Delivering Therapeutic Proteins - Drugs, Devices and Delivering Strategies

The complex structure of these therapeutic substances require special formulation and delivery strategies, creating special challenges for drug developers, their formulation technology , delivery device partners. The stakes are high. The current list of approved therapeutic proteins will grow at an exponential rate as the convergence of automated drug discovery and biotechnology production methods create new biological drugs for an expanding number of previously intractable ailments. Currently, more than two-thirds of all therapeutic proteins for chronic diseases are sold as combination pen or auto-injector products. We expect the impressive success of combination drug-device products to continue their dominance on a total market value basis. And while injection will remain the dominant route of administration for protein drugs for the rest of the decade, the recent clinical success of several inhaled protein products will result in escalating interest in inhalation as a protein drug delivery method. Work on stabilized oral formulations is also making progress. In the near term, the cost per dose of recombinant proteins will continue to provide device technologists with enough running room to continue developing rather elegant protein-device combination products.

In recent years, the number of protein-based pharmaceuticals reaching the marketplace has increased exponentially. The clinical application of these drugs is limited by a lack of desirable attributes for adequate absorption or distribution. It therefore becomes critical to formulate these drugs into safe, stable and efficacious delivery systems. Because these drugs face formidable enzymatic and penetration barriers when administered orally, peptide and protein drugs have until recently been marketed almost exclusively for parenteral administration.

A limitation of the parenteral route for delivery of peptides and proteins is the extremely short half-lives of these drugs – in the order of a few minutes. This demands repeated administration, which is inconvenient to the patient. For this reason, non-parenteral routes of administration are being pursued. Another approach is to incorporate controlled release parenteral formulations, where a single injection may release the drug over several weeks or longer.

These combination products, where the drug and device are clinically tested and approved as a single product entity, are becoming one of the fastest new drug categories. Combination drug delivery products are growing at an annual rate of fourteen percent across all technology segments, and will total $38 Billion in 2008. The growth of combination products is having a significant effect on the way drugs and devices are developed. Cooperation between device designers and drug developers is occurring much earlier in the drug development cycle, allowing device designs in many cases to be tailored to the bioavailability targets and pharmacokinetic profiles of specific drug therapies. In the near term, the cost per dose of recombinant proteins will continue to provide device technologists with enough running room to continue developing elegant protein-device combination products.

Methodology:

Research methodology is based on primary research in the form of in-depth interviews with key market participants, technology developers, distributors, industry experts, and market influencers, a list that includes regulatory officials, industry trade groups, and materials standards organizations.

Primary data is evaluated and normalized against secondary sources including trade journal articles, technical literature, industry publications, company data sheets and published information, and statistical data from government agencies and trade associations.

Forecasts and projections of market demand and future market activity are derived using standard modeling and statistical techniques.


The oral delivery of therapeutic proteins

Therapeutic proteins represent currently a significant part of the new pharmaceuticals coming on the market every year. The progresses in biotechnology have accelerated the economical, large-scale production of therapeutically active peptides and proteins, monoclonal antibodies, hormones and vaccines, making them readily on hand for therapeutic applications. At the present, they show a strong position in the novel area of nanomedicine, using nanotechnology for medical applications for both institutional and industrial fields. Most of these proteins are used for life-threatening and seriously debilitating diseases such as diabetes, cancer, rheumatoid arthritis or hepatitis. The high activity and specificity of proteins compared to the more conventional, low molecular weight drugs often allows for a better treatment of these diseases. However, the production and the delivery of these proteins occur under unfavorable stress conditions.

Advances on an effective oral delivery system for proteins require a comprehensive perception of their physicochemical properties, such as molecular weight, hydrophobicity, ionization coefficient and pH stability, as well as of the biological barriers that limit protein absorption through the gastrointestinal tract. The important therapeutic proteins and peptides being explored for oral delivery include insulin, calcitonin, interferons, human growth hormone, glucagons, gonadotropin-releasing hormones, encephalin, vaccines, enzymes, hormone analogs, and enzyme inhibitors. These are outstanding model proteins used in the pharmaceutical development, mostly due to its well-established physical-chemical properties and social impact of their therapeutical applications.

