gi targeted drug delivery: enhancing topical effects and ...€¦ · gi targeted drug delivery:...

Fassihi seminar presentation 10/22/2019

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GI targeted drug delivery: Enhancing topical effects and

mucosal concentration of drugs

Reza Fassihi Ph.D., AAPS Fellow

Professor of Biopharmaceutics and Industrial Pharmacy

School of Pharmacy, Temple University

Seminar Presentation

10/18/2019

10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 1

• The signs and symptoms vary based on which parts of the body are affected but may include:

• Anemia and bleeding disorders.

• Gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, and/or vomiting.

• Itching, hives, and/or flushing of the skin.

• Anaphylactoid reactions.

Intestinal Mastocytosis

It is a rare disease but could be life‐threatening

The biopsy in these colonic regions showed an increased number of mast cells with recruited eosinophils in the lamina propria (HE); eosin stain (HE).

The mast cells are highlighted by positive c‐kit staining.



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Estimated worldwide ~ 10 million people suffer from IBD. Other common abdominal diseases that can mimic IBD are diverticulitis, celiac disease, and colon cancer.

Crohn's Disease

Ulcerative Colitis

Outline:1. Introduction, history of IBD Current

state & gut dysbiosis Industrialization, particulate matters and Exposome in IBD.

2. Drug therapy approaches.

3. GI transit time of delivery systems and bioavailability.

4. Developed DDS for topical action of drugs at mucosal surfaces and mucosa.

5. Conclusion

6. Acknowledgement

Enhancing topical effects and mucosal concentration of drugs in IBD



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In 2004, there were:1.8 million prescriptions written for medications to treat Crohn’s Disease (CD) and 2.1 million prescriptions written for medications to treat Ulcerative Colitis (UC).

An estimated 3 million U.S. Patients

>2.5 million in Europe

Note: Considerable data discrepancies

Only 1/3 of the patients are in remission

Using available medications and therapy

IBD: A group of idiopathic chronic inflammatory diseases, is a relapsing and remitting condition

Annual direct costs: ~ $4 billion


Distinguishing Ulcerative Colitis and Crohn’s Disease

• CD

– Can involve any part of the GI tract (mouth to the anus)

– Affects the entire bowel wall

– 26-199 cases per 100,000 people

• UC

– Generally restricted to the colon

– Affects only the mucosa (inner lining) of the colon

– 37-246 cases per 100,000 people

Crohn’s Disease (CD)

Ulcerative Colitis (UC)



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The history of inflammatory bowel disease 1. The earliest descriptions of UC dating back to Hippocrates (~ 460–370

BCE) who discussed the many possible etiologies of diarrhea.

2. Several early 19th century medical schools discussed IBD. Broussais (1772–1838 CE) and Brown (1810–1882) put forth theories that “all diseases are derived from inflammation in the Gut”.

3. Swedish physician Nanna Svartz (1890–1986), observed symptom resolution in UC after treatment with sulfasalazine. Pharmacia’s first medical product, sold since the 1940s.

4. Following World War II, the era of randomized clinical trials (RCTs) began, ushering in the modern age of evidence‐based medicine.

5. In the 1960s and 1970s, the immunosuppressive drug mercaptopurine (6‐MP) and azathioprine were found to be efficacious in patients with UC. 1. The discovery by Sir James Black and B. Elion was recognized with the 1988 Nobel Prize in Physiology and Medicine.

6. Azathioprine was compared to sulfasalazine in 1975 and demonstrated similar efficacy.

7. Since 2000 New drugs are introduced including biologics Anti “TNF‐α , IL‐12/23, and Integrin”; Janus kinase (JAK) inhibitor was approved for IBD in 2018.

First female professor at a public university in Sweden.

Nanna Svartz


Nicholson. J.K. et.al.; SCIENCE VOL 336 8 JUNE 2012

The gut microbiota in human health:

The composition and activity of the gut microbiota codevelop with the host from birth and is subject to a complex interplay that depends on the host genome, nutrition, and life‐style.

Gut microbiota is also involved in drug metabolism, deterrence of pathogenic microbes etc.

