somerville, NJ positive cancers
Campath IH LeukoSite MAb chronic lymphocytic In clinical
Cambridge, MA leukemia trials
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status carcinoembryonic National Cancer vaccine brest, Phase I antigen peptide- 1 Institute gastrointestinal NCI Trial vaccine Bethesda, MD tract, lung cancer
CEACide™ Immunomedics MAb colorectal cancer Phase II humanized Morris Plains, antiOCEA antibody NJ
(hMN14) CEA-Scan™ Immunomedics MAb extent of disease Phase II technetium-99m- Morris Plains, staging of breast arcitumomab NJ cancer (breast)
CEA-Scan™ Immunomedics MAb extent of disease Phase III technetium-99m- Morris Plains, staging of lung arcitumomab NJ cancer (lung)
CEAVac™ Titan vaccine colorectal cancer Phase II anti-idiotype Pharmaceuticals antibody vaccine S. San Francisco, CA cell therapy CytoTherapeutic cellular cancer pain, Phase II s therapy untreatable/unreliev Providence, RI ed by other forms of treatment
Cereport™ Alkermes recurrent malignant Phase III
(RMP-7) and Cambridge, MA brain tumor carboplatin chemotherapy- Genetix gene therapy treatment of cancer Phase I II resistant bone Rye, NY patients requiring marrow chemotherapy chimeric MAb National Cancer MAb melanoma, Phase II
14.18 Institute neuroblastoma NCI Trial Bethesda, MD
CM 101 CarboMed cancer Phase I/II Brentwood, TN
CMA-676 Wyeth-Ayerst MAb relapsed acute Phase II/III Laboratories myelogenous Philadelphia, PA leukemia
CMB-401 Wyeth-Ayerst MAb ovarian cancer Phase I/II Laboratories Philadelphia, PA colon cancer cell Immune vaccine colon cancer Phase I line vaccine Response Corp. Carlsbad, CA Sidney Kimmel Cancer Center San Diego, CA
CP-358,774 OSI cellular cancer Phase I pharmaceuticals therapy
Uniondale, NY
Pfizer
New York, NY
CT-2584 Cell therapeutics ovarian, prostate Phase I Seattle, WA cancer, sarcoma cytosine deaminase GenVec gene therapy colon cancer Phase I gene-adenoviral Rockville, MD vector CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
DA/Hu(gamma).4 Chiron Viagene gene therapy metastatic Phase I (hlFN-XV) San Diego, CA melanoma Retrovector ™ hlFN-y retroviral vector
DA/Hu(gamma).15- Chiron Viagene gene therapy stage IV Phase I transduced San Diego, CA malignance autologous tumor melanoma cells and interferongamma expressing trasduced autologous tumor cells (combination therapy)
DA/Hu(gamma).15- Chiron Viagene gene therapy disseminated Phase I transduced San Diego, CA malignant autologous tumor melanoma cells; ITAT daniplestim Searle growth factor mobilization of Phase III Skokie, IL peripheral blood stem cells dendritic cell therapy Dendreon cellular advanced prostate Phase II/III Mountain View, therapy cancer CA multiple myeloma Phase I
E/A lipid complex Targeted gene therapy breast, head and Phase I (tgDCC-E/A) Genetics neck, ovarian Seattle, WA cancers
EGF fusion protein Seragen fusion protein non-small-cell Phase I/II DAB 389 EGF Hopkinton, MA lung cancer'
EPREX1* National Cancer erythropoietin neuroblastoma Phase II erythropoietin Institute NCI Trial Bethesda, MD Ortho Biotech Raritan, NJ
ERB-38 National Cancer fusion protein advanced stage Phase I immunotoxin fusion Institute solid tumors NCI Trial protein (recombinant) Bethesda, MD
Ewing's sarcoma and National Cancer vaccine sarcoma Phase I alveolar Institute NCI Trial rhabdomyosarcoma Bethesda, MD peptide vaccine
FLT3 ligand National Cancer growth factor melanoma, renal Phase I Institute cell cancer NCI Trial Bethesda, MD Immunex Seattle, WA
G3139 Genta antisense cancer Phase I
San Diego, CA gamma interferon Chiron gene therapy cancer Phase I gene therapy Emeryville, CA
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
Gastrimmune™ Aphton vaccine colorectal, Phase I/II neutralizing Woodland, CA pancreatic, G17 hormone stomach cancers (see also digestive)
GeneVax® Centocor vaccine colorectal cancer Phase I gene vaccine Malvern, PA
GLI-328 Genetic Therapy gene therapy glioblastoma Phase III Galthersburg, MD multiforme
GM-CSF Powderject vaccine melanoma, Phase I cellular cancer Vaccines sarcoma vaccine Madison, WI
GMK Bristol-Myers vaccine prevent recurrence Phase III garglioside Squibb following surgery antigen Princeton, NJ to remove pnmary Progenies melanoma Pharmaceuticals Tarrytown, NY gplOO National Cancer vaccine melanoma Phase I adenovirus Institute NCL Trial vaccine Bethesda, MD Genzyme Molecular Oncology Cambridge, MA gp 100 peptide National Cancer vaccine melanoma Phase I vaccine Institute NCL Trial Bethesda, MD
GVAX™ Cell Genesys vaccine prostate, lung Phase I/II cancer vaccine Foster City, CA cancers, melanoma
HER-2/neu National Cancer vaccine breast, colorectal, Phase I peptide vaccine Institute ovarian, prostate NCL Trial Bethesda, MD cancers
Herceptin™ Genentech MAb breast cancer Phase III trastuzumab S. San Francisco, completed
(anti-HER-2 CA humanized
MAb)
HPV 16, E6 and National Cancer vaccine cervical cancer Phase I
E7 peptide Institute NCL Trial vaccine Bethesda, MD
HPV E7 National Cancer vaccine cervical cancer Phase I lipopeptide Institute NCL Trial vaccine Bethesda, MD
Cytel
San Diego, CA HPV vaccine Medimmune vaccine cervical cancer Phase I Gaithersburg, MD (see also infectious SmithKline diseases) Beecham Philadelphia, PA
HSPPC-96 Antigenics hear shock melanoma, Phase I (autologous New York, NY protein pancreatic renal tumor derived) cell cancers human growth Transkaryotic gene therapy cancer cachexia Phase I hormone Therapies (muscle wasting) Cambridge, MA
IDEC-In88 IDEC MAb non-Hodgkin's B- Phase I/II
Pharmaceuticals cell lymphoma San Diego, CA
IDEC-Y88 IDEC MAb non-Hodgkin's B- Phase I II
Pharmaceuticals cell lymphoma San Diego, CA
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
Leucotropin Cangene colony mobilization of Phase III
GM-CSF Mississauga, stimulating peripheral blood stem
Ontario factor cells in patients with adjuvant breast cancer
Leukine™ Immunex colony prophylaxis and application sargramostim Seattle, WA stimulating treatment of submitted
(GM-CSF) factor chemotherapy-induced neutropenia, prophylaxis of chemotherapy- induced neutropenia in acute myelogenous leukemia (see also AIDS/HIV)
Leuvectin Vical gene therapy prostate cancer, renal Phase I
DNA/lipid San Diego, CA cell carcinoma, complex melanoma, sarcoma encoding iL-2
LP 2307 LIDAK vaccine malignant melanoma Phase I/II
Pharmaceuticals Lajolla, CA
LR-3001 Inex antisense chronic myelogenous Phase I
Pharmaceuticals leukemia in accelerated Hay ward, CA phase or blast crisis
LYM-1 Techniclone MAb lymphoma Phase II/III Tustin, CA
Lymphocide™ Immunomedics MAb non-Hodgkin's B-cell Phase I/II and CD22 Morris Plains, lymphoma humanized NJ
MAb LymphoScan™ Immunomedics MAb extent of disease staging Phase III technetium- Morris Plains, of non-Hodgkin's B-cell
99m- NJ lymphoma, detection of bectumomab residual disease
(lymphoma) following radiation/chemotherapy
MAb Glaxo MAb lung, prostate cancers Phase II Wellcome Rsch. Triangle Park, NC
MART-1 National Cancer vaccine melanoma Phase I adenovirus Institute NCL Trial vaccine Bethesda, MD Genzyme Molecular Oncology Cambridge, MA
MART-1 National Cancer vaccine metastatic melanoma Phase I melanoma Institute NCL Trial vaccine Bethesda, MD
MD Rxl™ Titan gene therapy enable high-dose Phase I
Pharmaceuticals chemotherapy with S. San reduced side effects Francisco, CA
MDX-447 Medarex MAb head and neck, renal Phase I/II bispecific Annandale, NJ cancers antibody
MDX-H210 Medarex MAb breast, colorectal, Phase I/II bispecific Annandale, NJ kidney, ovarian, prostate antibody cancers
Melacine® Ribi vaccine stage IV melanoma with Phase III melanoma ImmunoChem interferon alpha completed theraccine Hamilton, MT
(therapeutic Ribi vaccine stage II melanoma in Phase III vaccine) ImmunoChem patients with no
Hamilton, MT evidence of disease to
Southwest prevent recurrence
Oncology following surgery to
Group remove primary disease
San Antonio,
TX
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status myeloid Human interleukin chemoprotection Phase I progenitor Genome inhibitory Sciences factor- 1 Rockville, MD myelona- National Cancer vaccine multiple myeloma Phase I derived Institute NCI Trial idiotypic Bethesda, MD antigen vaccine NEUPOGEN® Amgen colony acute myelogenouse application Filgrastim (rG- Thousand Oaks, stimulation leukemia submitted CSF) CA factor (see also AIDS/HIV, respiratory)
Omcaspar® Enzon first-line treatment of in clinical