Strategies to improve the oral bioavailability of proteins have ranged from changing their physicochemical properties by modification of their lipophilicity and enzyme susceptibility, to adding novel functionality using transport-carrier molecules that are recognized by endogenous transport-carrier systems in the gastrointestinal tract and/or to their inclusion in specially adapted drug carrier systems. Marketed polymeric-based systems have attracted considerable attention in the controlled release in targeting particular organs/tissues, as carriers of DNA in gene therapy and in their ability to deliver proteins, peptides, hormones, antibodies and genes. They can effectively deliver the proteins to a target site and thus increase the therapeutic benefit, while minimizing side effects. Protein association with polymer-based carriers, such as polymeric microparticles, nanoparticles, hydrogels or patches is one of most promising approaches proposed to improve oral protein bioavailability. Polymer-based carriers can protect proteins from the gastrointestinal environment and allow the modulation of physicochemical and protein release properties and consequently the biological behavior. Also, from the perspective of improving oral absorption, the major effect of carriers is to increase epithelial membrane permeability, thereby leading to higher bioavailability.

The problems facing oral delivery of peptides and proteins have traditionally been approached from many different angles, namely formulation, encapsulation, macromolecular conjugation and chemical modification, but there are many other criteria that must be satisfied to bring an oral protein formulation to the market. For example, the low bioavailability implies a large variation in absorption and a high manufacturing cost, which is unacceptable for the development of most peptide and protein drugs. For proteins like insulin that has a relatively narrow therapeutic window, the effects on intestinal absorption of age, genomic factors, physiological conditions and other individual variations must be carefully investigated. Finally, most peptide and protein drugs require chronic administration and hence the effects of long-term oral administration of absorption carriers on both the intestinal and systemic physiology must also be carefully evaluated..

Delivery of therapeutic proteins to the mucosa using genetically modified microflora
Drug delivery through mucosal surfaces offers a panorama of opportunities. The advantages are clear and include safety, ease of administration and higher social acceptance, although the major disadvantages are drug availability and appropriate drug targeting. Most mucosa are well equipped to manage the presence of bacteria and many are actually permanently colonised with a specific microflora. Such microbiota may become attractive tools for the delivery of a specific niche of protein therapeutics. These proteins can be produced from genetically modified microbes that are common to the mucosa, and their delivery to the host tissues has been demonstrated. This concept is being developed for the delivery of proteins to the intestine, but has also been applied in delivery to the vagina, nose and mouth.

Plants: as a source of drug

Today there are at least 120 distinct chemical substances derived from plants that are considered as important drugs currently in use in one or more countries in the world. These chemical substances are shown in the table below. Several of the drugs sold today are simple synthetic modifications or copies of the naturally obtained substances. The original plant substance/chemical name is shown under the "Drug" column rather than the finished patented drug name. For example, many years ago a plant chemical was discovered in a tropical plant, Cephaelis ipecacuanha, and the chemical was named emetine. A drug was developed from this plant chemical called Ipecac which was used for many years to induce vomiting mostly if someone accidently swallowed a poisonous or harmful substance. Ipecac can still be found in pharmacies in many third world countries but has been mostly replaced by other drugs in the United States. Another example of this is the plant chemical named taxol shown in the drug column below. The name taxol is the name of the plant chemical orginally discovered in the plant. A pharmaceutical company copied this chemical and patented a drug named Paclitaxel™ which is used in various types of tumors today in the U.S. and many other countries.

The 120 substances shown below are sold as drugs worldwide but not in all countries. Some European countries regulate herbal sustances and products differently than in the United States. Many European countries, including Germany, regulate herbal products as drugs and pharmaceutical companies prepare plant based drugs simply by extracting out the active chemicals from the plants. A good example is the plant substance/drug shown below, cynarin. Cynarin is a plant chemical found in the common artichoke (Cynara scolymus). In Germany, a cynarin drug is sold for liver problems and hypertension which is simply this one chemical extracted from the artichoke plant or a plant extract which has been standardized to contain a specific milligram amount of this one chemical. These products are manufactured by pharmaceutical companies, sold in pharmacies in Germany and a doctor's prescription is required to purchase them. In the United States artichoke extracts are available as natural products and sold in health food stores. Some products are even standardized to contain a specific amount of the cynarin chemical. You can purchase these natural and standardized extracts over the counter without a prescription and you could not go to a pharmacy in the U.S. and obtain a cynarin drug with a prescription. Another similar example is the plant chemical, silymarin, shown in the drug column below. Silymarin is a chemical found in the milk thistle plant and natural milk thistle extracts standarized to contain specific amounts of silymarin are found in just about every health food store in the United States. However in Germany, silymarin drugs and milk thistle standardized extracts are sold only in pharmacies and require a doctor's prescription for liver problems.