10/22/2019Reza Fassihi Ph.D., AAPS Fellow 8

gut microbiota codevelop with the host from birth

Disruption of the gut microbiota (dysbiosis) can lead to a variety of different diseases


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Size comparisons for particulate matters (PM)

PM 0.1 μm to 2.5 μmMay get deep into lungs

Ultrafine PM: <0.1 μmMay penetrate cell walls

Particle pollution

WWW.EPA.GOV

Environmental Factors and IBD: Particulate matters (PM)



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Continued dramatic increase in incidence of IBD is largely associated with industrialization

The incidence of IBD started to increase in Northern Europe and the United States around the early 1960s. Changes in environmental factors are now developing in Asia and Africa and appear to increase the incidences of IBD.


Source: World Bank

Exposure is measured in micrograms / cubic meter

Intest Res. 2017 Jan; 15(1): 138–14110/22/2019 Reza Fassihi Ph.D., AAPS Fellow 12


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Exposome in IBD:

Indirect effects: Modulation of metabolic activity of the intestinal microbiota, immune functions

Direct effects on cells of the mucosal wall, immune cells or extra‐intestinal cells

Direct & Indirect effects on barrier function

Commensal microbiota, pathogens, Infections &

Stress

Air & Water

PollutionDiet

Drugs, Antibiotics

Food additives

Heterogeneity of Patient types and Genetic Predisposition

Dysregulated immune response

Initiation of flares of IBD

Stress: “range of tensions of modern life”.

The term “exposome” was first used in 2005 by the cancer epidemiologist Christopher Wild in which he suggested to complement the genomic data on cancer onset by environmental factors.


Four main factors which influence the disease:

1. Mucus the first line of defense against antigens and bacteria. Impairment of this & epithelial barrier function can contribute to IBD?

2. Genetic predisposition,3. Dysregulated immune response

(Increased Production of inflammatory cytokines such as IL and TNF‐α),

4. Environmental factors “Exposomeand Microbiome”

What causes IBD: Internal and External factors involved in Gut Dysbiosis

By 2012, over 160 genes had been identified which are involved in :Regulation of the immune system, Mucosal barrier and Growth of bacteria.

Epigenetic imprinting

“Microbiome”

Antigenic loadExternal

Internal

Trefoil factors‐ low in mucus



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Schematic representation of the interactions between exposome, infectome, microbiome, epigenetic imprinting, and genetic susceptibility of disease development in a patient with IBD over lifetime.

Genes affect three types of traits:Balance of the immune systemMucosal barrier (first line of defense in the intestine) Controlling the growth of bacteria.

10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 15Inflamm Bowel Dis. Vol.21, #2, February 2015.

Current Medications in IBD

First line approach‐ 5‐Aminosalicylic acid derivatives

- sulfasalazine, mesalamine, balsalazide, olsalazine

Antibiotics - metronidazole, ciprofloxacin,

rifaximin (F <0.4%)

Corticosteroid agents - hydrocortisone, Prednisone,

methylprednisolone, Prednisolone, Budesonide, dexamethasone

Immunomodulator agents - azathioprine, 6‐mercaptopurine,

Methotrexate, cyclosporine

Tumor necrosis factor inhibitors- Infliximab- Adalimumab- certolizumab pegol- golimumab

Anti‐integrin agents- natalizumab- vedolizumab

Anti‐IL‐12/23 agents- Ustekinumab

Janus kinase (JAK) inhibitor e.g. Tofacitinib tablets, FDA approved 2018

Fecal Transplantation (Bacteriotherapy): Treatment in recurrent C. difficile colitis.

Adverse effects recognized

Known efficacy and safety profiles



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IFX (0‐6 weeks) + AZA

+ Episodic IFX

Budesonide

Combined immunosuppression was more effective than conventional management for induction ofremission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn’s disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes. Lancet 2008; 371: 660–67

Budesonide

5‐Aminosalicylic acid derivatives/ Antibiotics


Side effects of 5‐ASA, Corticosteroids and Biologic agents may include:

Non‐Hodgkin’s lymphoma

FDA puts Black Box Warning on All Biologics in this category ?