PEG-L- Piscataway, NJ acute lymphoblastic trials asparaginase Phone-Poulenc leukemia (ALL) adult Rorer ALL non-Hodgkin's Titusville, NJ lymphoma, chronic lymphocytic leukemia
Oncolym® Techniclone MAb malignant glioma Phase I Tustin, CA
OncoRad® PR CYTOGEN MAb targeted radiotherapy for Phase II CYT-356-Y-90 Princeton, NJ prostate malignancies
OncoScint® CYTOGEN MAb detection, staging and Phase II CR/OV Princeton, NJ follow-up of breast satumomab cancer pendetide
ONYX-015 Onyx oncolytic p53 deficient cancers Phase I/II
Pharmaceuticals virus therapy Richmond, CA p53 and RAS National Cancer vaccine solid tumores Phase I vaccine Institute NCI Trial Bethesda, MD p53 tumor Schering- gene therapy lung cancers Phase II suppressor gene Plough solid tumors that carry Phase I Madison, NJ the p53 gene mutation or deletion
Panorex® Centocor MAb adjuvant therapy for Phase III edrecolomab Malvern, PA post-operative colorectal cancer peripheral National Cancer gene therapy ovarian cancer Phase I blood institute NCI Trial lymphocytes Bethesda, MD transduced with a gene encoding a chimeric T- cell receptor
Proleukin® Chiron interleukin acute myelogenous Phase II/III aldesleukin Emeryville, CA leukemia, non- (interleukin-2) Hodgkin's lymphoma (see also AIDS/HIV) promegapoletin Searle growth factor adjunctive hematopoietic Phase I Skokie, IL therapy following chemotherapy
Prostrac Therion vaccine prostate cancer Phase I/II recombinant Biologies vaccinia virus Cambridge, MA CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
RAS 5-17 National Cancer vaccine solid tumores Phase I peptide vaccine Institute NCI Trial Bethesda, MD rCEA Vaccine Protein Sciences vaccine breast, colon cacers Phase I recombinant Meriden, CT carcinoembryon ic antigen
Rebit® Serono Laboratories interferon colorectal cancers Phase III recombinant Norwell, MA (see also infectious interferon beta- diseases, la neurologic) non-small-cell lung Phase I II cancer recombinant Genetics institute interleukin cancer (see also Phase I/II human Cambridge, MA infectious diseases) interleukin- 12 Wyeth-Ayerst (rhiL-12) Laboratories Philadelphia, PA retroviral cevtor Chiron gene therapy melanoma Phase I with tumor Emeryville, CA necrosis factor gene rF-gp 100 Therion Biologies vaccine melanoma Phase I (recombinant Cambridge, MA fowlpox virus) rF-MART-1 Therion Biologies vaccine melanoma Phase I (recombinant Cambridge, MA fowlpox virus)
RIGScan® Neoprobe MAb colorectal cancer application CR49 Dublin, OH submitted 125 l-cc49 MAb
Rituxan® National Cancer MAb leukemia, Phase II rituximab Institute lymphoma NCI Trial Bethesda, MD IDEC
Pharmaceuticals San Diego, CA
Roferon®-A Hoffmann-La Roche interferon malignant Phase III interferon alfa- Nutley, NJ melanoma adjuvant 2a, recombinant rV-gplOO Therion Biologies vaccine melanoma Phase I (recombinant Cambridge, MA vaccinia virus) rV-MART-1 Therion Biologies vaccine melanoma Phase I Cambridge, MA
Serosilm™ Serono Laboratories human growth cancer cachexia Phase I/II somatropin Norwell, MA hormone (see also other) (rDNA origin) for injection
SlgOSlX Ares-Serono and interleukin hematological Phase I/II recombinant Serono Laboratories conditions interleukin-6 (r- Norwell, MA (myelodysplastic IL-6) syndromes, cancer)
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
SMART™ M195 Protein Design MAb acute myeloid Phase II/III Hun 195 Labs leukemia
Mountain View, acute Phase II CA promyelocytic leukemia advaced myeloid Phase I leukemia
(with Bismuth-213) stem cell factor Amgen stern cell adjunct to application
Tousand Oaks, factor chemotherapy submitted
CA
SU101 SUGEN PDGF- malignant glioma Phase III
Redwood City, receptor prostate cancer Phase II
CA tyrosine kinase solid tumors Phase I II inhibitor
SU5416 SUGEN angiogenesis solid tumors Phase I Redwood City, inhibitor CA
TBC CEA Therion Biologies vaccine colorectal and lung Phase I/II
(vaccinia virus Cambridge, MA cancers expressing carcinoembryonic antigen)
Tcell-HDM Coulter Cellular cellular cancer Phase I/II Therapies therapy Boston, MA
Theratope Biomira vaccine breast cancer Phase II synthetic Edmonton, completed carbohydrate Alberta therapeutic Chiron vaccine Emeryville, CA thrombopoietin Genetech erythropoietin thrombocytopenia Phase II
S. San Francisco, related to cancer
CA treatment
Thyrogen Genzyme detection and application recombinant Cambridge, MA treatment of submitted human thyroid- thyroid cancer stimulating metastases hormone
TNT Techniclone MAb non-Hodgkin's B- Phase II III Tustin, CA cell lymphoma solid tumors Phase I
TriAB™ Titan vaccine breast cancer Phase II anti-idiotype Pharmaceuticals antibody vaccine S. San Francisco, CA TriGem™ Titan vaccine small-cell lung Phase I anti-idiotype Pharmaceuticals cancer, melanoma antibody vaccine S. San Francisco, CA urate oxidase Sanoli recombinant prophylaxis for Phase III
(recombinantly- New York, NY enzyme chemotherapy- produced enzyme) related hyperuricemia, treatment of cancer-related hyperuricemia
CANCER AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status vaccinia-CEA National Cancer vaccine advaced colorectal Phase I
180KD vaccine Institute cancer NCI Trial Bethesda, MD Therion Biologies Cabridge, MA
Vaxid Vical vaccine B-cell and mantle Phase I anti-idiotype San Diego, CA cell lymphomas DNA vaccine
Xerecept™ Neurobiological brain tumor edema Phase II human Technologies corticorropin- Richmond, CA releasing factor (hCRF)
Zenapax® Hoffmann-La Roche MAb certain blood Phase II daclizumab Nutley, NJ cancers (see also
Protein Design Labs eye, neurologic
Mountain View, CA skin, transplantation)
DIABETES AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status
Beta Kine Genzyme Tissue growth factor chronic diabetic Phase II transforming Repair foot ulcers growth factor- Cambridge, MA beta 2
BetaRx-H VivoRx cellular insulin-dependent Phase I encapsulated Santa Monica, CA therapy diabetes human islets
BetaRx-P VivoRx cellular insulin-dependent Phase I encapsulated Santa Monica, CA therapy diabetes porcine islets BetaRx-Pr VivoRx cellular insulin-dependent Phase I encapsulated Santa Monica, CA therapy diabetes proliferated human islets
Glucagen ™ Novo Nordisk recombinant hypoglycemia Phase III recombinant Pharmacceuticals human protein (see also digestive) human Princeton, NJ glucagon
(protein) glucagon for Eli Lilly recombinant to treat severe application injection Indianapolis, IN human protein hypoglycemic submitted (rDNA origin) events in patients with diabetes and to aid in gastrointestinal diagnostic procedures insulinotropin Soios type 2 diabetes Phase II
Mountain View, CA memantine Neurobiological painful diabetic Phase II
Technologies neuropathy
Richmond, CA (see also AIDS/HIV) nerve growth Genentech growth factor diabetic peripheral Phase II factor S. San Francisco, neuropathy
CA
DIABETES AND RELATED CONDITIONS
Product Development
Product Name Company Category Indication Status pimagedine Alteon diabetic Phase III
Ramsey, NJ progressive kidney
Genentech disease, diabetic
S. San Francisco, end-stage kidney
CA disease (see also neurologic) pramlintide Amylin human amylin improved Phase III
Pharmaceuticals analog metabolic control,
San Diego, CA which includes glucose, weight and lipid profiles in type 1 and insulin- using type 2 diabetes rDNA insulin Inhale Therapeutic recombinant diabetes Phase II
System insulin
Palo Alto, CA
Trovert™ Sensus human growth diabetes-related Phase II Austin, TX hormone illnesses
(see also growth disorders) DIGESTIVE DISORDERS
Product Development
Product Name Company Category Indication Status
Avakine™ Centocor MAb Crohn's disease application chimeric anti-TNF Malvern, PA (see also submitted antibody autoimmune)
Gastrimmune™ Aphron vaccine gastroesophageal Phase I II neutralizing G17 Woodland, CA reflux disease, hormone peptic and nonsterioidal anti- inflammatory drug ulcers (see also cancer)
Glucagen™ Novo Nordisk recombinant gastrointestinal Phase III recombinant Pharmaceuticals human protein motility inhibition human glucagon Princeton, NJ (see also diabetes)
(protein) interleukin-10 (II- Schering-Plough interleukin Crohn's disease, Phase II 10) Madison, NJ ulcerative colitis (see also AIDS/HIV autoimmune, heart, neurologic, respiratory, skin)
ISIS 2302 Isis antisense Crohn's disease, Phase II
Phamaceuticals ulcerative colitis Carlsbad, CA (see also autoimmune, skin, transplantation)