Some of the drug/chemicals shown below are still sold as plant based drugs requiring the processing of the actual plant material. Others have been chemically copied or synthesized by laboratories and no plant materials are used in the manufacture of the drug. A good example of this is the plant chemical quinine, which was discovered in a rainforest tree (Cinchona ledgeriana) over 100 years ago. For many years the quinine chemical was extracted from the bark of this tree and processed into pills to treat malaria. Then a scientist was able to synthesize or copy this plant alkaloid into a chemical drug without using the original tree bark for manufacturing the drug. Today, all quinine drugs sold are manufactured chemically without the use of any tree bark. However, another chemical in the tree called quinidine which was found to be useful for various heart conditions couldn't be completely copied in the laboratory and the tree bark is still harvested and used to extract this plant chemical from it. Quinidine extracted from the bark is still used today to produce quinidine-based drugs. In the U.S. there are four patented brand-name heart drugs sold in pharmacies containing bark-extracted quinidine: Cardioquin™, Quinaglute Dura-tabs™, Quinidex Extentabs™ and Quin-Release™.

The following table below will help you begin your research on drugs made from plants. We don't have the time or resources to provide a full comprehensive list of all patented drug names and herbal drugs sold in other countries. The chemical/drug names and plant names will give you enough to start on to continue your research on important plant based drugs and medicines.