AminosalicylatesDiarrhea Dizziness, Joint pain, Headache; Lethargy, dry mouth, malaiseMild disorientation,Fever.


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Formulation and Delivery Strategies

Enemas, Suppositories, Foams, Gels

Self-emulsifying systems, Amorphous systems, Polymer-drug miscibility (Angstrom level), Biologics for GI delivery by using known GRAS materials.

Implants, Microspheres, Nanoparticles, Dispersed Systems, Biologics (Use of GRAS materials)


Drug delivery systems and targeting:

4 key factors:

Drug Delivery system Route of administration Target‐Drug Interaction‐

(response)

(Fassihi et.al. 2019 ‐Targeted Nanosystems for Therapeutic Applications: ACS Symposium Series; Washington, DC, 2019 edited by Sakurai and Ilies). 10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 20


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Most important barrier between the body proper and the external environment: A Single layer of cells


In the GI tract, gastric acid and pancreatic and biliary juices take part in barrier function by degradation of bacteria and antigens; pathogenic bacteria are kept under control by the normal flora and secretion of chloride by enterocytes.

From: Johan D. Söderholm Physiology of the Gastrointestinal Tract, Two Volume Set. DOI: © 2012 Elsevier Inc. 10.1016/B978‐0‐12‐382026‐6.00074‐9

Most important barrier between the body proper and the external environment: Molecular interplay in the GI tract



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Acute stress‐induced effects on mucosal function: Stress triggers mucosal nerves to release CRH (Corticotropin‐releasing hormone), which activates mast cells, degranulation and release of various mediators that affect epithelial cells. Mast cell mediators such as TNF‐ α, tryptase (via PAR‐2), NGF(nerve growth factor), and interleukins may affect paracellular permeability (e.g., by altering expression of various claudins in the TJs) or the transcellular uptake route (e.g., by increasing macropinocytosis) to disrupt the barrier to antigens and bacteria.

From: Johan D. Söderholm Physiology of the Gastrointestinal Tract, Two Volume Set. DOI: © 2012 Elsevier Inc. 10.1016/B978‐0‐12‐382026‐6.00074‐910/22/2019 Reza Fassihi Ph.D., AAPS Fellow 23

Targeting in the GI tract



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Drug absorption and transit time:Absorption Window Mapping of Drugs: Case Study 1

Compartmental absorption

Reza Fassihi (2017); Pharmaceutical Dosage Forms‐Capsules; Chapter 12, pages: 317‐344. “Taylor & Francis Group, LLC”.

Physiological Constraints: Transit time in GI tract / PK A Scintigraphic analysis using labeled CR pellets (Tc-99m) and an Osmotic

Pump tablet (In-111) or Sm153 Neutron activated Egalet system

26Reza Fassihi Ph.D., AAPS Fellow10/22/2019 (Wilson et al 2005)

Scintigraphic images for one volunteer, depicting the gastrointestinal transit of Sm153 Labelled microgranules.


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Types of Oral Drug Delivery Systems‐ FDA Approved

Bi-layer tablet

Tri-layer tablets

Enteric coated Minitablets and Pellets

Microporous CR mini-matrices

Push-pull Osmotic pump

Pellets in tablet

Tri-layer matrix caplet

Compression Coated

CR coated beads

From Fassihi (2017)10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 27

Structure of different prodrugs of 5‐AS and part of their metabolism.

Both 5‐AS and Ac‐5‐AS are partly secreted back into the intestinal lumen. Active transport of the two compounds from the basolateral to the apical site is probably accomplished by membrane‐bound drug transporters such as MRP2 or P‐glycoprotein.

Aminosalicylates


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0

0.1

0.2

0.3

0.4

0 10 20 30 40 50 60

Time (Hr)

Pla

sma C

onc.

(m

cg/m

l)

Fasted

Fed

In‐vivo data for Asacol tablets

F= 27% ???

(Fassihi, 1999, unpublished data)

Each Asacol (mesalamine) Delayed‐release Tablet (400‐800 mg dose)

Adverse reactions leading to withdrawal from Asacol included: Diarrhea Dizziness, Joint pain, Headache; Lethargy, dry mouth, malaise Mild disorientation, Fever.