LOP-02 Genentech MAb inflammatory Phase II
S. San Francisco, bowel disease
CA
LeukoSite
Cambridge, MA
LeukoScan® Immunomedics MAb inflammatory Phase II sulesomab Morris Plains, NJ bowel disease (see also infectious diseases)
Neumega® Genetics Institute interleukin Crohn's Disease Phase II recombinant Cambridge, MA human interleukin-11 recombinant ICOS pancreatitis Phase II platelet activating Bothell, WA (see also factor- respiratory) acetylhydrolase (rPAF-AH) EYE CONDITIONS
Product Development
Product Name Company Category Indication Status
BPD-MA QLT Photo age-related macular Phase III verteporfin Therapeutics degeneration Vancouver, British Columbia
MDX-RA Medarex MAb prevention of Phase III immunotoxin Annandale, NJ secondary cataract
Zenapax® Huffmann-La MAb uveitis Phase I/II daclizumab Roche (see also cancer, Nutley, NJ neurologic, skin, Protein Design transplantation) Labs
Mountain View, CA
GENETIC DISORDERS
Product Development
Product Name Company Category Indication Status
AAV CFTR Targeted Genetics gene therapy cystic fibrosis Phase I gene therapy Seattle, WA (see also respiratory)
CFTR/adenovir Genzyme gene therapy cystic fibrosis Phase I us vector Cambridge, MA
CFTR/lipid Genzyme gene therapy cystic fibrosis Phase I vector Cambridge, MA ex vivo stem Genzyme gene therapy cystic fibrosis Phase I cells/ retrovirus Cambridge, MA vector
GR2134B7B Glaxo Wellcome gene therapy cystic fibrosis Phase I/II Rsch. Triangle Park, NC
Megabios Burlingarne, CA
GV-10 Gen Vec gene therapy cystic fibrosis Phase I Rockville, MD
HP-3 Milkhaus signaling cystic fibrosis Phase II Laboratory B oxford, MA
Neuprex™ XOMA recombinant cystic fibrosis Phase I recombinant Berkeley, CA human protein human bactericidal/per meability- increasing protein
(rPBI-21)
Pulmozyme Genentech recombinant early intervention Phase III domas alpha, S. San Francisco, Dnas in cystic fibrosis recombinant CA x-galachosidase Transkaryotic enzyme fabry's disease Phase I A Therapies Cambridge, MA GROWTH DISORDERS
Product Development
Product Name Company Category Indication Status pralomerlin Wyeth-Ayerst human growth adult growth Phase I
(GPA-748) Laboratories hormone hormone Philadelphia, PA deficiency
ProLease® hGH Alkermes human growth growth hormone Phase III
Cambridge, MA hormone deficiency in
Genentech children
S. San Francisco,
CA
Saizen Serono Laboratories human growth management of Phase III somatropin Norwell, MA hormone adults with growth
(rDNA origin hormone disorder, for injection) intrauterine growth retardation in children
(see also other)
Trovert™ Sensus human growth acromegaly Phase II
Austin, TX hormone (see also diabetes)
HEART DISEASE
Product Development
Product Name Company Category Indication Status
AcuTect™ Diatide peptide detection of carotid Phase II
Tc-99m Londonderry, thrombus apcitide NH anti-CD- 18 Genentech MAb acute myocardial Phase II humanized S. San Francisco, infarction
MAb CA
BioByPass™ GenVec gene therapy cardiovascular disease, Phase I therapeutic Rockville, MD including cardiac artery angiogenesis disease and peripheral (VEGF) vascular disease, either as an adjunct or alternative to existing surgical approaches such as cardiac artery bypass grafts and angioplasty
Biostent™ NeoRx reduction of restinosis Phase I Seattle, WA (vascular remodeling)following ballon angiolasty)
Capiscint Centocor MAb atherosclerotic plaque Phase I
Malvern, PA imaging agent Corsevin™ M Centocor MAb thrombolytic Phase I
12D10-Fab Malvern, PA complications of
Corvas percutaneous
San Diego, CA transluminal coronary angioplasty, coronary arterial starts, disseminates intravascular coagulation
CPC-111 Cypros cellular coronary bypass surgery Phase II
Phamaceuticals therapy (see also blood) Carlsbad, CA factor Vila Corvas deep vein thrombosis, Phase I inhibitors San Diego, CA pulmonary embolism, unstable angina, myocardial infarction
FIBLAST® Scios growth peripheral vascular Phase II trafermin Mountain View, factor disease, coronary anery CA disease
Wyeth-Ayerst (see also neurologic) Laboratories Philadelphia, PA
HEART DISEASE
Product Development
Product Name Company Category Indication Status gene therapy Collateral gene therapy stable exertional Phase I/II Therapeutics argina San Diego, CA growth factor Chiron growth factor coronary artery Phase I Emeryville, CA disease h5Gl.l-SCFV Alexion cardiopulmonary Phase II (recombinant) Pharmaceuticals bypass-associated New Haven, CT inflammation using Enzon SCD® technology Piscataway, NJ
Hu23F2G ICOS MAb myocardial Phase II MAb Bothell, WA infarction (see also neurologic, other)
Intergrilin™ COR Therapeutics percutaneous application eptifibatide S. San Francisco, transluminal submitted (Ilb/IIIa platelet CA coronary aggregation Schering-Plough angioplasty, inhibitor) Madison, NJ unstable angina acute myocardial Phase II infarction interleukin-10 Schering-Plough interleukin ischemic Phase I (IL-10) Madison, NJ reperfusion injury (see also AIDS/HIV, autoimmune, digestive, neurologic, respiratory, skin) lanoteplase Bristol-Myers t-PA acute myocardial Phase III Squibb infarction Princeton, NJ
LR-3280 Inex antisense cardiovascular Phase II
Pharmaceuticals restinosis Vancouver, BC Schwarz Pharma Milwaukee, WI
MHl-Fab American MAb in vivo imaging Phase I/II imaging agent Biogenetic agent for the Sciences detection of Boston, MA cardiovascular thrombosis
MPL®-C Ribi ImmunoChem prevention/amelior Phase II immunomodula Hamilton, MT ation of cardiac tor ischemia reperfusion injury
Natrucor® BNP Scios acute congestive Phase III
Mountain View, CA heart failure completed/ application submitted cardiovascular Phase I pulmonary surgery
T_r
Novastan Texas heparin-induced application argatroban Biotechnology thrombocytopenia submitted Houston, TX thrombosis syndrome
ReoPro Centocor MAb unstable angina Phase III abciximab Malvern, PA (see also Eli Lilly neurologic)
Indianapolis, In acute myocardial Phase II infarction rhAntithromnin Genzyme control of blood Phase II
III Cambridge, MA clotting during completed
(recombinant) coronary artery bypass surgery
TNK Genentech t-PA acute myocardial Phase III
(second- S. San Francisco, infarction generation t- CA
PA)
HEART DISEASE
Product Development
Product Name Company Category Indication Status
TP10 T Cell Sciences recombinant heart attack Phase I Needham, MA soluble (see also receptor respiratory, transplantation)
VEGF Genentech growth factor coronary artery Phase I
S. San Francisco, disease
CA VEGF 121 Scios growth factor cardiovascular Phase I
(vascular Mountain View, CA disorders endothelial growth factor)
Xubix™ Genentech acute coronary Phase III sibratiban oral S. San Francisco, syndrome Ilb/IIIa CA antagonist
INFECTIOUS DISEASE
Product Development
Product Name Company Category Indication Status adefovir Gilead Sciences nucleotide hepatitis B Phase II dipivoxil Foster City, CA analogue
Alferon N Gel® Interferon Sciences interferon human Phase II interferon New Brunswick, NJ papillomavirus alfa0n3 infections
Alferon N Interferon Sciences interferon chronic hepatitis C Phase III Injection® New Brunswick, NJ infections interferon alfa- (see also n3 AIDS/HIV) genital warts Phase II
Ampligen® Hemispherx interferon hepatitis Phase I/II Biopharma (see also
AIDS/HIV, cancer, other) anti-tumor Chiron MAb sepsis Phase II/III necrosis factor Emeryville, CA
MAb
Campylobacter Antex Biopharma cellular traveler's diarrhea Phase II vaccine New York, NY vaccine (Campylobacter infections)
CMV vaccine Chiron vaccine cytomegalovirus Phase II Emeryville, CA infection
DTaP vaccine Chiron vaccine diphtheria, tetanus, Phase III Emeryville, CA acellular pertussis
Epstein-Barr Aviron recombinant prevention of Phase I virus vaccine Mountain View, CA subunit Epstein-Barr virus
SmithKline vaccine infection (cause of
Beecham mononucleosis
Philadelphia, PA infection) genital herpes Glaxo Wellcome vaccine genital herpes Phase I vaccine Rsch. Triangle Park,
NC
Helicobacter Antex Biologies cellular peptic ulcers Phase I vaccine Gaithersburg, MD vaccine (Helicobacter pylori infections) 57/ 1
INFECTIOUS DISEASE
Product Development
Product Name Company Category Indication Status hepatitis A Chiron vaccine hepatitis A Phase III vaccine Emeryville, CA hepatitis B Powderject DNA hepatitis B Phase I DNA vaccine Vaccines vaccine prevention Madison, WI hepatitis B SmithKline vaccine treatment of Phase II vaccine Beecham hepatitis B