Drug/Chemical Action/Clinical Use Plant Source
Acetyldigoxin Cardiotonic Digitalis lanata
Adoniside Cardiotonic Adonis vernalis
Aescin Anti-inflammatory Aesculus hippocastanum
Aesculetin Anti-dysentery Frazinus rhychophylla
Agrimophol Anthelmintic Agrimonia supatoria
Ajmalicine Circulatory Disorders Rauvolfia sepentina
Allantoin Vulnerary Several plants
Allyl isothiocyanate Rubefacient Brassica nigra
Anabesine Skeletal muscle relaxant Anabasis sphylla
Andrographolide Baccillary dysentery Andrographis paniculata
Anisodamine Anticholinergic Anisodus tanguticus
Anisodine Anticholinergic Anisodus tanguticus
Arecoline Anthelmintic Areca catechu
Asiaticoside Vulnerary Centella asiatica
Atropine Anticholinergic Atropa belladonna
Benzyl benzoate Scabicide Several plants
Berberine Bacillary dysentery Berberis vulgaris
Bergenin Antitussive Ardisia japonica
Betulinic acid Anticancerous Betula alba
Borneol Antipyretic, analgesic, antiinflammatory Several plants
Bromelain Anti-inflammatory, proteolytic Ananas comosus
Caffeine CNS stimulant Camellia sinensis
Camphor Rubefacient Cinnamomum camphora
Camptothecin Anticancerous Camptotheca acuminata
(+)-Catechin Haemostatic Potentilla fragarioides
Chymopapain Proteolytic, mucolytic Carica papaya
Cissampeline Skeletal muscle relaxant Cissampelos pareira
Cocaine Local anaesthetic Erythroxylum coca
Codeine Analgesic, antitussive Papaver somniferum
Colchiceine amide Antitumor agent Colchicum autumnale
Colchicine Antitumor agent, anti-gout Colchicum autumnale
Convallatoxin Cardiotonic Convallaria majalis
Curcumin Choleretic Curcuma longa
Cynarin Choleretic Cynara scolymus
Danthron Laxative Cassia species
Demecolcine Antitumor agent Colchicum autumnale
Deserpidine Antihypertensive, tranquillizer Rauvolfia canescens
Deslanoside Cardiotonic Digitalis lanata
L-Dopa Anti-parkinsonism Mucuna sp
Digitalin Cardiotonic Digitalis purpurea
Digitoxin Cardiotonic Digitalis purpurea
Digoxin Cardiotonic Digitalis purpurea
Emetine Amoebicide, emetic Cephaelis ipecacuanha
Ephedrine Sympathomimetic, antihistamine Ephedra sinica
Etoposide Antitumor agent Podophyllum peltatum
Galanthamine Cholinesterase inhibitor Lycoris squamigera
Gitalin Cardiotonic Digitalis purpurea
Glaucarubin Amoebicide Simarouba glauca
Glaucine Antitussive Glaucium flavum
Glasiovine Antidepressant Octea glaziovii
Glycyrrhizin Sweetener, Addison's disease Glycyrrhiza glabra
Gossypol Male contraceptive Gossypium species
Hemsleyadin Bacillary dysentery Hemsleya amabilis
Hesperidin Capillary fragility Citrus species
Hydrastine Hemostatic, astringent Hydrastis canadensis
Hyoscyamine Anticholinergic Hyoscyamus niger
Irinotecan Anticancer, antitumor agent Camptotheca acuminata
Kaibic acud Ascaricide Digenea simplex
Kawain Tranquillizer Piper methysticum
Kheltin Bronchodilator Ammi visaga
Lanatosides A, B, C Cardiotonic Digitalis lanata
Lapachol Anticancer, antitumor Tabebuia sp.
a-Lobeline Smoking deterrant, respiratory stimulant Lobelia inflata
Menthol Rubefacient Mentha species
Methyl salicylate Rubefacient Gaultheria procumbens
Monocrotaline Antitumor agent (topical) Crotalaria sessiliflora
Morphine Analgesic Papaver somniferum
Neoandrographolide Dysentery Andrographis paniculata
Nicotine Insecticide Nicotiana tabacum
Nordihydroguaiaretic acid Antioxidant Larrea divaricata
Noscapine Antitussive Papaver somniferum
Ouabain Cardiotonic Strophanthus gratus
Pachycarpine Oxytocic Sophora pschycarpa
Palmatine Antipyretic, detoxicant Coptis japonica
Papain Proteolytic, mucolytic Carica papaya
Papavarine Smooth muscle relaxant Papaver somniferum
Phyllodulcin Sweetner Hydrangea macrophylla
Physostigmine Cholinesterase Inhibitor Physostigma venenosum
Picrotoxin Analeptic Anamirta cocculus
Pilocarpine Parasympathomimetic Pilocarpus jaborandi
Pinitol Expectorant Several plants
Podophyllotoxin Antitumor anticancer agent Podophyllum peltatum
Protoveratrines A, B Antihypertensives Veratrum album
Pseudoephredrine* Sympathomimetic Ephedra sinica
Pseudoephedrine, nor- Sympathomimetic Ephedra sinica
Quinidine Antiarrhythmic Cinchona ledgeriana
Quinine Antimalarial, antipyretic Cinchona ledgeriana
Qulsqualic acid Anthelmintic Quisqualis indica
Rescinnamine Antihypertensive, tranquillizer Rauvolfia serpentina
Reserpine Antihypertensive, tranquillizer Rauvolfia serpentina
Rhomitoxin Antihypertensive, tranquillizer Rhododendron molle
Rorifone Antitussive Rorippa indica
Rotenone Piscicide, Insecticide Lonchocarpus nicou
Rotundine Analagesic, sedative, traquillizer Stephania sinica
Rutin Capillary fragility Citrus species
Salicin Analgesic Salix alba
Sanguinarine Dental plaque inhibitor Sanguinaria canadensis
Santonin Ascaricide Artemisia maritma
Scillarin A Cardiotonic Urginea maritima
Scopolamine Sedative Datura species
Sennosides A, B Laxative Cassia species
Silymarin Antihepatotoxic Silybum marianum
Sparteine Oxytocic Cytisus scoparius
Stevioside Sweetner Stevia rebaudiana
Strychnine CNS stimulant Strychnos nux-vomica
Taxol Antitumor agent Taxus brevifolia
Teniposide Antitumor agent Podophyllum peltatum
a-Tetrahydrocannabinol(THC) Antiemetic, decrease occular tension Cannabis sativa
Tetrahydropalmatine Analgesic, sedative, traquillizer Corydalis ambigua
Tetrandrine Antihypertensive Stephania tetrandra
Theobromine Diuretic, vasodilator Theobroma cacao
Theophylline Diuretic, brochodilator Theobroma cacao and others
Thymol Antifungal (topical) Thymus vulgaris
Topotecan Antitumor, anticancer agent Camptotheca acuminata
Trichosanthin Abortifacient Trichosanthes kirilowii
Tubocurarine Skeletal muscle relaxant Chondodendron tomentosum
Valapotriates Sedative Valeriana officinalis
Vasicine Cerebral stimulant Vinca minor
Vinblastine Antitumor, Antileukemic agent Catharanthus roseus
Vincristine Antitumor, Antileukemic agent Catharanthus roseus
Yohimbine Aphrodisiac Pausinystalia yohimbe
Yuanhuacine Abortifacient Daphne genkwa
Yuanhuadine Abortifacient Daphne genkwa