5‐ASA

Different Delivery Platforms for Drug Delivery to the Mucosa for topical Effects with insignificant absorption or bioavailability:1. Development of a CR and eroding system

2. Encapsulated Controlled Release Mini‐tablets for drug delivery to GI tract

3. Pellet systems

4. Microcapsules

5. Nanoparticles Undesirable in the case of IBD

Mesalazine is an aminosalicylate and anti‐inflammatory. It works by direct contact with the epithelial cells of the intestines.


Delivery Strategy in IBD: How to Limit Bioavailability and Enhance topical effect(drug delivery in a continuous and slow drug release rate throughout areas with lesions)

Many drug used in the treatment of IBD become systemically bioavailable with strong side effects


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Novel method for evaluation of hydration dynamics in hydrophilic matrices: Textural analysis of gel layers Versus water mobility in the matrix via NMR microscopy

Durig T. & Fassihi R.; Journal of Controlled Release 80 (2002) 45–5610/22/2019 Reza Fassihi Ph.D., AAPS Fellow 31

Yang and Fassihi; Pharma. Res. Vol:15, No.12, (1998)

Swelling / Gel layer Formation / Drug Diffusion and Matrix Erosion

Optimized Release Rate of 5‐ASA (800mg) from the designed delivery system.

Talukder and Fassihi (2005)

Complete degradation of matrix system in the GI tract

Hydrophilic matrix


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Proof of Principle: Development of Encapsulated Mini‐tablets for drug delivery to GI tract

Fassihi R. & Munday D.; J.Pharm. Pharmacol., (1989) 369‐372.10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 33

Release rate can be dictated by coating thickness and composition

Proof of principle‐Dissolution media effect and in‐vivo absorption in beagle dogs

10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 34Munday and Fassihi, Int. J. Pharmaceutics, 118, 251‐255; (1995) and (Vol 73; 89‐93; 1991)

Serum levels of theophylline‐Time at SS following oral administration of I unit (200mg) every 12 h in beagle dogs (n=4).

By controlling slow and desirable drug release rate in the GI tract with IBD, drug may not reach systemic circulation and act topically or accumulate in the mucosa.


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Typical force–displacement profiles for individual pellets subjected to compression forces that they can encounter during tableting operations.

Various coating layers on an extruded and spheronized pellet of acid‐labile pancreatic enzyme when fractured and viewed by confocal laser scanning microscopy.

Formulation‐3 Drug‐coated pellets for inclusion into a tablet or capsule

(Fassihi et.al. 2019 ‐Targeted Nanosystems for Therapeutic Applications: New Concepts, Dynamic Properties, Efficiency, and Toxicity ACS Symposium Series; American Chemical Society: Washington, DC, 2019 edited by Sakurai and Ilies).


Typical design of an enteric‐coated compressed tablet containing multiparticulate drug‐coated beads for more predictable drug delivery to the distal intestine and colon.

Cross‐sectional image (viewed by laser scanning microscopy) of intact drug‐coated pellets after compression into a tablet with cushioning excipients.

Drug‐Coated Pellets for Inclusion into a Compressed Coated TabletBudesonide (9 mg) multiparticulate system



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Dissolution profile of enteric‐coated extended‐release budesonide (9 mg) multiparticulate tablets (n = 3). Dissolution testing was done according to the USP 34 dissolution method, apparatus II, at 50 and 75 rpm in 900 mL of buffer at pH 7.0. Inset: Tablet cross section and confocal laser photomicrograph.


Drug‐Coated Pellets compressed into a dis‐integradable enteric coated system for slow and continuous drug release in the GI tract

Formulation‐4Development of multiparticulates for methotrexate delivery to the inflamed regions

Calcium‐pectinate and calcium‐alginate‐pectinate beads

From: Talukder and Fassihi; DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, Vol. 30, No. 4, pp. 405–412, 2004

In vitro release profile of methotrexate (MTX) commercial tablets (10mg) and Ca‐alg‐Pectinate drug loaded beads (10mg) prepared in our lab. (n = 3). USP II, mesh‐ring modified, at 75 rpm, pH 1.5 & 7.0

Sodium alginate or pectin solutions can undergo sol‐to‐gel transformation in the presence of cross‐linking polyvalent cations and produce a cross‐linked "egg‐box" model.