(recombinant) Philadelphia, PA herpes simplex SmithKline vaccine prevention of Phase III vaccine Beecham herpes simplex
(recombinant) Philadelphia, PA infection
HPV vaccine Medimmune vaccine genital warts Phase I Gaithersburg, MD (see also cancer) SmithKline Beecham Philadelphia, PA human anti- Protein Design Labs MAb liver Phase I/II hepatitis B Mountain View, CA transplantation due completed antibody (OST to chronic hepatitis 577) B infection
Intron®A Schering-Plough interferon pediatric hepatitis application interferon alfa- Madison, NJ B, self-injectable submitted
2b dosing system for
(recombinant) hepatitis C (see also cancer) hepatitis C (PEG- Phase III intron A)
Intron®A/ Schering-Plough interferon relapsed hepatitis C application
Rebeiol™ Madison, NJ submitted interferon alfa- naive hepatitis C Phase III
2b (not previously
(recombinant)/ri treated with bavirin interferon) hepatitis C (PEG- Phase I intron A/Rebetol)
LeukoScan® Immunomedics MAb diagnosis of application sulesomab Morris Plains, NJ osteomyelitis, submitted infected prosthesis, appendicitis (see also digestive)
Lyme Pasteur Merieux vaccine Lyme disease Phase III borreliosis Connaught protein vaccine Swiftwater, PA
Lyme disease SmithKline vaccine prevention of application vaccine Beecham Lyme disease submitted
(recombinant) Philadelphia, PA
MAK 195F Knoll MAb sepsis Phase III
Pharmaceutical Mt. Olive, NJ
MEDI-491 Medimmune vaccine B 19 parvovirus- Phase I parvovirus Gaithersburg, MD induced B 19 vaccine miscarriages and anemia 57 2
mentngococcus Chiron vaccine meningococcus C Phase II C vaccine Emeryville, CA
INFECTIOUS DISEASE
Product Development
Product Name Company Category Indication Status
MPL® Ribi vaccine infectious diseases in clinical immunomodulator ImmunoChem (see also trials
(25+ antigens for Hamilton, MT AIDS/HIV) adult and pediatric applications)
Neuprex™ XOMA recombinant meningococcemia Phase III recombinant Berkeley, CA human protein (see also genetic, human other) bactericidal/perme ability-increasing protein (rBPI-21) antibiotic adjuvant Phase II in intra-abdominal infections
Protovir™ Protein Design MAb cytomegalovirus Phase II human anti-CMV Labs infections in bone completed antibody Mountain View, marrow transplant CA patients
Rebir® Serono interferon viral infections Phase II/III recombinant Laboratories (see also cancer, interferon beta- la Norwell, MA neurologic) recombinant Eli Lilly recombinant treatment of severe Phase II human activated Indianapolis, IN human protein sepsis protein C (rhAPC) recombinant Genetics Institute interleukin infectious diseases Phase I II human Cambridge, MA (see also cancer) interleukin- 12 Wyeth-Ayerst (rhiL-12) Laboratories Philadelphia, PA
Rotashield™ Wyeth-Lederle continuous cell prevention of application rotavirus vaccine, Vaccines & line vaccine rotaviral submitted live, oral, Pediatrics gastroenteritis in tetravalent Philadelphia, PA infants rotavirus vaccine Virus Research vaccine rotavirus in infants Phase II Institute Cambridge, MA
Savvy™ Biosyn microbicide infectious disease Phase I
C31G Philadelphia, PA
Tenefuse® Hoffmann-La recombinant septic shock, Phase III lenercept (TNF- Roche soluble severe sepsis receptor fusion Nutley, NJ receptor protein) tifacogin Chiron tissue factor sepsis Phase II
Emeryville, CA pathway
Searle inhibitor
Skokie, IL 57/ 3
INFERTILITY
Product Development
Product Name Company Category Indication Status
Antide™ Ares/Serono and hormone- female infertility Phase I gonadotropin Serono releasing hormone- Laboratories hormone releasing hormone Norwell, MA antagonist antagonist
(GhRHA)
Gonal-P® Serono recombinant male infertility Phase III recombinant Laboratories fertility human follicle- Norwell, MA hormone stimulation hormone (r-FSH)
LhADI® Ares/Serono and recombinant female infertility- Phase II/III recombinant Serono fertility follicular support, human leutinizing Laboratories hormone stimulation of hormone Norwell, MA follicular
(r-hLH) development
Ovidrel® Ares/Serono and recombinant female infertility Phase III recombinant Serono gonadotropin (see also human chorionic Laboratories AIDS/HIV) gonadotropin Norwell, MA
(r-hCG)
NEUROLOGIC DISORDERS
Product Development
Product Name Company Category Indication Status
Activase® Genentech t-PA acute ischemic Phase III alteplase, S. San Francisco, stroke within 3 to 5 recombinant CA hours of symptom onset
AnergiX™ MS Anergen functional multiple sclerosis Phase I Redwood City, CA antigenics immunotherapy
Antergren Athena MAb multiple sclerosis Phase II natalizumab Neurosciences flames S. San Francisco, CA
ATM027 T Cell Sciences MAb multiple sclerosis Phase I humanized Needham, MA
MAb
Avonex® Biogen interferon secondary, Phase III interferon beta- Cambridge, MA progressive
Ta multiple sclerosis (see also cancer)
Betaseron® Berlex Laboratories interferon chronic progressive Phase III recombinant Wayne, NJ multiple sclerosis interferon beta- Chiron (see also cancer) lb Emeryville, CA 57/4
brain-derived Amegen growth factor amyotrophic lateral Phase I neurotrophic Thousand Oaks, CA sclerosis factor (BDNF) Regeneron Pharmaceuticals Tarrytown, NY
NEUROLOGIC DISORDERS
Product Development
Product Name Company Category Indication Status
CPC-211 Cypros cellular ischemic stroke, Phase II
Pharmaceuticals therapy traumatic brain Carlsbad, CA injury enlimomab Boehringer MAb stroke Phase II III
(antiOICAN-l Ingelheim (see also other)
MAb) Pharmaceuticals Ridgefield, CT
FIBLAST® Scios growth stroke Phase II/III tragermin Mountain View, CA factor (see also heart)
Wyeth-Ayerst
Laboratories
Philadelphia, PA
Hu23F2G ICOS MAb multiple sclerosis, Phase II MAb Bothell, WA ischemic stroke (see also heart, other) interleukin-10 Schering-Plough interleukin multiple sclerosis Phase I (iL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, respiratory, skin)
IR 208 Immune Response vaccine multiple sclerosis Phase I therapeutic Corp. vaccine Carlsbad, CA
LDP-01 LeukoSite MAb stroke Phase I/II Cambridge, MA (see also transplantation)
MS-TCR Connectics vaccine multiple sclerosis Phase I/II Pal Alto, CA
Myotrophin® Cephalon growth amyotrophic lateral application rhIGF-1 West Chester, PA factor sclerosis submitted Chiron peripheral Phase II Emeryville, CA neuropathies
NeuroCell™- Diacrin cellular focal epilepsy Phase I
FE Charlestown, MA therapy
(cellular transplantation therapy)
NeuroCell™- Diacrin cellular Huntington's Phase I
HD Charlestown, MA therapy disease completed
(cellular Genzyme Tissue transplantation Repair therapy) Cambridge, MA 57/5
NeuroCell™- Diacπn cellular Parkinson's disease Phase II
PD Charlestown, MA therapy
(cellular Genzyme Tissue transplantation Repair therapy) Cambridge, MA neurotrophιn-3 Amgen growth enteric Phase I/II
Thousand Oaks, CA factor neuropathies
Regeneron
Pharmaceuticals
Tarrytown, NY pimagedine Alteon overt neuropathy Phase III
Ramsey, NY (see also diabetes)
Genentech
S San Francisco,
CA prosaptide Myelos growth neuropathic pain Phase II TXI4(A) Neurosciences factor and penpheral San Diego, CA neuropathy
NEUROLOGIC DISORDERS
Product Development
Product Name Company Category Indication Status
Rebit* Serono Laboratoπes interferon relapsing, remitting application recombinant Norwell, MA multiple sclerosis, submitted transitional multiple sclerosis (see also cancer, infectious disease)
ReoPro" Centocor MAb stroke Phase II abciximab Malvern, PA (see also heart) Eli Lilly Indianapolis, IN
Spheramine™ Titan cellular Parkinson s disease Phase I
Pharmaceuticals therapy S San Francisco, CA
Zenapax® Hoffmann-La Roche MAb tropical spastic Phase I/II dac zumab Nutley, NJ paraparesis Protein Design Labs (model for multiple Mountain View, CA sclerosis)
(see also cancer, eye, skin, transplantation)
RESPIRATORY DISEASES
Product Development
Product Name Company Category Indication Status
AAV CFTR Targeted Genetics gene therapy sinusitis Phase I gene therapy Seattle, WA (see also genetic) acelluiar Chiron vaccine pediatnc pertussis application partussis Emeryville, CA (whooping cough) submitted vaccine anti-igE Genentech MAb allergic asthma Phase III humanized S. San Francisco,
MAb CA
Novartis
Pharmaceuticals
East Hanover, NJ
Tanox Biosystems 57/6
allergic rhinitis Phase II influenza rHAO Protein Sciences vaccine prevention of Phase II
Vaccine Meriden, CT influenza influenza vaccine influenza virus Aviron vaccine prevention of Phase III vaccine (live, Mountain View, CA influenza attenuated) interleukin-4 Immunex recombinant asthma Phase I receptor Seattle, WA soluble receptor interleukin-10 Schering-Plough interleukin acute lung injury Phase I (iL-10) Madison, NJ (see also AIDS/HIV, autoimmune, digestive, heart, neurologic, skin) lisofylline Cell Therapeutics acute lung injury Phase II Seattle, WA (see also other)
NEUPOGEN® Amgen colony multilobar Phase III Filgrastim (rG- Thousand Oaks, CA stimulation pneumonia, CSF) factor pneumonia sepsis (see also AIDS/HIV, cancer)
RESPIRATORY DISEASES
Product Development
Product Name Company Category Indication Status
Oxsodrol® Bio-Technology dismutase bronchopulmonary Phase III rhCu2r super General dysplasia in dismutase Iselin, NJ premature infants parainfluenza Aviron vaccine prevention of Phase II type-3 vaccine Mountain View, parainfluenza type-
(live, attenuated CA 3 infection (cause bovine) of croup in infants)
PIV vaccine, Wyeth-Lederle continuous cell prevention of Phase I live attenuated Vaccines & line vaccine parainfluenza Pediatrics virus-mediated Philadelphia, PA lower respiratory disease in infants
Quillmmune-F Aquila vaccine pneumococcal Phase II
B iopharmaceutical infections in the s elderly
Worcester, MA recombinant ICOS acute respiratory Phase II platelet Bothell, WA distress syndrome, activating factor- asthma acetylhydrolase (see also digestive) (rPAF-AH) 57/7
RSV subunit Wyeth-Lederle continuous cell prevention of Phase II vaccine Vaccines & line vaccine respiratory Pediatrics syncytial virus- Philadelphia, PA mediated lower respiratory disease in the elderly and at-risk children
RSV vaccine, Wyeth-Lederle continuous cell prevention of Phase I live, attenuated Vaccines & line vaccine respiratory Pediatrics syncytial virus- Philadelphia, PA mediated lower respiratory disease in infants soluble ICAM-1 Boehringer recombinant prevention and/or Phase II
(BIRRA) Ingelheim soluble treatment of
Pharmaceuticals receptor rhinovirus-induced
Ridgefield, CT common cold
Synagis™ Medimmune MAb prevention of application
MEDI-493 Gaithersburg, MD respiratory submitted humanized RSV syncytial virus
MAb disease
TP10 T Cell Sciences recombinant acute respiratory Phase II
Needham, MA soluble distress syndrome receptor (see also heart, transplantation) truncated ICAM Bayer adhesion rhinovirus-assoc- Phase I Berkeley, CA molecule iated exacerbations of asthma
SKIN DISORDERS
Product Development
Product Name Company Category Indication Status anti-CDl la Genentech MAb moderate to severe Phase II humanized MAb S. San Francisco, psoriasis (hul l24) CA
XOMA
Berkeley, CA gamma Connetics interferon keloids Phase II interferon Palo Alto, CA
ICM3 ICOS MAb psoriasis Phase I Bothell, WA
IL-2 fusion Seragen fusion protein moderate to severe Phase I/II protein Hopkinton, MA psoriasis
DAB389 IL-2 (see also autoimmune, cancer) interleukin-10 Schering-Plough interleukin psoriasis Phase I (IL-10) Madison, NJ (see also
AIDS/HIV, autoimmune, digestive, heart, neurologic, respiratory) 57/8
IR 502 Immune Response vaccine psoriasis Phase II therapeutic Corp. vaccine Carlsbad, CA
ISIS 2302 Isis antisense psoriasis Phase II
Pharmaceuticals (see also Carlsbad, CA autoimmune, digestive, transplantation) keratinocyte Human Genome growth factor wound healing Phase I growth factor-2 Sciences (see also other)
(KGF-2) Rockville, MD
LFA3TIP Biogen recombinant psoriasis Phase II Cambridge, MA T-cell inhibitor
Regranex ™ Chiron growth factor pressure ulcers Phase III becaplermin Emeryville, CA (see also other)
(recombinant R.W. Johnson human platelet- Pharmaceutical derived growth Research Institute factor-BB) Raritan, NJ
T4N5 Liposome Applied Genetics protection against Phase III
Lotion Freeport, NY actinic keratoses in
T4 endonuclease patients with
V encapsulated xeroderma in liposomes pigmentosa
TGF-beta3 OSI growth factor impaired wound Phase II
Pharmaceuticals healing Uniondale, NY (see also other) transforming Novartis growth factor wound healing Phase II growth factor- Pharmaceuticals beta-3 East Hanover, NJ
Zenapax Hoffmann-La MAb psoriasis Phase I/II daclizumab Roche (see also cancer, Nutley, NJ eye, neurologic, Protein Design transplantation) Labs
Mountain View, CA
TRANSPLANTATION
Product Development
Product Name Company Category Indication Status allogeneic SySternix cellular correct genetic Phase I hematopoietic Palo Alto, CA therapy diseases by in utero stem cells transplantation of genetically unaffected cells from a sibling or parent
CBL antibody Abgenix MAb graft versus host Phase II
(ABX-CBL) Foster City, CA disease
CTLA41g Bristol-Myers recombinant immunosuppression Phase II Squibb soluble Princeton, NJ receptor 57/9
HSD-Tk Genetic Therapy gene therapy treatment of graft Phase I retroviral vector Gaithersburg, MD versus host disease Systernix in allogenetic Palo Alto, CA hematopoietic stern cell transplantation
HSV-tk Chiron gene therapy graft versus host Phase I Emeryville, CA disease in bone marrow transplantation
ISIS 2302 Isis antisense renal transplant Phase II Pharmaceuticals rejection (see also autoimmune, digestive, skin)
LDP-01 LeukoSite MAb kidney Phase I/II Cambridge, MA transplantation (see also neurologic)
MEDI-507 Medimmune MAb graft versus host Phase II
(humanized Gaithersburg, MD disease
MAb) BioTransplant acute kidney Phase I/II Charlestown, MA transplant rejection
ORTHOCLONE Ortho Biotech MAb prevention of organ Phase II
OKT4A Raritan, NJ transplant rejection (see also autoimmune)
Simulect Novartis MAb transplantation application basiliximab Pharmaceuticals submitted East Hanover, NJ
SMART™ Anti- Protein Design MAb organ Phase I
CD3 Labs transplantation
HuM291 Mountain View, (see also CA autoimmune)
TP10 T Cell Sciences recombinant transplantation Phase I/II
Needham, MA soluble (see also heart, receptor respiratory)
Zenapax® Hoffmann-La MAb liver Phase II daclizumab Roche transplantation Nutley, NJ (see also cancer, Protein Design eye, neurologic, Labs skin)
Mountain View, pediatric kidney Phase I/II
CA transplantation
Zenapax® Hoffmann-La MAb kidney transplant Phase I/II daclizumab and Roche rejection,
Cellcept® Nutley, NJ cyclosporine Protein Design elimination Labs
Mountain View, CA
OTHER
Product Development
Product Name Company Category Indication Status
Recombumin Centeon excipient use Phase I recombinant King of Prussia, human albumin PA 57/ 10
Regranex™ Chiron growth factor venous ulcers Phase III becaplurmin Emeryville, CA (see also skin)
(recombinant R.W. Johnson human platelet- Pharmaceutical derived growth Research Institute factor-BB) Raritan, NJ rhBMP-2 Genetics Institute growth factor bone and cartilage in clinical
Cambridge, MA repair trials
Saizen® Serono human growth chronic renal Phase III somatropin Laboratories hormone failure in children
(rDNA origin for Norwell, MA (see also growth injection disorders) post-operative Phase II recovery
Serostim™ Serono human growth metabolic Phase II somatropin Laboratories hormone conditions
(rDNA origin for Norwell, MA (see also cancer) injection
Somatokine® Celtrix growth factor hip fractures, Phase II recombinant Pharmaceuticals severe acute burns insulin-like Santa Clara, CA growth factor-V binding protein-3
TGF-beta3 OSI growth factor oral mucositis Phase II
Pharmaceuticals (see also skin) Uniondale, NY
The content of this survey has been obtained through government and industry sources based on the latest information.
Survey current as of March 13, 1998. The information may not be comprehensive. For more specific information about a particular product, contact the individual company directly.
PhRMA internet address: http://www.phrma.org
Provided as a Public Service by PhRMA. Founded in 1958 as the Pharmaceutical Manufacturers
Association.
Copyright © 1998 by the Pharmaceutical Research and Manufacturers of America. Permission to reprint is awarded if proper credit is given.
58
In one aspect, particular benefit is obtained with this invention when used with biopharmaceuticals, which include, for example, any proteins, polypeptides, enzymes, immunoglobulins, polynucleic acids, and plasmids or other biopolymers. Specific examples of biopharmaceuticals to be included in the crystal formulations of the present invention include the following: insulin, glucagon, Glucagon-Like Peptide- 1 (7-37)OH (GLP-1), human growth hormone, leptin, follicle-stimulating hormone (FSH), ribozyme, and analogs thereof .