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Formulation-5 Biodegradable MicrocapsulesLow methoxy pectin Prednisolone microcapsules by an emulsion-interface-reaction

O/W microemulsion

(Oil, aqueous phases, SAA, CaCl2 and prednisolone)

W/O microemulsion

(pectin solution/ prednisolone, oil

phase+ SAA)

Encapsulation interfacial reaction

Microcapsule formation

Interfacial precipitation

Adding pectin solution or CaCl2to either O/W or W/O emulsion,

stabilization

Emulsion droplet containing drug

Calcium pectate gel-film formation

(Muhiddinov and Fassihi ; J. Microencapsulation, vol.21, No.7, 729‐741; 2004)10/22/2019 Reza Fassihi Ph.D., AAPS Fellow 39

Egg‐Box Model

Micro-capsules

code

Physicochemical properties Kinetics parameters

Type and content ofMicroparticles

Mean diameter, um

Encayield,

%

T ½, h

pH 1.5 pH 6.4

6 O/W, VO‐ AP‐SDS‐Ca2+ 1.65 84.5 6.90 14.43

9 O/W, VO‐AP‐SDS‐Ca2+ 1.83 18.2 11.80 16.34

10 O/W, VO‐AP‐BzACl 1.92 14.6 10.86 24.84

14 O/W, EtAc‐AP‐BzACL 2.10 31.0 51.70 128.3

(Muhiddinov , Fassihi 2004, J.Microencapsulation, 21; 7: 729‐741).

Properties of microparticles and drug release (Prednisolone)

Microparticle size and size distribution analysis

Using Model 770 AccuSizer (particle size systems,Inc.SantaBarbara, CA).

Prednisolone loaded pectin microcapsules


2.1 µm m

ean

diameter


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Rate of Prednisolone release from Microparticulates 10‐13 at medium pH 6.4 and subsequent pectinase (EC 3.2.1 15, pH 6.07) treatment.

Muhiddinov , Fassihi; ACS Symposium Series; American Chemical Society: Washington, DC, 2008. November 7, 2008 | doi: 10.1021/bk‐2008‐0992.ch011.

Microcapsules (30‐100 mg) were suspended in 60‐100mL of dissolution medium in a glass vial in a bath at 37±0.8 C.

Evaluation of release kinetics:Prednisolone loaded pectin microcapsules

Addition of Pectinase to the dissolution medium



Schmidt et.al. Journal of Controlled Release 165 (2013) 139‐145

PLGA nanoparticles (250 nm) are not visible on the mucosal surface of a patient with UC in remission. PLGA microparticles (3.0 µm) (green) are visible in a CD patient with mild disease activity.

“Nanoparticles may not be required for local drug delivery to intestinal lesions in humans.”

39 patients with IBDM/F & Control

First in‐vivo study in human patients: Nano vs Microparticles for targeting inflamed mucosa


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Conclusion• The goal of IBD therapy is to induce and maintain remission

• The optimization of older therapies, including drugs such as immunomodulators, 5‐aminosalicylic acid (5‐ASA), and Budesonide, with limited BA through release rate control is conceivable.

• Particulate systems(≥ µm diameter) in IBD with leaky membrane will continue to appeal to research scientists and pharmaceutical industries.

• Intimate muco‐adhesion via coated particles for GI targeting is achievable.

• Oral drug delivery remains the most convenient, popular and cost‐effective route.


Conclusion continued• Many drugs can be regarded as a candidate for topical delivery with potential for 505(b)(2) new drug application (NDA) path, and “Life Cycle Management” should be considered.

• Shift away from the “one size fits all” approach and consider Personalized Medications and customized treatment plans.



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Thanks For Your Attention.

45Reza Fassihi Ph.D., AAPS Fellow10/22/2019

I hope that I have shed some light on drug delivery technologies and relevancy of Biopharmaceutics in delivery system design.

gi targeted drug delivery: enhancing topical effects and ...€¦ · gi targeted drug delivery:...

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