The API's useful with the present invention include those which themselves may form crystalline products, as well as those which do not. By way of example, any proteins can be prepared as microcrystalline suspension products, but the results have frequently been unsatisfactory using existing technology. However, inclusion of these biomolecules into a host crystal system in accordance with the present invention overcomes this limitation on crystallization. The invention further finds utility even with API's that are readily crystallized, such as insulin. The incoφoration of such API's into a single crystal lattice can be used to enhance stability or provide means of delivery that have different characteristics. Solvents for preparation of the saturated and supersaturated crystal lattice component include, but are not limited to, water, alcohols (e.g., ethanol, isopropanol), other organic solvents, acids, bases, and buffers. The crystals of the present invention are prepared to have a predetermined amount of active pharmaceutical ingredient. The desired amount of active pharmaceutical ingredient will depend on typical considerations, such as the effective amount of API used for administering to a patient. The concentration of API in the crystal is controlled, such as by previously described means, to yield crystals which are readily used in preparing pharmaceutical formulations for administration. The active pharmaceutical ingredient can be incoφorated into the crystals at any of a wide variety of molar or weight percentages. Preferred percentages can be easily selected by a skilled artisan taking into account the usual considerations for later formulation of the desired pharmaceutical compositions, depending on the application, route of delivery, and desired pharmacological profile. Preferred percentages include, for example, concentrations of 0.01 - 1 weight percent. As used herein, all weight percentages are given as the percent 59 based on the weight of the crystal including the crystal lattice component, the active pharmaceutical ingredient and any other components included within the crystals, unless stated otherwise.
The crystals may be prepared at varying size distributions, similarly depending on the subsequent formulating to be done with the crystals, or on crystal growth parameters. The crystals may be harvested and then sorted directly to desired size ranges, or may first be processed, such as by grinding or milling, and then sorted such as by sieving. As will be appreciated, a desired amount of active pharmaceutical ingredient may be obtained simply by obtaining a determined weight of crystals containing the active pharmaceutical ingredient at a known weight concentration. The useful size or weight range of the crystals of the present invention accordingly varies widely, depending on such factors as the inclusion level of the active pharmaceutical ingredient, the dosage amount for the active pharmaceutical ingredient, and the method of delivery of the crystals. By way of example, suitable crystals may have an average size distribution of 1 μm to 1 mm . The crystals of the present invention will typically be used in a formulation comprising a large number of crystals. It is a feature of the present invention that the active pharmaceutical ingredient is included within the crystal lattice component in a predictable, oriented fashion. This leads to a uniform concentration of the active pharmaceutical ingredient as a molar, and therefore weight, percentage of the crystals. In one aspect of the present invention, there is provided a composition of crystals having a substantially uniform weight concentration of active pharmaceutical ingredient as between crystals. The term "substantially uniform weight concentration" refers to the fact that the weight concentration of active pharmaceutical ingredient in the various crystals is sufficiently uniform that an acceptably accurate weight of active pharmaceutical ingredient can be obtained based on the weight of the crystals and the average concentration of active pharmaceutical ingredient in such crystals. In one preferred embodiment, there is provided a composition of crystals in which the size distribution of active pharmaceutical ingredient does not vary between crystals by more than about 20 percent. However, alternate embodiments may be equally 60 useful, including mixtures of different size crystals. A desired quantity of active pharmaceutical ingredient is then accurately obtained by measuring a weight amount of crystals which, given the concentration of active pharmaceutical ingredient, yields the selected weight of active pharmaceutical ingredient. The crystals and included API's are useful in the crystal form for both the stabilization and storage of the API and for the administration of the API to a patient. As used herein, it will be appreciated that the term patient refers to either humans or non-humans, depending on the nature of the active pharmaceutical ingredient. The crystals may be used as such, and in one aspect of the present invention the crystals consist essentially of simply the crystal lattice component and the API. Alternatively, the crystals include the crystal lattice component and the API in combination with other pharmaceutically-acceptable adjuvants also contained within the crystals.
The crystals of the present invention are preferably formulated as pharmaceutical materials for ultimate delivery in solid or liquid form. In such applications, the crystals are typically formulated with common, compatible, pharmaceutically-acceptable adjuvants, such as excipients, diluents, carriers or mixtures thereof. For puφoses herein, the term "pharmaceutically-acceptable" refers in this context to the excipients, diluents or carriers, as well as coatings or other components referred to elsewhere, being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Examples of excipients, diluents, and carriers that are suitable for such dosage forms are well known in the art, and include the following: suspension additives such as tonicity modifiers, buffers, precipitants, and preservatives; fillers and extenders such as starch, lactose, dextrose, sucrose, sorbitol, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin, and polyvinyl pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resoφtion accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol and glycerol monostearate; adsoφtive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate, and solid 61 polyethyl glycols. Additionally, the adjuvant may comprise crystals of the crystal lattice component that are prepared without the included API.
The crystals may be coated to achieve various effects. In one approach, the crystals are coated with the same crystal lattice component which forms the underlying crystal, but without the included API. This assures that the coating and the underlying crystal have compatibility. The coating is then applied at a thickness which provides the desired effect, such as further protection of the active pharmaceutical ingredient, bulking of the crystal for handling, and/or effecting a sustained or delayed release of the active pharmaceutical ingredient. Alternatively, the same effects can be accomplished by coating the crystals with other compatible coating compositions, such as those which are well known in the pharmaceutical coating art. The crystals can also be coated so as to release the active pharmaceutical ingredient only or preferably in a particular part of the intestinal tract or other route of administration, possibly over a period of time. This is accomplished, in known fashion, using coatings, envelopes, and protective matrices made, for example, from polymeric substances or waxes.
It is a feature of one aspect of the present invention that the crystals and included API's may be packaged and administered to patients in discrete pharmaceutical dosage forms. The crystals may be used as such in solid form, or may be formulated into liquid solutions or suspensions prior to use. The compositions may accordingly be administered by various routes, for example, by the oral, rectal, vaginal, ocular, buccal, nasal, pulmonary, iontophoretic, topical or parenteral routes. Such compositions form part of the present invention and are prepared in manners well known in the pharmaceutical art. The API's of the present invention are effective over a varied dosage range.
Such dosages are readily accommodated by the present invention by permitting various sizes of crystals, concentrations of API, etc. It will be understood that the amount administered will be determined in light of the relevant circumstances, including the condition to be treated, the choice of API to be administered, the size of the patient being treated, and the chosen route of administration. Therefore, specific dosage ranges will differ accordingly, and are not limiting of the scope of the invention in any way. 62
The compositions are formulated in one embodiment as a unit dosage form. The term "unit dosage form" refers to physically discrete units, such as tablets, capsules, and suspensions in vials or cartridge/pen systems suitable as unitary dosages, particularly as unitary daily dosages. Each discrete unit contains a predetermined quantity of active pharmaceutical material calculated to produce the desired effect, e.g., a prophylactic or therapeutic effect. The amount of active pharmaceutical ingredient contained in a given dosage unit can be varied depending on the manner of delivering the crystals. For example, a single dosage unit in tablet form may contain 1/4, 1/3, 1/2 or 1 times the unit dose for the active pharmaceutical ingredient, according to which 1 to 4 tablets would be administered to achieve a unit dose of the active pharmaceutical ingredient.
Therefore, in one aspect of the present invention, there is provided a pharmaceutical product in dosage form comprising a pharmaceutical delivery unit including a dosage amount of active pharmaceutical ingredient. The API is contained within the crystal lattice component, and a sufficient amount of crystals is included within the delivery unit to constitute the dosage amount of the API. It will be appreciated that the dosage amount of pharmaceutical may be obtained by provision of one or more crystals of the present invention. One form of the product consists essentially of a dosage amount of the crystals. In an alternative form, the pharmaceutical product consists of the dosage amount of the crystals. The ultimate delivery forms may include, for example, tablets, soft and hard gelatin capsules, pellets, granules, marumes, lozenges, sachets, cachets, elixirs, suspensions, ointments, suppositories, injection solutions and suspensions, nonpareils, spheres and sterile packaged powders. The crystals may be coated or uncoated, and may be combined with various pharmaceutical adjuvants, including excipients, diluents and carriers, as already described. One preferred form of the pharmaceutical product consists essentially of the crystals, and an alternate form consists of the crystals and the pharmaceutically-acceptable adjuvants. The delivery forms are prepared by conventional techniques such as disclosed in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Company, Easton, PA (1995), which is incoφorated herein by reference, or other treatises available to the skilled artisan. 63
Compressed tablets, for example, are prepared by well-known means which are conventional in the art. The tablets may be prepared by wet or dry granulation methods or by direct compression, and may be produced by any of a wide variety of tabletting machines. Tablet formulations usually incoφorate diluents, binders, lubricants and disintegrators, as well as the crystals with included API's. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride, and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders are substances such as starch, gelatin, and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including acacia, alginates, methylcellulose, polyvinylpyrrolidine and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
Certain solid pharmaceutical dosage forms of the present invention, most notably tablets, may be coated in conventional fashion with a wide variety of materials utilizing various processes. Typically, the products of the present invention may be sugar coated or film coated in accordance with well-known techniques. The coatings serve an aesthetic puφose as well as a practical one. Coatings can mask an unpleasant taste or odor, can increase ease of ingestion by the patient, and can serve to improve the ultimate appearance of the dosage form. Similarly, coatings can protect the product from the effects of air, moisture and light, can improve product identification, and can facilitate handling in packaging and fill lines during manufacture.
Various adjuvants may be included in the coating formulations as is well known in the art. These include, for example, permeability enhancers, plasticizers, antitacking agents and the like. A discussion of coating techniques and adjuvants is presented in United States Patent No. 5,015,480, issued to Childers et al. on May 14, 1991, the pertinent portions of which are hereby incoφorated herein by reference. Further information pertinent to coating processes and equipment may be obtained from Remington's Pharmaceutical Sciences, supra. Tablets are often coated with sugar as a flavorant and sealant, or with film- forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets by using large amounts of 64 pleasant-tasting substances such as mannitol in the formulation, as is now well- established practice. Instantly dissolving tablet-like formulations are also now frequently used to assure that the subject consumes the dosage form, and to avoid the difficulty in swallowing solid objects that bothers some subjects. A lubricant is used in a tablet formulation to prevent the tablet and punches from sticking in the die of the tabletting machine. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablet disintegrators are substances which swell when wetted to break up the tablet and release the crystals. They include starches, clays, celluloses, algins and gums. More particularly, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp and carboxymethylcellulose, for example, may be used, as well as sodium lauryl sulfate. Enteric formulations are used to protect crystals and the included API's from the strongly acidic contents of the stomach. Such formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in acidic environments, and soluble in basic environments. Exemplary films are cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate.
The crystals with included API's may similarly be formulated into capsules for administration. Such capsules are prepared utilizing conventional encapsulating methods. A general method of manufacture involves preparing the crystals for use in capsules, such as by milling the crystals to a suitable size. The crystals are blended with desired excipients, diluents or carriers, and the resulting mixture is filled into suitably-sized capsules, typically hard gelatin capsules, using conventional capsule-filling machines. The usual diluents include inert powdered substances such as starch of many different kinds, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders.
When it is desired to administer the crystal formulations as a suppository, the usual bases may be used. Cocoa butter is a traditional suppository base, which 65 may be modified by addition of waxes to raise its melting point slightly. Water- miscible suppository bases comprising, particularly, polyethylene glycols of various molecular weights are also in wide use.
The crystals can also be similarly formulated as elixirs or suspensions for convenient oral administration or for parenteral administration, for instance by intramuscular, subcutaneous or intravenous routes.
The inventive crystals enable the design of sustained-release formulations based upon various factors to yield both the desired amount of active pharmaceutical ingredient and the desired pharmacokinetic profile for delivery of the active pharmaceutical ingredient. Selectively incoφorating the active pharmaceutical ingredient into the crystal lattice, e.g., into a specific crystal growth sector, modulates the release profiles and can therefore be used to effect desired pharmacological properties. The choice of the crystal component and the process used to grow the crystals of excipient host and guest active pharmaceutical ingredient can be selected and/or modified to adjust parameters such as the delivery rate of the active pharmaceutical ingredient upon use of the formulation. The active pharmaceutical ingredient is incoφorated into the crystal matrix at a selected rate, typically as only a small weight percentage of the overall crystal. This permits moderate and uniform rates of release. Various approaches may be used to accomplish a delayed or sustained release of active pharmaceutical ingredient from the crystals. In a typical application the crystals of the desired size are combined with a compatible preservative and the mixture is injected subcutaneously or surgically implanted to provide a prolonged payout as the crystals dissolve as a result of contact with the surrounding body tissue and fluid. In one approach, the concentration of the active pharmaceutical ingredient in the crystals is reduced in order to effect a sustained release over time. Alternatively, larger crystals may be used to provide for more prolonged payout of the active pharmaceutical ingredient. In another approach, coatings on the crystals are used to affect the rate of release of the active pharmaceutical ingredient. Such coatings may comprise the same crystal lattice component but without the included active pharmaceutical ingredient, as well as other coating compositions useful for this puφose. 66
In the alternative, the crystals of the present invention can be used to isolate and/or store the active pharmaceutical ingredient for later reconstitution into solution. The crystals may be stored for extended periods of time prior to reconstitution in view of the added stability accorded the API's by the encompassing crystal lattice component. The crystals are then combined with pharmaceutically-acceptable excipients, diluents or carriers to prepare the solutions for subsequent administration. The crystals are readily dissolved or suspended in appropriate diluents, which may be selected, for example, from the list previously provided with regard to diluents used to initially prepare the crystals. Such solutions of dissolved crystals provide the active pharmaceutical ingredient free of the previously encompassing crystal lattice component. The solutions are useful, for example, for oral administration, parenteral use, or as suppositories. For parenteral administration, for example, the crystals may be formulated in a pharmaceutically-acceptable diluent such as physiological saline (0.9%), 5% dextrose, Ringer's solution, and the like, along with other additives to reduce the solubility of the crystals in suspension.
The resulting pharmaceutical formulations provide an active pharmaceutical ingredient which is included within the host crystal and has enhanced stability and shelf-life. The present invention therefore satisfies the desire to provide certain pharmaceuticals having an acceptable, room-temperature shelf-life. Depending on the circumstances, particularly the API involved, the desired shelf-life can be as little as one month, or may be at least one year, two years or more. The pharmaceutical molecules are generally isolated from one another and from the environment by the surrounding crystal lattice. The containment of the API in the solid crystal lattice also fixes the conformational orientation. This eliminates most of the potential degradation mechanisms, such as polymerization, oxidation, deamidation and proteolysis, that could otherwise reduce the stability of the pharmaceutical.
Methods demonstrating stability include but are not limited to high- performance liquid chromatography for purity and potency, FT-IR for secondary structure, in-vitro and in-vivo bioassays, and pharmacokinetic profiles. 67
The crystals of the present invention are readily prepared and are useful in containing the included API in an isolated, oriented position within the lattice. The utility of the present invention is demonstrated in the following examples, which are illustrative in nature, and are not to be considered limiting of the scope of the present invention.
Example 1
To demonstrate the potential kinetic stabilization of proteins, green fluorescent protein (GFP) was incoφorated into deionized α-lactose monohydrate.
GFP was selected because it is known to fluoresce only in its native conformation. Upon denaturation, the interior of the β-barrel of the molecule is exposed and the fluorescence of the p-hydroxybenzylideneimidazolinone chromophore is rapidly quenched. Typical crystal growth conditions involved the addition of 8 volumes of an approximately 1 mg/mL (approximately 37 μmole) solution of GFP in 10 mM tris-HCl, pH8 and 10 mM EDTA to 100 volumes of a supersaturated aqueous solution (approximately 1.15 M) of deionized α-lactose monohydrate. The mixed solution was allowed to stand for 3-4 days at room temperature in a 24-well plate. Crystals were harvested between 1-3 days and displayed a hatchet moφhology as shown in Figure 1 with a broad base (010) further bounded by { 100}, { 110}, { 1- 10}, and {0-11 }. Small (0-10) and { 1-50} faces are also occasionally present. When illuminated with a long wavelength UV lamp, the crystals exhibited a bright green fluorescence localized within a shaφly defined pyramid corresponding to the (010) growth sector. This indicates that GFP is selectively recognized and overgrown by the (010) face in preference to the others. More importantly, it is evidence that the GFP is in its native conformation. The level of GFP to lactose is approximately 0.008% (w/w).
GFP fluorescence intensity was measured as a function of time and temperature in three environments: saturated aqueous α-lactose solution, lyophilized α-lactose, and crystalline α-lactose monohydrate. As shown in Figure 2, both the solution and lyophilized preparations lost nearly half of the fluorescence intensity at 333°K within one hour. The crystal showed no change at 333°K or even 343°K. 68
Example 2 To investigate the potential for incoφoration of a biopharmaceutical into crystals of biocompatible excipients, studies were conducted using rhodamine- labeled glandular glucagon and lactose. As in the previous studies, the rhodamine label was used to facilitate the visualization of glucagon in the host crystals. Typical crystal growth conditions involved the addition of 5 volumes of a supersaturated solution of deionized α-lactose monohydrate to 1 volume of an approximately 1.5 mg/mL (approximately 300 to 400 μmole) of rhodamine-labeled glucagon in purified water. The mixed solution was allowed to stand at room temperature in a 24-well plate. Crystals were harvested between 1-3 days and displayed a hatchet moφhology with a broad base. With the rhodamine label, glucagon inclusion was visible in the crystals as a well-defined pyramid corresponding to the (010) growth sector. The level of inclusion was determined to be approximately 0.1% (w/w). In-vitro dissolution experiments were performed on the glucagon lactose crystals to evaluate potential for in-vivo, sustained-release pharmacokinetics. The release of rhodamine-labeled glucagon into solution was followed by fluorescence spectroscopy. In a typical experiment, 1-2 crystals were added to 100 microliters of phophate buffered saline solution at room temperature and the increase in fluorescence of the solution was monitored over time. The release of glucagon from the dissolving crystals was generally complete after 24-48 hours depending on crystal size and was linear until the last few hours of dissolution. Additional details are contained in the article entitled "Stabilization of Proteins in Single Crystal Hosts: Green Fluorescent Protein and α-Lactose Monohydrate," M. Kurimoto, P. Subramony, R. Gurney, S. Lovell, J.A. Chmielewski, B. Kahr, J. Am. Chem. Soc. 1999, 121, 6952-6953, which article is hereby incoφorated herein by reference.
Example 3 To demonstrate the universality of this technology for incoφoration of a diversity of biopharmaceuticals into crystals of biocompatible excipients, studies were conducted using biosynthetic human insulin and insulin analogs, 69
V8-GLP-l(7-37)OH, a glucagon-like insulinotropic peptide- 1 analog, exendin, and human growth hormone in deionized α-lactose monohydrate or phthalic acid. Information regarding N8-GLP is available in United States Patent No. 5,705,483, issued to Galloway and Hoffman on January 6, 1998, which patent is hereby incoφorated herein in its entirety. For information regarding exendin, see, e.g., R. Goke, H.C. Fehmann, T. Linn, H. Schmidt, M. Krause, J. Eng, B. Goke, "Exendin- 4 is a High Potency Agonist and Truncated Exendin-(9-39)-amide an Antagonist at the Glucagon-like Peptide l-(7-36)-amide Receptor of Insulin-secreting Beta- cells," J. Biol. Chem. 1993, Sep 15, 268(26), pp. 19650-5, which reference is hereby incoφorated herein in its entirety.
Typical crystal growth conditions involved the addition of 1 volume of an approximately 10 mg mL rhodamine- or Texas red-labeled peptide or protein in 0.1M phosphate-buffered saline solution (PBS, pH7.4) to 10 volumes of a supersaturated α-lactose solution or phthalic acid solution. Supersaturated solutions of purified α-lactose were obtained by adding 0.41 grams of α-lactose to 1 mL of purified water, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature. Supersaturated solutions of phthalic acid were prepared by adding 0.05 grams of phthalic acid to 1 mL of either 70/30 (v/v) water/acetonitrile or 90/10 water/ethanol, allowing to dissolve in a 50-70°C water bath, and cooling to room temperature. Larger volumes of supersaturated solutions are obtained by using the same solute-to-solvent ratio.
The solutions of labeled peptide or protein with the supersaturated α- lactose or phthalic acid were mixed by swirling, transferred to a 24-well crystallization plate or other suitable glass or polypropylene container, and allowed to stand at room temperature. Crystals were harvested in 4-5 days and rinsed with hexanes, ethanol, or methanol. All preparations yielded crystals with dye-labeled protein inclusions as determined by microscopic examination using an Olympus SZ-40 microscope with a CCD vision camera.
The shape of the crystals formed was dependent on the solvent system used for the phthalic acid. The crystals formed with phthalic acid in water/ethanol were long, petal-shaped clusters. The crystals formed with water/ethanol were smaller 70 and rhombic. Crystals of labeled-insulin/lactose were dissolved in PBS and analyzed by HPLC. The level of insulin inclusion was determined to be approximately 0.1%. This process is scalable from 100 μL to several liters. The larger volume crystallizations were performed using glass beakers, or other appropriate large containers, covered with watch glasses.
Using the same process, unlabeled insulin and exendin have also been incoφorated into α-lactose monohydrate and phthalic acid crystals. Upon dissolution of the crystals with 0.01N HC1, purified water and/or methanol, the level of peptide included in these hosts was determined by analysis of the sample solutions with an HPLC system in the flow-injection analysis mode using a chemiluminescent nitrogen-specific detector (CLND). The level of peptide inclusions ranged from approximately 0.1% to 10% (w/w). These data demonstrate that the level of inclusion can be manipulated by appropriate choice of guest and host molecules in addition to crystallization conditions. See also the following references which are hereby incoφorated herein in their entirety: M. Windholz, (editor). Merck Index, 10th edition, p. 769; R.A. Visser, Neth. Milk Dairy Journal, 34, 1980, pp. 255-275; J. Chmielewski, et al., JACS, 119, 43, pp. 105665-10566.

Claims

71WHAT IS CLAIMED IS:
1. A pharmaceutical composition comprising: a single crystal of a pharmaceutically-acceptable crystal lattice component; and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
2. A pharmaceutical material comprising: a mixture of single crystals, each crystal comprising a pharmaceutically- acceptable crystal lattice component and an active pharmaceutical ingredient different from and included within the crystal in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
3. The pharmaceutical material of claim 2 in which the crystals comprise at least two crystal lattice components, the first crystal lattice component being characterized by first pharmacokinetics and the second crystal lattice component being characterized by second pharmacokinetics.
4. The pharmaceutical material of claim 2 in which said mixture comprises a mixture of two different types of said crystals, the first type of the crystals comprising a first crystal lattice component and the second type of the crystals comprising at least one crystal lattice component different from the first crystal lattice component.
5. The pharmaceutical material of any of claims 2 to 4 in which the active pharmaceutical ingredient comprises discrete units and the units are included within the crystals in isolation from one another.
6. The pharmaceutical material of any of claims 2 to 5 in which the active pharmaceutical ingredient is included within the crystal at a concentration of about 0.001 to 1 weight percent based on the weight of the crystal including the active pharmaceutical ingredient.
7. A method of preparing a pharmaceutical product which comprises: including an active pharmaceutical ingredient into single crystals of a pharmaceutically-acceptable crystal lattice component, the including being 72 conducted under pharmaceutically-acceptable conditions to provide the active pharmaceutical ingredient in the crystals in a growth-sector specific orientation; and harvesting the single crystals.
8. The method of claim 7 and which further includes dissolving the harvested crystals into a pharmaceutically-acceptable diluent to form a solution containing the pharmaceutical free of the crystals.
9. A method of stabilizing an active pharmaceutical ingredient which comprises including the active pharmaceutical ingredient into single crystals of a pharmaceutically-acceptable crystal lattice component, the including being conducted under pharmaceutically-acceptable conditions to provide the active pharmaceutical ingredient in the crystals in a growth-sector specific orientation, the active pharmaceutical ingredient comprising discrete units and the units being included in the crystals in isolation from one another.
10. A method of administering an active pharmaceutical ingredient which comprises administering to a patient a pharmaceutical composition comprising single crystals of a pharmaceutically-acceptable crystal lattice component and an active pharmaceutical ingredient different from and included within the crystal lattice component in a growth-sector specific orientation, the crystal lattice component and the active pharmaceutical ingredient being pharmaceutically pure.
11. The invention of any of claims 1 to 10 in which, for each crystal, the active pharmaceutical ingredient is included within the crystal in a growth- sector specific orientation.
12. The invention of any of claims 1 to 11 and further comprising a pharmaceutically-acceptable adjuvant selected from the group consisting of excipients, diluents, carriers and mixtures thereof.
13. The invention of any of claims 1 to 12 in which the active pharmaceutical ingredient is a biopharmaceutical.
14. The invention of any of claims 1 to 13 in which the crystal lattice component is selected from the group consisting of: sucrose, lactose, trehalose, maltose, galactose, sorbose, mannitol, lactitol, sorbitol, glycine, alanine, lysine, 73 arginine, ascorbic acid, nicotinamide, thiamine, adenine, pyridoxine hydrochloride, caffeic acid, vanillic acid, ferulic acid, benzoate, sorbate, methyl paraben, sodium ascorbate, sodium saccharin, potassium citrate, zinc, calcium, and any derivatives, salt forms, or mixtures thereof.
PCT/US2000/016140 1999-06-11 2000-06-12 Pharmaceutical materials and methods for their preparation and use WO2000076480A2 (en)

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US10/018,043 US7001892B1 (en) 1999-06-11 2000-06-12 Pharmaceutical materials and methods for their preparation and use
AU54836/00A AU5483600A (en) 1999-06-11 2000-06-12 Pharmaceutical materials and methods for their preparation and use

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US60/138,912 1999-06-11

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US7001892B1 (en) 1999-06-11 2006-02-21 Purdue Research Foundation Pharmaceutical materials and methods for their preparation and use
US7138262B1 (en) 2000-08-18 2006-11-21 Shire Human Genetic Therapies, Inc. High mannose proteins and methods of making high mannose proteins
PL1986612T3 (en) 2006-02-07 2013-02-28 Shire Human Genetic Therapies Stabilized composition of glucocerebrosidase
RU2568831C2 (en) * 2009-07-28 2015-11-20 Шайр Хьюман Дженетик Терапиз Compositions and methods for treating gaucher disease
WO2013130963A1 (en) 2012-03-02 2013-09-06 Shire Human Genetic Therapies, Inc. Compositions and methods for treating type iii gaucher disease

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DE3306250A1 (en) * 1983-02-23 1984-08-23 Basf Ag, 6700 Ludwigshafen SPHERICAL SINGLE CRYSTALS FOR PHARMACEUTICAL PURPOSES
NL194389C (en) * 1984-06-14 2002-03-04 Novartis Ag Process for preparing a solid dispersion of a pharmaceutically active agent that has low water solubility in a solid matrix of a water-soluble polyalkylene glycol as a carrier.
DE3882011T2 (en) * 1987-10-27 1993-09-30 Fujitsu Ltd Method and device for producing biopolymer single crystal.
US5075291A (en) * 1989-11-22 1991-12-24 Ici Americas Inc. Crystalline sugar alcohol containing uniformly dispersed particulate pharmaceutical compound
GB9411129D0 (en) * 1993-06-16 1994-07-27 Ici America Inc A crystalline polyol composition
FR2742164B1 (en) * 1995-12-11 1999-01-29 Beghin Say Eridania MICROCRYSTALLINE SUGAR: COMPOSITION AND METHOD OF OBTAINING

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AU5483600A (en) 2001-01-02
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WO2000076480A3 (en) 2001-04-19

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